Doctorx Unscripted Bold Conversations about Patient-Driven Science - Bristol Myers Squibb

Myeloma on the Brink: The New Playbook [Part 1)
 

Dr. Small [00:15] 20 years ago, a diagnosis of multiple myeloma meant 3 to 5 years to live. Today, patients are living for decades with CAR T, bispecifics, quad therapies.

Dr. Mikhael [00:26] The prediction now after a quadruplet and transplant is that these patients are probably going to go over 10 years on average before their first remission. Moving from trials into practice, patients are finally gaining real access to therapies unthinkable just a few years ago. The field is dynamic, there's a lot to choose from. We have 20 drugs if you take the whole field over the last two and a half decades. And in that, we need all of them. We’re closer than ever to transforming myeloma into a chronic disease and maybe even asking, can we cure it?

Dr. Gharibo [00:55] We have an opportunity to potentially bring in more functional cure therapies for patients. 

Dr. Small [01:00] I'm Dr. Tania Small, and on this episode of DoctoRx Unscripted, I'm joined by 3 remarkable voices: Dr. Paul Richardson of Dana-Farber in Harvard, who has helped pioneer nearly every major therapy in use today. Dr. Joseph Mikhael, Chief Medical Officer of International Myeloma Foundation, a true change agent who has shaped how we think about myeloma. And Dr. Mecide Gharibo, who went from Associate Professor of Hematology and Bone Marrow Transplants to driving the development and delivery of new medicines in hematology. Together we'll cut through the complexity and ask the provocative questions shaping the future of myeloma care. Now let's get started. Section: Hematology Origin Stories: Written in  Blood?

Before we go into the science, I want the listeners to get to know you. So if you could do me a favor and think back way back to when you were in med school, were you able, you know, you were able to identify that person was going to go into plastics or that person who was going to go into ortho, and definitely you could figure out who's going to go into psych. Did your colleagues know? What did your colleagues think you were going to go into and what made you decide to go into hematology? And I'll start with you, Mecide.

Dr. Gharibo [2:28] Well, I knew at very early age that I had a passion for going into medicine, but more importantly, hematology was something that I was very much interested in. So, through my undergrad, I had an opportunity to spend some time in research labs. And then going into medical school, I actually did my best to get as many electives as possible in inpatient leukemia service, outpatient hematology clinic at different hospitals that we had opportunity to rotate through. So, my classmates knew that my passion was heme malignancies, and I loved the fact that the complexity of the spectrum of heme malignancies, but more importantly that we had made so much advancements that we could actually talk about a cure for patients with leukemia. And then while I was in medical school, I saw an advancement in multiple myeloma, that's when things were starting to emerge with Bortezomib, and then you had lenalidomide emerging in a treatment. So, we started to see the impact of those therapies. So, it really excited me to be able to go into a field and just build on where that field started.

Dr. Small [03:45] What about you, Joe?

Dr. Mikhael [3:46] I think if you asked my classmates in med school, they would say that I would go into internal medicine because they all knew that at some point I wanted to be involved with international health and that was going to maybe facilitate that. But then really what ultimately happened to what I call the double hit of going into what I did was my mentors. We know that actually most medical students are very heavily influenced by who they had as mentors.

The individual who was assigned to me to teach me physical exam skills was a hematologist. And to this day, I’m grateful for him. Then lastly, when I was an internal medicine resident, I was called by the emergency doctor to help him with a case that didn't make sense. It was this young guy, remember I grew up in Canada, he had been playing hockey. He got checked into the boards and they showed me his x-ray and he had all of these fractures and all of these lytic lesions in his spine. It turned out to be one of my friends from high school and he's still with us today, almost 30 years later, which is a miracle. He's one of the few people that had myeloma and had an allo transplant from his bigger brother. And that made me realize I really wanted to take care of the sickest of the sick. And those were days where sadly, myeloma survival was maybe one to two years. And here we are 30 years later with survival as you know, well over a decade. And I don't regret a single decision because I love what I do.

Dr. Small [05:06] So what about you Paul?

Dr. Richardson [05:08] Well, my mother was a nursing director, so my early life was literally with her in the hospital, because very sadly my father passed when I was very young, so my mom was basically single, a widow, and so she would take me to the floors. So my first experience of medicine was serving tea and biscuits to patients for my mum. And then it was actually great. And then I was very fortunate in high school to spend time with a really gifted biology teacher, gave me a project in cancer and basically, I got absolutely intrigued in it and by, just because of his good guidance it got a prize. And so basically, I thought, this is amazing, what is cancer all about?

And then went to a fabulous med school, St. Bartholomew’s in London, Bart’s, and it by happenstance was very strong tradition in cancer medicine. And I had the privilege of working just as you alluded to Joe with some mentors who really could just drive that. And I'll never forget my yearbook at the end of my year, one of my buddies wrote the yearbook and he had a picture of me and he said, it was a quote from me, it said, sorry guys, I'm late, but all of my mates have got cancer. And it was so funny because what he was doing was obvious. Take a big swipe of me because I tend to run a little behind.

Dr. Small [06:17] I just heard just a little bit.

Dr. Mikhael [06:21] I've never heard that Paul

Dr. Richardson [06:24] My mum explained that I was a few weeks overdue, so I've never caught up. I had the privilege of working with some really great people and one was Jim Malpas who was a founder in myeloma. And I'll never forget my first myeloma patient with Jim. She was a lovely matriarch from East London and I admitted her and three months later, very sadly, had to sign her death certificate. that was back in 1986. And I'll never forget her and I used to take her down to the square of Bart’s so she could look at the sky. She was so devastated by bone disease, she was bedridden. And so to give her time to actually see daylight and sunshine and it was just such a moving experience with her. And then I also had the opportunity to work with Tim McElwain, who was the founder of high dose melphalan.

And it was amazing to work with Tim because what we would do is we do autologous stem cell transplant and then we would use alpha interferon as immune therapy. The problem was the toxicities. And I'll never forget Tim McElwain saying to, and I was stunned. He looked at me, he said, Paul, if we can do better than high dose melphalan, we'll be doing our patients a service. Wow. And here we are today. So it is very interesting and it was a privilege to have that background. And so that's kind of what took me in that direction.

Dr. Small [07:35] Very interesting. And it is interesting because I mean I guess except for you, most people knew they were going to go into heme, because I can tell you I actually thought I was going to go into either, I thought I was going to go into OB initially and then I ended up going, I did a rotation actually in med school with my old mentor who they used to call a cowboy because we were transplanting sickle cell patients and curing them. And so I rotated with him in med school and then ended up going to do my fellowship under him, and that's what brought me in. So, it's actually the sickle cell route. So benign heme brought me in to then heme, and then Peds, because I was Peds heme onc, you do heme solid as well as transplant all in one as a fellow. So that's what actually brought me in.

Dr. Richardson [08:22] Wow.

Section: The Bleeding Edge of Hope: What’s New in Myeloma

Dr. Small [08:28] I want to talk about the biology of multiple myeloma because if you think about even years ago, treatment has changed dramatically. You know, before we just had a few options now, I mean the field is dynamic, there's a lot to choose from and there's a lot that we've learned both from the biology standpoint as well as treatment standpoint. So what do we know now when it comes to multiple myeloma and the biology that we didn't even know five years ago? I'll start with you, Paul, and then move it this way.

Dr. Richardson [09:00] That's an incredible question, Tania. I would say that the biology is incredibly complex and I think that the heterogeneity of myeloma has always been very daunting to me. And I have to say very humbling because ultimately what we're now seeing in myeloma, first of all, there was this appreciation of the tumor microenvironment that this disease, unlike the linearity of leukemia or the relative lineage fidelity of lymphoma, myeloma was extraordinarily complex. And I always bring it back to the fact, if you think about what a normal plasma cell does, it all sort of makes sense. To my mind it's the queen of immunological cancers, myeloma, because the normal plasma cell is designed to recognize an antigen, say when you're 12 years old and then 20 years later, if you're exposed to that same pathogen, this remarkable cell will wake up and deliver you antibody literally within hours to fight that same pathogen. Now unfortunately, when that particular cell becomes malignant, it retains that extraordinary sophistication, but at the same time, of course it's adverse. So, I think as we understand myeloma pathobiology, this complexity of interaction of tumor cell microenvironment, the immune system, the host, the patient, every aspect of it tells me that this is an extraordinarily diverse disease. And so we must think all hands to the pumps. It's not one approach versus another. It is an incredibly inclusive one as we tackle the disease.

Dr. Small [10:31] I agree. And I don't know if Joe or Mecide you had anything to add.

Dr. Mikhael [10:36] I mean, all I would add to that is just taking it a step further that Paul's described beautifully. I mean we almost say it was back in the day when it was described as multiple myeloma called multiple because it was really identifying multiple plasmacytomas throughout the body, but it's heterogeneity is perhaps greater than almost any other malignancy and Paul's outlined that beautifully. I think we have done some groupings of some of the biology, but even with that, even just recently with our joint IMWG and IMS classification of high-risk myeloma, it's become very difficult. So, to me, the take home message from it is I have to look at every patient individually, which I should be anyway, I say all the time to my mentees, I don't treat myeloma, I treat people. And so when you're looking at that person, you look at the whole of the context, what do we know of the biology of their disease?

I sometimes use the analogy, what do we know about the horsepower of this engine? But then pragmatically, how is that horsepower being used? Sometimes the Prius is passing the Porsche. So we have people who on paper it doesn't look like they have high-risk myeloma, you'd expect them to do well or vice versa, they have very high-risk myeloma, but that Porsche is not driving fast or the Prius is driving quickly. So it requires us to have this sort of dynamic response to patients, always putting them in their own social context, always putting them in the context of who they are and what their preferences are. And I think that's perhaps changed the most, is not just using, as Paul said, that sort of cookie cutter approach of treating everybody the same way. And lastly, I think what makes it even more challenging is that because it is relatively rare, 2% of all cancers, and we estimate 75 to 80% of people being treated for myeloma in the US are treated in the community, it makes it very hard for that community oncologist who's treating the big four: breast, lung, colon, or prostate and 30 other tumor types to enter that complexity when they are treating their patient with myeloma, which I think underscores all the more the importance of a dynamic relationship between the expert myeloma community and the general oncology community to support each other. Otherwise, I don't know how these community oncologists could do it.

Dr. Small [12:49] Keep up, keep up, yeah.

Dr. Mikhael [12:51] It's so challenging.

Dr. Small [12:53] And I'm going to throw it to you, but can I ask you a different question?

Dr.Gharibo [12:55] Yes.

Dr. Small [12:56] So again, we talked about how much everything has changed. What is the biggest breakthrough over the last 12 months that you're excited about?

Dr.Gharibo [13:05] Well, I think for me, bringing in new therapies as quickly as possible is really critically important. We made a lot of advancements for patients, but when we look at how we have designed studies in the frontline setting where to get a full approval, it's based on progression-free survival. And because of the innovation in the past decade, we know it takes many years to achieve that endpoint, right? So I think for me, a critical milestone in the myeloma treatment landscape was getting the FDA to recognize MRD as a surrogate endpoint and be in corporate now as a co-primary endpoint where we can now get earlier readout based on MRD negative CR rates as a surrogate to, for progression-free survival.  And maybe just to give some context, MRD means that you can detect at levels right now, but using next generation sequencing like clonoSEQ, you can actually detect minimal residual plasma cells that are clonal at one to a hundred thousand, that's 10 to the minus five.

And now we're actually also incorporating one in a million. So what this now means is that we can actually bring in faster new therapies to patients. So traditionally even when you do randomized phase three studies, you have to enroll several hundreds of patients, right? Eight, 900 

Dr. Small [14:43] Wait for OS. Especially if you're talking about the frontline.

Dr.Gharibo [14:46] Exactly. So enrollment takes two to three years. Then waiting for that PFS to happen another 5, 6, 7 years. It could take us from start to end a decade to bring new innovation in the frontline setting. So now actually you can validate an early readout at nine months, 12 months based on MRD CR negative and you can actually bring in these therapies from an accelerated approval, but still make sure that you follow for that final primary endpoint of PFS. So to me, this is going to revolutionize how we are going to bring in new therapies not only in the frontline setting but early relapse. And that's where I think we have an opportunity to potentially bring in more functional cure therapies for patients. And I think that's the gold standard we need to achieve for myeloma.

Dr. Small [15:34] I think you've read my mind because I'm excited to talk about MRD. Before I go into MRD. I just didn't know if any one of you wanted to answer that question as well. What exciting innovation happened in.

Dr. Richardson [15:46] Well, it is a beautiful question, Tania, we need every option. And I think that's the point. It's not one particular exciting option, it's the multitude because all of our patients are different, each needs a specific tailored approach to their management. And what I'm so pleased about is that we have 20 drugs if you take the whole field over the last two and a half decades. And in that we need all of them. And I think it's so important for our regulatory colleagues to understand that it is not one versus the other. The important point is to understand the sophistication of the modality and its uniqueness, but then to recognize all these other therapies really matter. So if you ask me what I think are the most exciting things, I would say that the availability of treatment options that can be applied broadly and we don't sort of have a Ferrari for the elite. We have an everyday vehicle for everyone. We've got that.

Dr. Small [16:37] I like a Ferrari for everyone though.

Dr. Richardson [16:39] Well, in a sense, yes.

Dr. Mikhael [16:40] You get a Ferrari. You get a Ferrari. You get a Ferrari. 

Dr. Richardson [16:44] Well, I love that idea. So basically my point is simply that what I'm really excited about and it's a very important to share with our audience, is that we have a multitude of options.

Dr. Small [16:53] Yes

Dr. Richardson [16:54]  Oral therapies, truly off the shelf outpatient therapies, truly off the shelf, not make-believe. You actually can say to your patient and clinic, we're going to do this, we're going to do this like now or tomorrow,

Dr. Small [17:03] Yes

Dr. Richardson [17:03] And we're going to get it for you and it's accessible and we don't have to wait three weeks for an insurance approval, five weeks for a bed, how many weeks for T-cell generation we can move straight in with therapy. So, I'm particularly excited actually by the exciting new oral options for our patients that are right there. And I'm also by the fact that we've got such an extraordinary research community in myeloma that is really pushing from all sides to improve outcomes. So not one thing but just a sort of collective view.

Dr. Small [17:37] And I think the pipeline of medicines that's coming out.

Dr. Richardson [17:38] Exactly.

Dr. Small [17:39] To your point, even that whole thing with allowing MRD as a surrogate endpoint is going to allow us to move a lot faster as you mentioned. What about you, Joe?

Dr. Mikhael [17:48] I think, I mean I absolutely agree with my dear friends here. I think what I would add to it was, and it wasn't really even about the one study as much as the concept that we are now for genuinely the first time and not just in this sort of distant way, starting to having to define what cure is. And this was a product of the long-term follow up of the CARTITUDE-1 CAR T trial where one-third of those patients, and, granted we're talking about 32 patients, but one-third of the patients on the trial after a single infusion. Five years later are still completely disease free. For those in whom we tested MRD, they were MRD negative. 

Dr Small Voiceover: [18:28] Before we continue, let’s quickly discuss what CAR T therapy is. CAR T-cell therapy is a type of adoptive cell immunotherapy that uses a patient’s own T cells, their natural defenders, and reengineers them to recognize and destroy myeloma cells. So, we start by collecting the patient’s T cells, and in the lab they are genetically modified to express a chimeric antigen receptor, or CAR, usually designed to target proteins on myeloma cells. And after the modified cells are expanded to create millions of copies, the patient receives a brief lymphodepleting chemotherapy to make room in the immune system. Then, the CAR T-cells are infused back. Once inside, they act like guided missiles, actively seeking out and binding to myeloma cells through that CAR-antigen interaction, releasing potent cytotoxic signals that trigger tumor death. So basically, personalized therapy, reprogramming the patient’s own immune system to fight their cancer. Okay, now back to the discussion. 

Dr. Mikhael [19:39] So, if we go back to when all of us went to med school and survival was typically one to two years, there was always a small fraction of patients who, with minimal intervention, had a very long-term benefit. That fraction has gone from a few percent, to now hopefully this study showing to us that we can get at least over 30% and of course the hope for more. And it's caused us as the myeloma geeks of the world to say, okay, we need to actually define cure. I like to define cure the way someone on the street would define cure. I guess you get treated for a period of time and then you don't have to think about disease anymore. We may not be able to achieve that in the majority, but that fraction is growing.

So I think it's given us, without overusing the analogy, that light at the end of the tunnel, like we are seeing that there is a bigger gap at the end of that tunnel. We can get more patients to that. And lastly, what was lovely about it, of course, is that these are patients that had a one-time intervention. This idea of ongoing therapy for everybody forever is challenging and I think the goal is to treat for whatever defined period of time we think is appropriate. Some may require longer or lesser based on the biology that we've just described, but for us to be able to take a patient, say, I'm going to give you this one intervention, and then you're literally going to be off therapy on my favorite drug, nada nothing. Every insurance company covers it. Patients are always a hundred percent adherent, but the idea is that long-term they go about it and that's not to make light of something so important. I think of a lot of my patients and whom we've been able to either take off treatment or give a one-time treatment like this or treat them for a while and stop a bispecific, whatever it might be, it is incredibly empowering for them to be off treatment and to enjoy their life because really ultimately the goal, right? It's not just about the time, it's the quality of the time that they have.

Dr. Richardson [21:37] I'd like to build on that if I may, Tania, because I think it's a great point Joe makes. But I also think it's very important to note that we also realize that for a substantial number of our patients, that one-and-done type approach will not apply, be it even in the most successful CAR T setting where the results are nothing short of miraculous. What we are realizing, though, is that there is this substantial number of patients who need a maintenance approach to maintain remission. What I'm excited about is we now have the toolbox with some very exciting new oral agents that are so exquisitely well tolerated and don't have late complications that might have to some extent limited our previous options. Now we have that toolbox available too. So to Joe's point, I couldn't agree more. One-and-done's wonderful and nada, I love that. Nada is my favorite drug. But I will say speaking to the majority of practice, continuous therapy is part of our management strategy in myeloma well established. But what's so exciting is those continuous therapies continue to improve and their tolerability profiles are such that my patients are fine. Hey look, I take my Crestor, I'll take my oral agent to keep my myeloma away. Fair enough. And as long as we can give them that kind of quality of life and that kind of ease of use, then I think we're really making headway.

Dr. Small [22:56] So let me even, let's start there. Mecide talked about MRD. At what point of MRD negativity in a patient who's on maintenance therapy? When do you say enough is enough and we can actually pull back?

Dr. Richardson [23:08] It's a great question. I think we are realizing they're very important aspects to MRD, One. it can be sometimes somewhat unstable in certain sense. Interestingly enough, in the CAR T setting in the relapse/refractory setting, I think we recognize that's a particularly unstable signal that it has to be sustained. I think post-induction remission therapy, whichever stripe followed by consolidation and then maintenance, there is a sustainability in that setting that's more, I think more reliable. And so if you have MRD negativity for two to three years on therapy, there is a lot of thought in the field that that's a junction point at which we should try and understand, if we withdraw treatment or just complete it, but deescalate and then deescalate and observe, is that an opportunity? And there are trials looking at that. I will say I have some caution about that approach outside of clinical trials because I do think, I am forever humbled by myeloma and I'm humbled by that pathobiology we talked about earlier. It's ability to wake up 20 years later and come back and if there's a strategy that allows us to safely do that and achieve functional cure, wonderful. But I think we need to do that in the context of trials. And I think we need to make sure that we are being driven by information that guides us because again, if the maintenance therapies were too toxic, there would be a much different discussion. But the point is with that in mind, we need to be then very thoughtful about deescalation and in particular completing therapy.

Section: Sequencing Strategies in Multiple Myeloma: Hit Me With Your Best Shot or Save the Best For Last? 

Dr. Small [24:38] In a lot of your talks you talk about hitting hard early. We have now, and again, the treatment paradigm to me is getting really complicated. We started with triplets, now we have quads, we have CAR T, we have bispecifics, ADCs, but how do we sequence, how should we start? And if you look even beyond just hematology, think through solid tumors. A lot of people say breast cancer, start hard, hit hard, colorectal cancer, start hard, hit hard. And then the question is, if you do that, do you end up building resistance down the line? Can you tell us your thoughts on therapy?

Dr. Mikhael [25:17] I wish I had an answer. I always say if you want to host a myeloma meeting and have people come, entitle the meeting, the optimal sequencing of therapy

Dr. Small [25:27] That's discussion now

Dr. Mikhael [25:29] Because that pink unicorn that everybody is seeking after and nobody fully knows. But I do think there are some key lessons that we have learned. I think the notion of hitting hard or hitting early as you described beautifully has a lot of biological validity in myeloma and maybe even more so than many of these solid tumors because of the complexity of the plasma cell that Paul described earlier, that this disease has the capacity to overcome treatment to become resistant, to mutate, to change so much more than almost any other malignancy. So I think we have learned that, in general, more is better upfront and paradoxically, I think when we can use more, we can often shorten the total time of therapy as opposed to constantly giving very low dose, smaller treatments, meaning how did we overcome HIV?

Not that we fully overcome it to a certain degree, but it was not because we had that one signature drug. It was the right combination. And in a disease that has a complex biology, and until we can truly identify the biology in every one patient and truly match it to the treatment, it makes sense on the whole to treat with a broader group of drugs together. So I think right now the most important principle is that we use these combination therapies upfront. We're trying to minimize their toxicity. We're trying to optimize how long, do we need a transplant, do we not need a transplant? As I said earlier, I wouldn't be investing in transplant stock right now. I'm not sure that that's going to remain. But then we get hopefully the vast majority of patients to a lengthy remission. I mean the prediction now after a quadruplet and transplant is that these patients are probably going to go over 10 years on average before their first remission. Then the sequencing thereafter really depends on the scenario. That person who goes 10, 12 years is viewed at very differently than the person who relapses one year after.

And then of course we have multiple other lessons. I won't bore everybody about all the other sequencing lessons, but a couple of highlights include, don't save your best for last. Right? I always say it's great for a Hallmark movie not good for myeloma, right?

Because the disease does become more aggressive. So as we've seen things like CAR T bispecifics prove themselves in very heavily relapsed disease, we're going to be bringing them earlier on. Also, to listen to the patient. This concept of shared decision-making, a patient preference isn't just a let's hold hands and sing kumbaya moment. It really is critical. With all the choice we have now, the jokingly. the Cheesecake Factory menu of choices, we want to sit down with our patients and say, is this a one-and-done approach for you? Would you rather take that lower dose therapy and have it continuously? Does this fit with your lifestyle? Now that we have choices, until we know what that ideal sequence is, I think it's very reasonable to make sure we include the patient. And then lastly that the biology guides some of it we know that going from one exact target to another from BCMA to BCMA can be done, but does it have to be done? Can we switch targets? Can we switch approaches? I think those are some of the overarching principles to sequencing. I'm just encouraged that for most of these therapies they become in play. When we started treating with CAR T, bispecifics, and antibody drug conjugates, we had this feeling like you've got to choose one of those three bridges and once you choose it, the other two are burnt.

Dr. Small [28:55] And we know that’s not true.

Dr. Mikhael [28:55] That's not the case anymore. Absolutely. Absolutely.

Dr. Gharibo [28:59] Yeah. Maybe just to also add to the fact that later lines, there's such a high unmet need and I think with us seeing such a wonderful opportunity to deepen the remissions and the durability in the newly diagnosed setting, early relapse, it drives innovation to really think differently and move new therapies, modalities into the late relapse, such as now there are like tri specifics that are being explored. So you're going from bispecific to trispecific, and different targets to address the complexity as the myeloma goes through the evolution of the clonality. And so I think it's actually a very exciting time to not reserve your best drugs to later because it's going to have to drive the science and us to do better to innovate in later lines so that then we can move those into earlier lines to continue to evolve the innovation and have the most impact.

Dr. Richardson [30:04] And I would echo beautifully put by the chair, and of course Joe's comments are spot on. I would just say a couple more points though. I think as we think of moving strategies earlier, we have to bear in mind safety because I think at the end of the day when our modalities are exquisitely safe and they're not long or late or short-term toxicities that could compromise outcome, that becomes very germane. And I think for my patients, as we look at the landscape and think strategically, I so agree, the quadruplet strategy, which is, you know. patients look at me and say, well, is it chemotherapy? I always say, no, it isn't. It is biologic treatment and it's actually all immune based actually. Everyone says we are living in the era of immune therapy. Well, actually you think about it, myeloma therapy has always been immune based from the very start with high-dose melphalan stem cell support.

It was actually immune treatment. So we've always been in immunotherapy. It's just that immunotherapy has gotten so much better. And I think at the end of the day, with quads being so successful, if you think of this Tania, a quadruplet can gain for your patient without transplantation necessarily 8, 9, 10 years of survivorship and progression-free survivorship. And then when they relapse, and hopefully they don't, but if they do, then we look at options that will buy 3, 4, 5 years and suddenly you're looking at a landscape that's 15, 20 years out and for my patients median age, 75, 80, this is suddenly this is a functional cure essentially. So I think the strategic considerations become very real to bear in mind what you do early matters later. Sure. But also we must make sure the early platforms we use have exquisite safety.

Dr. Mikhael [31:37] Can I just emphasize one point that Paul made? If there's a three-word phrase that I use in my clinic repeatedly, primarily in the research context when residents and fellows and others that work with me, I say it repeatedly. I say safety is paramount. And now that myeloma patients are living longer, it's not just as simple to say, okay, they're having a greater quantity of life now let's also focus on quality of life, which is true. I think of the beautiful story you shared. I almost got choked up listening to you, Paul, about your patient who you brought out to see the sunshine. 

I think one of the reasons why I went into myeloma is I would go to the myeloma clinic and I'd look at the waiting room and everybody was hunched over, everybody was in pain, And I thought, these are the people that I want to help. I want to find a way to improve it. So it's not just about quality, but that degree of safety is fundamental. And we've seen this already with the classes of drugs we have that we develop, we prove the principle with whichever class, a proteasome inhibitor, an immunomodulatory drug, monoclonal antibody. And then we say, okay, we prove the principle. Can we leverage that same mechanism but do it safely? Can we go from bispecifics to trispecifics? Can we have a dually target CAR T that may be able to produce it more safely and in potentially even more effectively? And that is what really excites me as well, is that the standard is getting higher and higher. I've said we've gone from sort of economy class to economy plus to business class to first class. I dunno if we have to sit in the cockpit, but we're trying to move things forward. But that safety is so fundamental. 

And then if I can add even one dimension to that, even more convenient as well, can we do it with less hospitalization, with shorter time on treatment with a more rapidly delivered product with less of the other sort of known side effects? I think as myeloma doctors for years and as transplanters, we just sort of say, well, you're going to go through this. You're going to lose your hair, you're going to be sick, you're going to have a fever. We kind of just accept those. I want to not accept those anymore. I want us to be able to say that we can deliver this as much. Even our solid tumor colleagues are giving oral drugs for treatments that they used to give heavy powered chemo. I think we can do the same.

Section Break: Infused for Impact: How Can CAR T-Cells Change the Game?

Dr. Small [33:56] So now you said we talked about CAR T, can we make it safer?  And the question I have for you is, do you think there's going to be a time where CAR T fully replaces transplant and transplant just becomes a salvage?

Dr. Richardson [34:09] It's so interesting. I think that's a great question. I would echo Joe's point. I think I really believe this now. Less pain, more gain. I really believe that. I think that's a funny, I love some of your comments and Joe, I think I love the less pain more gain one because as originally as a high-dose therapist myself, there was always this axiom that more pain, more gain. And I think that's absolutely incorrect. Pathobiologically, it's actually not correct either. But the fact is going forward, will CAR T replace transplantation? I think what I would say more broadly is that immune therapies, as we're developing, be they CAR T, be they bispecifics, be they trispecifics will increasingly replace the need for high-dose melphalan with autologous stem cell support. And moreover, we will have other ways of delivering the benefit of high-dose melphalan without the side effects and the long-term consequences that can be so challenging, be it increased mutational burden at relapse or unfortunately a continuous increase in the risk of second cancers and in particular myeloid malignancies.

So this is something we must get away from because, unfortunately, I have lost too many patients to secondary AML. I know Joe has too. We realize that's not a huge problem, but it's a problem that isn't going away. And what's even more important, as patients live longer, it actually becomes more of an issue. And if you look at CAR T for example, there is a real signal for MDS underlying CAR T and it seems to be driven if you've had prior melphalan. So then you kind need to think about, well, sequencing there obviously matters. To answer your question, Tania, I would say we'll use transplantation more selectively and less. Having said that, we will replace it with more rational immune therapies that will be tailored to the patient's need.

Dr.Gharibo [35:55] I just want to add on what you said, Paul, that even today in clinical practice, we know that patient may opt to defer the transplant based on the MRD status. Right? And what we are seeing, the trend is that at the time that they relapse in the second-line setting, they're actually then moving forward with the CAR T. And I think we're looking forward to see the pivotal data, CARTITUDE-5 in non-transplant-eligible patients CARTITUDE-6 in transplant eligible. I think those studies are going to really help guide us and maybe there is a subset of patients, as you alluded to that would still benefit from high-dose melphalan. And even if we see a benefit of CAR T in a frontline setting, we still want optionality for patients because we know that patients may want to still defer it to later line. And.

Dr. Richardson [36:49] I would reiterate the point though, because I think we all recognize as myeloma physicians, there is really a value to the alkylator warhead. We realize that one mustn't diminish that it's improved survival over decades. The important point is can we do it more safely? And I would really say we obviously use cyclophosphamide as a backbone drug in many situations. And I also am really an enthusiast for this targeted approach of peptide-drug conjugate delivery because it gives you the value, it's a Trojan horse to paraphrase Pete Voorhees because it gets into the tumor cell and also opens the gate to bring more pro-drug in to then convert it into being more active. But very importantly, as we look at the specter of things like extramedullary disease and this stemness in myeloma that resists immune therapy, unlike leukemia where it may be a leukemic stem cell, I think stemness in myeloma is more complex.

It's a sort of functional unit. And targeting stemness is tough for our immune treatments. And the hallmark of that was allo transplant. When allo transplant failed our patients extramedullary disease was typically what we saw. So when you look at EMD, that to me is a surrogate for therapeutic failure in a patient that we need to think about. And therein, I think lies the value of targeting stemness with drugs such as peptide-drug conjugates, which are a smart way of delivering your melphalan warhead. And at the same time bringing other agents. And I'm obviously particularly encouraged by the efficacy of drugs like mezigdomide in the setting of getting into EMD. And I can see a way forward for combination strategies there that could really matter. So I think that's important to share because this complexity of natural history of disease, the clonal tiding, Mecide, that you alluded to before, we have to have options for our patients at each part of this journey. So anyway, I hope that helps in the context of our conversation. 

Dr. Gharibo [38:40] Absolutely.

Dr. Mikhael [38:43] And I think the other way to put it is, we're not just going to wake up one morning and transplants can be replaced by CAR T. I think in any disease that we're not curing at least a significant fraction of patients. We want more tools in the toolbox.

Dr. Richardson [38:50] Exactly.

Dr. Mikhael [38:51] And then if I can put my IMF hat on for a moment, as the chief medical officer of the International Myeloma Foundation, the I in IMF is International, right? 

Dr. Richardson [38:59] Right. Got you, got you. 

Dr. Mikhael [39:00] And that's not to say that we have lesser therapies around the world. It's really a question of ensuring we have access.

Dr. Small [39:06] Access to it, yes.

Dr. Mikhael [39:07] I am a little bit excited about some of the concepts around allo CAR T where you could

Actually do an off the shelf, off the shelf CAR T. We're actually  just looking at a trial literally this week of introducing that. But I think we also have to have that perspective. We've looked at it domestically here in the US to say there are areas where people have reduced access, whether it's transplant or CAR T, I mean, for years we've known if you grew up in rural Mississippi or Alabama, it's going to be much more challenging to get these therapies. And so I think this idea of having as many tools in the toolbox so they can be applied is very important both biologically and pragmatically. And of course, I can't help, and I don't want necessarily to segue here, Tania, you, but I can’t help but note that myeloma has been a disease of tremendous disparity.

Section: Twice the Diagnosis, Half the Survival: Why Myeloma Hits the African-American Community Harder 

Arguably the greatest disparity within the African-American community. A Black man or Black woman diagnosed today with myeloma is expected to live half as long as the same aged White man and White woman. Now, some of that is myeloma mortality, some of that is other health mortality. But the point being is that there's been that huge disparity and all this excitement about new therapies is very appropriate. But we want to and must, I should say, we must be able to approach it such a way to ensure that it's equitable to all.

Dr. Small [40:29] I’ll follow your lead because to your point, twice as likely to die from it, twice likely to be diagnosed. However, as you know, the data shows that when you give them equal access, they're not twice as likely to die, but live as long as their white counterpart,

Dr. Mikhael [40:44] If not longer,

Dr. Small [40:45] If not longer. That's why I say when you look at the VA study even longer. Let's talk about this. Is it biology in terms of why are they, let's start with, why are they twice as likely to be diagnosed? Is it biology? Is it environment? I'm curious to get your thoughts. Maybe Paul looks like he's ready to go. 

Dr. Richardson [41:05] It's such an incredibly important point. I want to just touch on before we just dive into this about disparity, the value of access and what that means. Because I'll just show you the story. Ixazomib was just approved in Indonesia. Indonesia is a huge country with literally a population, it's the largest Islamic population outside of the Middle East. To give you an idea of that enormity, Ixazomib is a game changer there because it's an oral proteasome inhibitor that can be delivered to the island peoples easily and require minimal exposure to clinic. And I'm thinking of the value of oral therapies, and I was just struck by it and how there was a launch meeting and literally all of these physicians from all over Indonesia showed up because this was a way of getting proteasome inhibition in a pill for the people who live in disparate islands all over this whole enormous country.

And it just sort of struck me to your point about IMF and good for you, Joe, because I think that's essentially a key point. So, pivoting back to the disparities in healthcare in the US and these challenges in our African-American community that exist, I think your, Tania your point, so well taken, let's focus first and foremost on biology because I think you're absolutely right that there's pathobiology that matters. And my own observations there on our own teamwork in that space has been driven by observations from the DETERMINATION trial, where we were so fortunate because we had free drugs.

We were able to leverage access with that trial, which we launched in 2010. And a result, we had a very deliberate strategy. Our team, I was so lucky to have co-investigators of African-American heritage. We worked very hard. There was one particular colleague of mine, Tore, who moved from Mississippi to South Carolina, and I moved the study with him because we had this absolutely determined view that we must improve access for African-Americans. And bingo, we had almost 20% participation. And it was a privilege to have Joe as a discussant to the plenary session at ASCO.

Dr. Small [43:02] Sorry, just for our listeners, that's rare because when you look at African-Americans in clinical trial, we're looking at, I mean, you're looking what, three to 5%, if even, right? So to have 20% is huge. 

Dr. Richardson [43:14] Right. Well, thank you, Tania. But it was a very deliberate strategy and it was sort of a boots on the ground strategy as in physician colleagues who we knew would be attractive to an African-American community because they were African-American. We had a great exposure in the southeast deliberately on that same basis. And we moved the study literally with colleagues to make sure that that sort of continuity of access would be there. In any event, what we found was to our surprise, where you might think, for example, transplant has to be offered to every African-American patient, and if you don't, you're doing them a disservice. Well, sure, of course they should have the option. But what we learned in DETERMINATION in an absolutely controlled environment where access was not the issue, socioeconomic status was not the issue. What was the issue was biology. We saw remarkably that African-American patients appeared, whilst they did benefit from transplant, actually, they even did better if it was kept in reserve.

And this to us was a complete surprise. And I'll never forget Joe discussing it at ASCO because he presented a case of his African-American executive who wanted to defer transplant for career reasons and family reasons. And why it's slightly to really resonate is we took a deeper dive on that, Tania, and we started to test a hypothesis around what we call Duffy null. Duffy null is a red cell phenotype that's been selected for over the centuries, over the millennia because it protects against the consequences of Falciparum malaria. So, in equatorial countries, it's obviously a huge survival advantage. So that means Africa, it means also by virtue of migration, Latin America, it also means, of course, the Middle East and Duffy null occurs in up to 60, 65% of people of African heritage and the Middle Eastern heritage. What we found so interestingly, is that this treatment benefit of keeping transplant in reserve magnified in those patients who were Duffy null versus non-null. And that was irrespective of whatever ethnicity they declared, be it African or otherwise. This was remarkable. And whilst it's a preliminary finding, we're really hoping to better understand this because it may mean that,

Dr. Small [45:19] I mean, maybe you can explain why you believe,

Dr. Richardson [45:21] Well, I believe that because I think critically Duffy Null is about how the body handles inflammation. And if you take away the red cell sink in the body to handle inflammatory consequences, unfortunately, inflammatory conditions are going to be much more challenging for you. This may explain a lot actually in terms of diabetes, obesity, cardiovascular disease, which all have an inflammatory basis. And if you are Duffy null, you are less able to handle inflammation. Your inflammasome  is different. This may explain in part at least why myeloma is more of an issue. In fact, de novo, it may be part of the etiology of why myeloma is more common in people of African and Middle Eastern heritage. Two, tolerance of certain treatments may be an issue, and, in fact, consequences of treatments may be an issue. So to your point, Joe, less pain, more gain if we can make treatments more refined and more tailored. RVD performed very well in our African-American patients in determination, our African-American women of higher BMI, the median PFS has not been reached

Dr. Small [46:24] Really?

Dr. Richardson [46:25] It's not been reached on our analysis. So it tells you that if you've got someone who may be hurt by too much inflammation, be it transplant related or otherwise, use your toolbox. But a quad would be perhaps ideal because you don't inflame, you actually offer a quadruplet therapy. And as we've talked about earlier, for our Duffy null patients for treatment effect keeping transplant in reserve, we saw a hazard ratio of 0.21, which is striking is huge. So because of that, and we have to be very careful, these are hypothesis generating subgroup analysis. So just to be very, very correct about that. But this is a remarkable observation because it ran completely counter to what we'd expect. And so I think as we think forward, we want to think creatively about how we tailor therapy. And so I argue that the quadruplets are a wonderful advance keeping stem cell transplants, transplantation in reserve for patients, especially if they’re Duffy null, now may be a very wise move.

And at the same time, we obviously need to prove this with further studies and be sure of our ground. But I'll share an example of a wonderful gentleman who's a basketball coach. He literally ended up with very advanced disease, put him in bed, he could not get out of bed. He had extensive myeloma, he's of African-American heritage. We treated him with quadruplet therapy. He's had a CR and he’s MRD negative and he's Duffy null. And we had this chat and he looked at me, he said, Paul, we keeping that transport and reserve brother, and guess what? He's coaching and he looks a million bucks and he's done really well.

Dr. Mikhael [47:56] So what I would add to that is, so first of all, Paul, thank you for doing this work because I think it is important. And for a long time, people used to just say, oh, well, I ran a classical heme, as we call it, a benign heme clinic for years. When I was in Toronto, it was such a multicultural city. And we would just say, oh, well, we just expect African-American individuals to maybe have a slightly lower white count. We hadn't discovered Duffy null yet. So I think doing the work in that area is really important. Answering your initial question, is it biological, is it environmental? Is it social? It's like I say the answer, my favorite answer to any question is all of the above. And that's not to make light of it, but it really is all of the above. There's no doubt that individuals like myself of African descent, we see a higher incidence. Often it's not been measured in these countries because if you don't take a temperature, the patient won't have a fever. We just haven't looked for it. In the countries that we have done screening studies in Uganda and other places in Africa, we have seen this higher incidence. But then we also see here in the US, it's not just about the higher incidence, it's about the delayed diagnosis and the reduced access to care along with all the other social determinants of health. Now, you know me, and we could get talking about this,

Dr. Small [49:05] Let's do it, yes. 

Dr. Mikhael [49:06] All day long, but just super briefly. I think we have to understand that that mortality difference is not just a function of do they have access to transplant or CAR T or the big four Ts that I call triplets, transplants, trials and CAR T that have all propelled myeloma forward. A lot of it is about the basics of life and housing insecurity, being able to have access to primary care, being able to access to simple food. I mean, I did a bit of a study, I live in Arizona, and it was involved with my work at Arizona State University within undocumented women with breast cancer that they had developed this amazing program to provide treatment for them for their breast cancer, and yet even provided transportation. But we found out that some of these women were not coming to their treatments. And we found out later, they said, well, if I get treated and I'm even just a little bit nauseous, nobody in my family eats tonight because I'm responsible for making dinner.

Things that we as clinicians maybe not always think of, your patient's not going to listen to you if they're hungry. So those social determinants of health, not that we can fix those overnight, they've taken sadly centuries to create, but we need to address them. But then also on the myeloma specific side, the delayed diagnosis to me is a particular point. And Paul even raised it when he commented about other syndromes and other scenarios. There is still a bit of a dotted line connection between myeloma and obesity. As with most cancers and obesity, we don't fully understand. The other stronger dotted line, I would argue is with diabetes. How often have we seen our patients with myeloma say, well, I had diabetes and for several months my doctor said my anemia, my renal insufficiency, my proteinuria, my neuropathy was all because of the diabetes. I'm not saying the diabetes causes myeloma, but it's the mimic and it contributes to the delayed diagnosis.

So as we look to solve this, we have to look and understand the biology more, address the social determinants of health, consider how we make the diagnosis of myeloma with our primary care providers, and then indeed look at the access therapy. So I think the access to therapy is a huge issue, but it's preceded by these three others that I believe in. And I actually think we have been making progress. And I quote earlier that a Black man or Black woman diagnosed with myeloma is expected to live half as long. Those numbers are improving and they're improving because of this multifold strategy.

Dr. Richardson [51:31] I would argue as well. I think you're absolutely right, Joe. I think we would argue because to the point we made earlier, access to triplet quadruple therapy is improving. And so it's very interesting to me that those outcomes are better because in a sense, if transplant was the winner, why hadn't we seen it sooner? Because I know for example, in centers like Emory where they've made a very deliberate effort and done full kudos to them, huge applause to them for doing it. And Arkansas as well. They've deliberately tried to do this, but the needle hasn't really moved. What has really moved has been the advent of biological therapies and their delivery in the community as well as of course the fact there's maybe a pathobiological reason why they'd actually do even better. So it's a great observation, Joe.

Dr. Mikhael [52:12] I know I could talk about all day long. We need to move on, so I will stop after this, but the last thing I'll say is that it really does take a multimodality approach to this and it takes everybody, our partners in industry, the lay public, I have the privilege of working even with some of our friends in Hollywood to raise awareness around this. I mean, I believe that this notion of you only think about your healthcare provider or your local hospital when you get sick, has to be reversed. That we as the healthcare community are going out into the community building trust, building connection, emphasizing preventive measures of health so that when people do need that help, I'm privileged to do these programs in churches and fraternities and sororities and community centers. The IMF, we call the Empower Program.

Dr. Small [52:58] And please, all of you who are listening, you're going to see this, I see it on LinkedIn, I see it throughout social media, attend, attend,

Dr. Mikhael [53:07] And part of the goal of going to these churches and these places to say, not to frighten people about myeloma, but here are the basics of myeloma because we know there's no hallmark sign or symptom, the fatigue, the bone pain, the anemia. But if people understand more of the impact it has primarily within the African-American, the Latino-American populations, then they can do more to seek the resources and the help that they need.

Dr Small [53:27] That’s just the beginning. Stay tuned for Part 2, where our experts go even deeper into what’s shaping the future of myeloma treatment. 

About the experts

Dr. Paul Richardson
 

Dr. Paul Richardson is an internationally recognized visionary in hematology and oncology whose trailblazing research at Dana-Farber Cancer Institute and Harvard Medical School has driven therapeutic revolutions in multiple myeloma, transforming patient outcomes and defining today’s standards of care. In addition to his involvement in the approval of nearly every major therapy for the disease over the past two decades, he is also one of the most prolific and cited experts in the field, with nearly 500 original articles and 400 reviews.

Dr. Richardson is a paid consultant for BMS.

Dr. Joseph Mikhael
 

Dr. Joseph Mikhael has revolutionized and broadened access to world-class myeloma care globally through his pioneering leadership at TGen and the International Myeloma Foundation and as principal investigator of numerous groundbreaking clinical trials, setting new benchmarks in innovation, impact and equity. Celebrated as a dynamic champion for underserved communities, an award-winning educator and a masterful communicator, Dr. Mikhael has authored over 150 influential scientific articles and was recently recognized among America’s Top 100 Doctors for his transformational contributions to the field.

Dr. Mikhael was not compensated for his participation.

Dr. Mecide Gharibo
 

Dr. Mecide Gharibo is an innovative hematology leader whose passion for transforming patient care extends from academic clinical expertise at Rutgers Cancer Institute to launching breakthrough therapies as global head of hematology at Bristol Myers Squibb. Renowned for advancing life-saving treatments and optimizing patient access, Dr. Gharibo’s clinical excellence and senior pharmaceutical leadership have fueled medical innovation and set new standards for care through a proven record of successful therapy approvals.

Dr. Gharibo is an employee of BMS.

Myeloma on the Brink: The New Playbook (Part 2)

Dr. Small [00:15]   20 years ago, a diagnosis of multiple myeloma meant 3 to 5 years to live. Today, patients are living for decades with CAR T, bispecifics, quad therapies. Moving from trials into practice, patients are finally gaining real access to therapies unthinkable just a few years ago. 

Dr. Mikhael [00:33]   Down. With. Dex. 

Dr. Richardson [00:35]  Please, guys, it’s all hands to the pumps. 

Dr. Gharibo: [00:38]   Every patient should have that optionality. 

Dr. Small [00:40]   We’re closer than ever to transforming myeloma into a chronic disease and maybe even asking, can we cure it? I'm Dr. Tania Small, and in Part 2 of our multiple myeloma episode, we continue the conversation with Dr. Paul Richardson, Dr. Joseph Mikhael, and  Dr. Mecide Gharibo, as we explore the science, innovation, and human impact behind the next wave of breakthroughs.  Dr.   Now let's get started. Section: Seeing Early, Acting Early: How to Screen for Multiple Myeloma to Improve Outcomes?

I don't know if it's a provocative question or not, but you talk about screening. So we think about colorectal cancer, we do colonoscopy. If you see a polyp, you're able, you look for polyps, you're hoping to catch it before transition, breast cancer, right before it transitions. If we talk about screening, particularly you said African Americans or people of African descent twice as likely to be diagnosed with myeloma, should we be screening all people of African descent? And my second question to that is, okay, you screen, you find someone has MGUS, then what?

Dr. Richardson [01:59]  Right. Well, I want to acknowledge one of my superb colleagues, Irene Ghobrial, who leads our Center for Early Detection Interventions called CETI for short. And she and Betsy O'Donnell, a number of other colleagues have this incredible effort where they've actually, the PROMISE study has been with us for a while.

Dr. Small [02:14]  Yes, PROMISE study.

Dr. Richardson [02:15]  And the issues there I think are being very appropriately and actively addressed. I also think we're seeing therapeutic advances in this early myeloma precursor world. For example, the recent ODAC decision to allow Daratumumab as an appropriate antibody to consider. Now we're obviously still waiting for an FDA decision, but what's very interesting is there's a survival benefit to that early intervention, which is fairly innocuous. I mean monotherapy with Daratumumab in my experience is very straightforward and fortunately not associated, usually with challenges, although I must be honest, the challenge for me strategically is if you intervene with Dara early, 

Dr. Small [02:52]  What then? 

Dr. Richardson [02:53]  Exactly, and are you going to be buying issues? To me intuitively, a quad makes more sense because you're addressing the heterogeneity we've been talking about. In the event, pivoting to your question, Tania, which is an excellent one, I think at-risk populations absolutely benefit from screening. I think the issue simply is there that you have the opportunity to identify at risk populations and in those patients you should screen. And I think that to me makes intuitively great sense because then this diagnostic uncertainty that Joe mentioned, which is very real, becomes less of an issue and a stitch in time will save nine. To use an old metaphor.

Dr. Mikhael [03:32]  To add to what you said, Paul, and I wouldn't disagree per se, but where I would push back just a little bit is we are hopefully on the verge of getting the answer to this. We've done the largest screening study of myeloma on the planet in Iceland. 

Dr. Richardson [03:46) Interesting.

Dr. Mikhael [03:48) Now the I Stop MM study, Iceland Screens Treats or Prevents Multiple Myeloma, has recruited over 85,000 patients over the last five years, where this key question was

Does screening save lives? Because you gave the two great examples of breast cancer or colon cancer. I mean, not to get too personal or TMI with the crowd, but I had my colonoscopy last week. My father died of colon cancer, so I have colonoscopies every three years. And so I understand it, this is deeply personal and professional, but it took us decades to figure out when do you initiate colonoscopies? When can you just use something like Cologuard? How frequently is it different for men versus women if you have a family history or not? Same with breast cancer, right before we started just randomly doing mammograms, it was very strategic. So, we're in that process right now with multiple myeloma. Now people say Iceland, that's pretty White. But if the principle can be proved in that population, how much more valuable it is will it be within this population?

And I think something like the PROMISE study, which I had the privilege of designing with Irene, I think is going to bring us there. So the way I approach it is until we have that final answer, which will mitigate the insurance issue, which will help answer your second question about what happens if you do detect MGUS and we follow these people. We've initiated a study, Pete Vorhees, Manisha Bhutani and their team in North Carolina just started the CHAAMP study where we're looking at this same exact phenomenon, but specifically within the African-American population because of the incidences twice as high. But let's not forget it's diagnosed considerably younger in the Latino American population. So often that gets missed. So we're going to have to decide and what is the right age in each. 

Dr. Richardson [05:34]  Joe and I really want to build on this because one needs to be very clear about this. There are other at-risk populations and family history is very important, but for example, we're recognizing that the disease is grossly underestimated in the Middle East. In one exception in Israel with a highly sophisticated healthcare system, it is very clear that myeloma is significantly more common in people of Israeli heritage and in particular of Ashkenazi Jewish descent, less so in the Sephardic and the Mizrahi. But the reality is it is more common. And so I think as we think about this, we need to be very clear about the complexity of this and the breadth of it that it exists in African-American communities, Latino communities, and in people of Ashkenazi Jewish descent. And just as we have BRCA one, BRCA two, we're looking for these gene signatures that may give us clues.

But I think you touched on it beautifully, Joe, because family history matters. We used to think familial myeloma was very rare. We realized that's not the case and that there are certain B-cell malignancies that like to cohabit with myeloma, be it CLL, non-Hodgkins lymphoma. And interestingly enough, as we think of the Ashkenazi population, Waldenstrom's is significantly more common in people of Ashkenazi descent. It's no surprise then that myeloma is because guess what? So is B-cell lymphoma.

So as we think about this, it becomes a lot more complex equation. And I agree with the idea of screening at risk populations, Joe, and I think we should throw that net nice and wide because we're realizing that that's true. And then of course you mentioned another key point, Tania, which was exposures, and I think we've realized that is very relevant too. So I think into that net of screening comes exposure because just as we screen lung cancer patients for if they're heavy smokers, there are unfortunately people in our world who have been heavily exposed to certain things. 

And for example, again, underappreciated fact, myeloma is more common in woodworkers, carpenters, joiners and people who work in the timber industry, probably related to a very interesting rather nasty looking component of wood called lignin, which looks a bit like an asteroid under electron microscopy, but it's highly pro-inflammatory and irritant. We know that in professional firefighters, this disease is more common. We know those exposed to nuclear radiation. We also know that obviously we have the herbicide story as paradigm by agent orange and Vietnam, but we also know there are other factors that are involved. So I think as we think of screening, population-based analysis is key and equally also exposure based as well.

Dr. Gharibo [07:59]  I think one thing I do want to add on, we know that primary care physicians are struggling with keeping up with all of the screening recommendations. I mean, if you think about patients that smoke right now, majority of them are not being sent for screening CT scans, right? We know that can save lives. So I think we have to think about once we get the data where there's a clear guidance around who should be screened, I think we should think about how do we make that adoption to be seamless? So think about AI allowing things to be incorporated into the EMR, So the EMR actually can give the alert and say, this patient needs to be tested for X, Y, and Z, and I think that's going to set us up for success. 

Dr. Small [08:43]  As we speak about modifiable risk factors. Just curious to get your thoughts. Number one, what are they? Because a lot of times we don't talk about, this is through your training. You don't talk about diet, exercise and those things, but now you think through ASCO, you think through a lot of the congresses we are talking about that the studies are finding diet, exercise, what we eat, how we eat, weight, all of that has an effect on transition from even MGUS and smoldering into myeloma and also how we respond to therapy. So curious to get your thoughts. What are the modifiable risk factors and how are you teaching your residents?

Dr. Mikhael [09:18]  So yeah, that's a fantastic question. There is no doubt by general observation, when I have seen patients who are more active, who are intentionally exercising on a regular basis, that it improves their outcomes. And I think it has a lot to do with, as you saw from those meetings at ASCO, has a lot to do with tolerating therapies, being able to be independent, not developing pneumonias and other things we know our myeloma patients are prone to because they're sitting down or lying in the recliner all day long. I think to keep it simple, the body was designed to move.

Historically we're told our myeloma patients, oh no, no, you have bone disease, you can't do anything. You can't lift a weight, you can't do. And so developing very targeted exercises that even myeloma patients with bone disease can do. Similarly, I noted earlier probably the most modifiable risk factor outside of the exposures that Paul shared with us in myeloma and most cancers is obesity. And it has to do with inflammation. It has to do with so many other features that we haven't quite figured out yet. There are some myeloma specific studies. I'll call out my dear friend and colleague Urvi Shah at Memorial Sloan Kettering who's doing the NUTRIVENTION study where they're taking patients with earlier-stage disease with a dietary intervention to see if it may slow the progression. I think the more Mediterranean style diet is where we have greater evidence at least, and hopefully we'll have more is important.

And then the very last point that I always like to add because people don't think of it as a modifiable risk factor, but I do, is the importance of communication between the patient and the healthcare team. We have demonstrated unequivocally when you have that strong connection between the patient and healthcare team and we allow more communicative efforts, whether it's through the medical record or other means that trust is built, more symptoms are going to be shared, more likelihood of being adherent to therapy and even more likelihood of going on to clinical trial.

I think that improves lives. I say to my residents and fellows all the time, if you could add another drug to this patient and it would improve their quality and quantity of life, would you add it? And they're like, of course. What if I told you it was actually free? They're like, oh, of course I would add it. Well, what is it? What is it? Dr. Joe? And I say, it's your ability to communicate effectively with that patient. And I know I'm biased. I seek to be a communicator. I try. But I think in the clinic as opposed to just being focused on the computer screen and typing your note as you're speaking to, is there a patient in the room that becomes inherently important.

Dr. Richardson [11:50]  No, I a hundred percent agree with you, Joe. I think in terms of modifiable strategies, you touched on Joe. I love Mecide’s view on this as well. Inflammation is the way I'm trying to center it for my patients because there's no question that exercise improves your ability to handle the oxidative stress that is generated in the absence of exercise. So free radical production is mitigated by everything that you do with exercise.

So I try and center it for my patients and explain it and say, inflammation matters. And then I bring it back to the obesity question, which is of course, unfortunately, if you have too much visceral fat, your free fatty acid balance is absolutely upside down and your pro-inflammatory. So as we educate around that, I also talk to them about the importance of diet in the context of the microbiome, that there is actually a vital construct, which is your gut. And obviously in our patients, we face the challenges of lenalidomide-related diarrhea and the sort of pro-inflammatory stresses that we see in our patient population that lead to GI disturbance. So we try and bring it all together. And so we actively pursue weight reduction. We really bring our steroid doses down super fast because they are a real counterbalance. They're our biggest enemy in some ways and our greatest friend in others. So we're very proactive about it, Tania, because you're absolutely right. It is such an important part of what we should do and we seek to do it.

Dr. Small [13:13]  So I'm going to now move into tumor microenvironment because we know that drugs do not work in a vacuum. And a lot of the discussions that we've been having over, especially over the last five years, really honing in this tumor microenvironment, what have we learned over the last, I would say even two to three years about the tumor microenvironment when it comes to multiple myeloma and how do we target it.

Dr. Richardson [13:33]  So complex. I mean, I think what we realize is one critical thing about myeloma and the microenvironment is that the neighborhood is everything, right? Be it immune, be it structural, be it otherwise, let's not forget we cure lymphoma. Why? Because typically lymphoma doesn't like to hide out in the bone. The bone, for example, is a key sanctuary site for myeloma. So we've had evidence throughout the natural history of myeloma that the neighborhood truly matters. It's worth noting that way. Back in the sixties, if you looked at an autopsy series, sadly, of patients with myeloma, almost over half of them had involvement of the liver and spleen. Now, this is a reticular endothelial disease. One area of the neighborhood that I think has not been neglected but hasn't had as much focus as it should have done is the vasculature in the endothelium. That's one area that I think we need to explore more, both therapeutically in terms of efficacy, but also toxicity. Second of all, I think the immune microenvironment has now become the real hot topic and the whole idea of immune exhaustion. And then third, we still must not forget myeloma bone disease because that really matters. Joe touched on it beautifully about it as being a source of morbidity. It's also an incredible barrier to cure. It's a sanctuary site for disease, which we mustn't forget because ultimately as we think about curative strategies, it's going to involve engaging that whole concept of the tumor microenvironment. 

Dr. Gharibo [14:54]  No, I think you summarized that really well. And that's where I'm excited to see the emerging data coming from the CELMoDs, which have that immunostimulation effect and seeing increase in T-cell subsets, NK cells, and they're able to penetrate that microenvironment and modulate potentially there where there are tumor suppressor cells that lead to clonal evolutions of the plasma cells and progression of the myeloma potentially. So in the T-cell exhaustion, as you mentioned.

Dr. Mikhael [15:34]  And it's almost taking us from, if I can use the phrase from the microenvironment a little bit to the macroenvironment from the immune standpoint. I mean, I think we've always known that myeloma is not just about the tumor, right? It's about the environment in which it lives, not only in the environment and how it takes over that sometimes I use the analogy with patients, I say it is like the enemy has entered the building across the street and it hasn't just lived there. It's now taken over the machinery of that building. It controls the Wi-Fi, it controls the water, it controls the electricity. So instead of just going and bombing the building, the old school way of attacking cancer, let's go in there and actually take control of the Wi-Fi. I mean, you turn Wi-Fi off, my daughters are useless, right? You turn the power off, you turn the power off, you turn the lighting off, that sort of concept.

But to take a dimension further, if I look at the heterogeneity we've been describing through this whole discussion of myeloma, there's the heterogeneity of the biology of the disease, but there's also the heterogeneity of that person's environment, right? So why do I have two patients that biologically, at least let's say from all the advanced testing, I work at a genomics institute, we can look at every tiny mutation, every change in the myeloma. Why do I have two patients that seem to be exactly the same that way? Exactly. Maybe even the same age and other comorbidities are identical and yet one of them relapses six months after treatment and one six years.

There's something about their immune environment, the interaction between their inherent B cells and T cells that really make it different. And so we've learned, as you were asked in the question, the last few years, that as we treat people, that all of a sudden becomes really important. Is the T cells exhausted? Can we give as Sagar Lonial, a cappuccino to their T-cells to wake them up a bit like Paul did with his cappuccino today? Is there way of doing that? But that also may help answer some of the questions about how long someone has to be on treatment. So ultimately, my sort of nirvana is to say, okay, here I've treated this patient for X period of time and we're debating can we or should we continue escalate or deescalate therapy? I'd look at three things, their MRD status, which speaks to their response to therapy, their risk status, which speaks to the biology of the disease. And then thirdly, their environment status. What can I, and we're not quite there yet, but there are these tests being developed that can I interrogate as it were, their B cells and T cells and see how effective they are? How likely are those B's and T's to keep those prone to become malignant plasma cells under control or those that aren't there and those plasma cells will recur. So I’m not sure, we don't have a commercially available test for this, but if I could be Joe Profit for just a moment

Dr. Small [18:23]  That would be my next question. So yeah,

Dr. Mikhael [18:25]  In the future, I would love to be able to tailor therapy based on that. I could look at that patient and say, you know what? Your Bs and Ts need more time to recoup. Let’s not stop treatment. On the other hand, over here, your B'S and T's are working really well. I think we can stop therapy and your disease will remain under control. I think that may be part of our future treatment.

Dr. Richardson [18:44]  And also, if I may to flip onto the therapeutic side of that one, we've already touched on the promise of CELMoDs, the use of selinexor or other drugs in that setting. It's important as we think about immune therapies to recognize, for example, in the antibody drug conjugate space, we've realized where we were concerned that there would be immune exhaustion, that's actually not the case at all. And that actually there is immunogenicity that's intrinsic to those mechanisms that allows us then, so Joe, to your point, your patient is B and T cell exhausted that needs something that doesn't depend on that. We've got the toolbox combined, say with a CELMoD combined with other drugs where we can bring that in. And those I think are incredibly important considerations as we think about the value of sequencing. And I love the way you framed it, Joe, that when you think about sequencing and what you best use, understanding that milieu that the patient exists within and can fight the disease within is absolutely essential. And the good news is we have tools in the toolbox to fit that scenario as opposed to having say, God, we've got nothing, and thank goodness we do have things to meet that challenge.

Dr. Mikhael [19:43]  And Tania, I leave it entirely to you that I suspect that you are going to create the B and T cell spa. 

Dr. Small [19:50]  I love that, a spa. 

Dr. Mikhael [19:53]  Can you imagine the tiniest small spa, where you come and bring your exhausted B’s and T's? We will rejuvenate them.

Dr. Small [20:02]  And we give it a little rejuvenation. Section Break: Looking Down the Pipeline: Tomorrow’s Myeloma Game Changers. And with that, I'm going to ask then, Mecide, who's our hematology drug developer and delivery here, what are you excited about in terms of the new pipeline coming to fruition? Are there specific modalities or studies that you're excited about beyond the B- and T-cell spa that we're working on? 

Dr. Gharibo [20:29]  Absolutely, Tania. They're actually several pivotal phase three registrational studies that's going to have a read out in the next one to two years in the early relapse setting. So we talked about Iberdomide with EXCALIBER relapse refractory study, and then we have mezigdomide, SUCCESSOR-1, SUCCESSOR-2, and then we have several of the bispecifics right in the second line plus setting. And I think those studies collectively is going to really be very impactful for us to see the readout and then again, have the optionality for patients with different modalities. But then the question about sequencing again, it's going to pop up again. It's going to pop up.

Dr. Small [21:13]  It’s going to pop up again. It’s going to be a forever question. Which is not a bad thing, right? More tools

Dr.  Gharibo [21:18]  But, tons of exciting future data in the next one to two years that's going to potentially change the treatment landscape in early relapse. 

Dr. Mikhael [21:30]  I mean, I think similarly to me, I think it's the 202 of a lot of these 101 therapies that we've developed, meaning can we now take them to another level? Like you've described the CELMoDs as being sort of the 202, in my mind, of what we've been able to do with immune modulation.  To take it a step further, the next generation of CAR T cell therapies are now being developed that may potentially have as much efficacy as the earlier ones, but actually with even more safety, especially for some of those neurological things that we're challenged with, especially the late effects, similarly with bispecifics going towards bispecifics that don't need step up, that don't need admission, that can be given once a month right off the start. Or even trispecifics that have a greater affinity to the tumor cell and have less offsite effects. So to me, it's hard to pick one exactly, but this whole notion of saying, okay, we've proved in principle that we can immune modulate, we can do a CAR T, we can do a bispecific, we can even some of these small, simple, easily delivered molecules, can we make them even better by providing the same degree, if not higher efficacy with considerably more safety?

I think that will give us the double win of not only providing safer and more effective therapies, but then we'll make it more accessible to others because we ultimately would love to be able to provide these. I mean, I love the idea of an off-the-shelf CAR T. I know that allo CAR T has really struggled for many reasons just from even the technology side of it. But imagine if we could just go to Costco, okay, my wife thinks I'm addicted to Costco, but go to Costco and buy some T-cells. I mean obviously that's not going to happen. But there the point being that instead of going,

Dr. Small [23:10) I thought he was going to say a different type of place, not Costco. 

Dr. Mikhael [23:14]  But instead of having to go through the T-cell collection and the challenges, and Paul mentioned earlier, the delays of all those, I mean we're not quite there yet, but looking into the future, to me that would be so valuable because we have seen the value of an easily delivered off-the-shelf treatment already. And our myeloma patients are older, they often live in more rural areas. Worldwide, we're talking about not just Indonesia, but so many countries where it's so inaccessible that we can't depend on this inordinately complex multi-step inpatient requiring a process that ultimately if we could deliver it more easily, I think it's going to change the world. And I'm thankful for that.

Dr. Richardson [23:56]  Well, I build on that. I'd say we have, just to step back a little bit to say myeloma to quote, my colleague Clif Mo has become a tale of two cities. And what I mean by that is that we are doing great in a significant number of patients, but we mustn't forget this one-third of patients who are either at diagnosis or become functionally high-risk. So this remains a very challenging area, and we need to continue to really deliver therapies. And I love what you said earlier Mecide, about this being the wide open area for new agent development. So I think as we think about this, what I'm really encouraged by Tania is that we have existing options that are already there. We talked earlier about the antibody drug conjugate space. I mean, let's not forget in DREAMM-7, the median overall survival estimate is in excess of three years. It's about three and a half to four. That's comparable to CARTITUDE-4. 

Dr. Small [24:46]  Yes.

Dr.Richardson [24:47]  Please let's not forget that because that is a very simple outpatient strategy

Dr. Small [24:51]  Off the shelf

Dr. Richardson [24:51]  Incorporating one of our old good old war horses, bortezomib, and at the same time an antibody drug conjugate that generates immunogenicity that synergizes with the immunogenicity of proteasome inhibition. And I honestly think that, Joe, you touched on this earlier, that we've got this wealth of opportunities. What I see us doing is refining those combinatorial strategies and having a wealth of opportunity for each individual patient that meets that need. And I think this is so important because at the end of the day, refining the existing toolbox as well as new advances remains such an important structure or strategy because you touched on this earlier, Joe, healthcare jurisdictions are resource-limited.

We have to be aware of what that means. We have to be real about what that means. And so I'm particularly excited by the fact that we've got oral agents, the CELMoDs. I also love some of the existing platforms we have already, the antibody drug conjugates for that matter. I firmly believe in the peptide-drug conjugate concept. I think alkylators matter. I think we've got existing small molecules. We've got p300 inhibitors, all sorts of things. KRA S inhibitors. We've got an incredible wealth of science that's going to inform us going forward. So I love the idea of the immune therapies and getting better CAR Ts that are truly miraculous. I also think the bispecifics are going from strength to the strength and the trispecifics the same. But please guys, it's all hands to the pumps. Because that's, I think what we must have for our patients above all, and to meet the challenge of what myeloma really is.

Section: Shifting Perspectives: Retiring Outdated Myeloma Beliefs

Dr. Small [26:26]  I'm going to do a quick round-robin.

Dr. Richardson [26:28]  Yeah, of course. 

Dr. Small [26:28]  Starting with you. What is, I guess one of the old beliefs of multiple myeloma, old dogma, of multiple myeloma that needs to be retired?

Dr. Richardson [26:39]  A retired concept in myeloma is I think what I would call a therapeutic parsimony. What that means is in a frail, elderly patient who's very sick, you can do a monotherapy or a BiTE or a dual treatment, but you mustn't give them a triplet or you mustn't give them a quad. I think that's a misunderstanding. I think the construct is that you use components of each at much lower doses to generate more. So I would love Joe and Mecide’s view on this because it's a complicated, complex concept, but this idea that the frailer, older patient can only tolerate two drugs or even just one recognizing that obviously has to be tailored, but the reality is actually morbidity and mortality associated with disease can be grossly underestimated and misunderstood. It can be seen. You have a patient who literally three months before was golfing, swimming, and everything. They come in, they're in their eighties, they're disabled by their disease, they're deemed to be frail,

Therefore, we’re therapeutically cautious. I think that's an old dogma that I think we need to rethink because we are not giving chemotherapy. We're giving targeted biological therapy. And literally you've got the synergy of the army, the navy, the Air Force, the Marines, the Coast Guard, and the special forces. That means you don't just use one arm, you use 'em all together.  So is that, I hope that's interesting, but that's kind of what I would think of. I was just going to say the same thing, Paul. There's an age prejudice. Once they hit a certain age, if it's 70 or 75, there's this notion that those individuals may not tolerate more combination therapies. So even being referred to treatments like CAR T therapies. Yeah, exactly.

Dr. Gharibo [28:29]  And to your point, there's a thoughtful approach to how you can do it as a step wide fashion. Maybe you start up with three drugs and then you add your fourth one. But I think every patient should have or at least be given that optionality and then it being a shared decision-making. And you can always pause and stop and redirect depending on how the patient's journey goes with those initiation of treatment.

Dr. Mikhael [28:54) Three words. Down with dex. I had the privilege of writing an editorial with the incredible nurse practitioner that I work with. And it was in response to as an editorial that was accompanied in Blood by the article, the main article that Rahul Banerjee, one of my mentees, my incredible doctor up in Seattle, wrote where they looked at two upfront SWOG studies and compared the outcomes of patients who had reduced their dose of dexamethasone versus those that did not and did not show a difference in their outcome.

So the dogma has been, you'll take the dex and you'll like it, right? And I think, that dogma is being broken and very pragmatically for clinicians listening in, instead of saying, we're going to give 40 milligrams every week indefinitely. And going back, of course it was a patient, actually a patient at the IMF, Mike Katz who convinced Vincent Raj Kumar and the ECOG clinical trial community to say, can't you do a study with less dexamethasone? And that's where we went from high-dose dex, which was 12 out of 28 days of 40 milligrams to low-dose dex of 40 milligrams once a week. We're the only people on the planet that would consider 40 milligrams of dexamethasone once a week to be low-dose, right? So what I'm saying is we need to be moving to even lower, if not optimal dosing of Dex.

We love dex because dex has an anti-myeloma effect. Dex reduces infusion or administration reactions. Dex reduces nausea and dex reduces pain. Most of the primary effect of that is within the first cycle or two. And then we go down with dex, we dial it down over the subsequent few months and so that patients can be off of it at four to six months after they've started. I think we're going to break that old stigma that it's dex forever and now it's down with dex that we only give for the first few cycles.

Dr. Richardson [31:02]  I think, Joe, if I just add one little vignette to that, I think it's a beautifully said, and I think the other thing to remember for our clinicians listening is don't forget the value, if you've got someone who's getting a lot of psychoemotional difficulties with even the lowest doses of steroid, be it dexamethasone, never forget methylprednisolone, solumedrol, which does not cross the blood-brain barrier. And that can be a very useful substitute because essentially that emotional piece, which you have to ask the spouse about, not the patient, because they do not have insight, typically, you have to say, how is he or she doing? And you get the truth here and the hypothesis here. The fact is that solumedrol, I've found a very useful tool to avoid that blood-brain barrier issue and just a vignette for the clinicians because it's sometimes underappreciated and it can make a difference.

Dr. Small [31:48]  Listen with this, thank you so much for an intriguing and engaging conversation. This was fun. Dare I say one of the more fun ones that I've had.

Dr. Mikhael  [31:57]  Of course it was. 

Dr. Small [31:58]  It was. And I mean, again, just thank you for this dialogue, for this unfiltered dialogue, for this bold conversation, for pushing the limits on how we're thinking. And I'm sure those listening will take away a lot from this. Section: Closing Thoughts: Who Are We Fighting for in Multiple Myeloma? And before I end, I usually ask people, and this to me is one of the most important pieces. Who are you fighting for? And I'll start with you, Mecide.

Dr. Gharibo [32:25]  I’m fighting for patients today, patients in the future. To me, any incremental improvement in outcomes is what I'm fighting for and for that goal of a future cure in myeloma.

Dr. Mikhael [32:43]  It's hard to top that of course. I get very close to my patients and I love that. I think that's maybe another modality that we broken is that we have to have this distance. I mean, yes, there is a professional relationship, but I love getting very close to my patients and to me it's such a privilege. And so obviously we ultimately fight for them. And Paul and I have reached stages of our career where I'm also fighting for that next generation of myeloma doctors because I want them to succeed. I am happy to step into the background to let these next generations come. They are brilliant. Despite what we might think about this next gen, we have some brilliant and highly motivated physicians from across the planet because I want to not just fight for my patients, I want to fight for the patients across the planet. And that’s the IMF, of course, the international component. There are so many people today not being diagnosed and not being treated appropriately on this planet that I really think we have the opportunity, if we can culture the right mentorship in our junior faculty around the world, to have even a greater impact, more than what I or one person could ever do, that we can do in a combination way, obviously in a way altogether.

Dr. Richardson [33:56]  I think beautifully said by both Mecide and Joe, I think that our patients above and all, and I've always felt best research always puts the patient first. And by doing that, you can really not, you don't lose your path. I think you're so right, Joe. Our teams are everything. And that team doesn't just include my physician, colleagues who I'm privileged to work with, but also everyone in our team. We're very nurse strong, we're very clinical research coordinator, strong. We build a culture of working together at every level so that everybody feels truly valued. And I think that kind of approach to our research and to our clinical practice and to our patients continues to really deliver. And one thing I do feel passionately about and very strongly about given events of the summer has been the importance of us in partnership with our pharma colleagues. Because ultimately a drug approved means a drug helps a patient.

Dr. Small [34:47]   That's right. And one of the things, to your point earlier, we talk about here in the show, and part of the tagline is patient driven science, where the patients are the ones driving our science. And we can't forget. That's why we are here. That is our why, our universal why, and we all have to hold hands. So whether it's in the academic centers, the community, the regulators, the payers, the pharma company, we have to come together to hold hands. And you guys have already broken the ceiling, topped what we thought could be possible. Imagine if we come together even stronger to hold hand and how much further we can push. So again, thank you all for all the work you've done for patients, all the work you've done for the community, all the work you've done overall for healthcare. And thank you for being here today.

Dr. Richardson [35:31]  Thank you. Thank you very much. Thank you for having us, Tania.

About the experts

Dr. Paul Richardson
 

Dr. Paul Richardson is an internationally recognized visionary in hematology and oncology whose trailblazing research at Dana-Farber Cancer Institute and Harvard Medical School has driven therapeutic revolutions in multiple myeloma, transforming patient outcomes and defining today’s standards of care. In addition to his involvement in the approval of nearly every major therapy for the disease over the past two decades, he is also one of the most prolific and cited experts in the field, with nearly 500 original articles and 400 reviews.

Dr. Richardson is a paid consultant for BMS.

Dr. Joseph Mikhael
 

Dr. Joseph Mikhael has revolutionized and broadened access to world-class myeloma care globally through his pioneering leadership at TGen and the International Myeloma Foundation and as principal investigator of numerous groundbreaking clinical trials, setting new benchmarks in innovation, impact and equity. Celebrated as a dynamic champion for underserved communities, an award-winning educator and a masterful communicator, Dr. Mikhael has authored over 150 influential scientific articles and was recently recognized among America’s Top 100 Doctors for his transformational contributions to the field.

Dr. Mikhael was not compensated for his participation.

Dr. Mecide Gharibo
 

Dr. Mecide Gharibo is an innovative hematology leader whose passion for transforming patient care extends from academic clinical expertise at Rutgers Cancer Institute to launching breakthrough therapies as global head of hematology at Bristol Myers Squibb. Renowned for advancing life-saving treatments and optimizing patient access, Dr. Gharibo’s clinical excellence and senior pharmaceutical leadership have fueled medical innovation and set new standards for care through a proven record of successful therapy approvals.

Dr. Gharibo is an employee of BMS.

Dr. Small [00:00]  The script has changed. Colorectal cancer used to be the 50 and up disease. Today it's surging in young adults and devastating multiple communities. But it's not just about who's getting sick. We're now unraveling the root cause drivers.

Dr. Lenz [00:20] We identified the gene and this gene is highly predictive and prognostic for outcome.

Dr. Small [00:24] And rethinking what true prevention can look like.

Dr. Lenz [00:27] Colon cancer is the most preventable cancer of all

Dr. Small [00:30] Today. We define what that is now and into the future,

Dr. Lenz [00:35] And the future will lie in the tumor microenvironment as targets for novel treatment.

Dr. Small [00:40] It is my honor to welcome a true pioneer of colorectal cancer care, Dr. Heinz-Josef Lenz. He's led one of the largest translational colorectal cancer research programs and defined the molecular subtypes guiding today's therapy. There's no one better to lead us into the next frontier. I'm Dr. Tania Small, and this is Doctors Unscripted. Now let's get started.

Dr. Small [00:40]  So welcome, Dr. Lenz to Doctors Unscripted.

Dr. Lenz [01:14] Thank you very much for having me. I'm very excited about today's show and to really talk about colorectal cancer.

Dr. Small [01:21] Well, in that case, I ask the hardest question first.

Dr. Lenz [01:24] Okay.

Dr. Small [01:25] Do you remember when you were in med school and you knew you could predict where other people, what other people are going to become? So your professors or colleagues, what specialty did they expect you to go into and how did you get into GI Oncology?

Dr. Lenz [01:42] I had no idea I would be an oncologist. I liked a lot of different areas. I thought I would end up as an internist or general practitioner in the village I grew up. That was actually how I started. And during medical school you have to study a lot. You don't see the world. So, I decided doing to hold medical school to do all my rotations abroad. I ended up in a very interesting ward on hepatology in University of Vienna and next to the ward was an outpatient clinic and it was a breast cancer clinic. And I started going there and I knew this is the right thing for me because the patients were extremely kind. You developed a relationship, you talked, you got to know the patient and their families. So before I decided to go really in oncology, I said I will do a rotation in the US—three months oncology at George Washington University. And then I decide to choose oncology and I had a blast. And after that I applied only for hematology/oncology fellowships. But, the university I choose, University of Tübingen in the south of Germany, the professor was very famous. He discovered glucose six phosphate dehydrogenase. In the SHA family.

Dr. Small [03:15] So you went from that to GI Oncology? So tell me more.

Dr. Lenz [03:20] I was basically trained as a hematologist in oncology. There was very little, so I knew I wanted to always do some bench research. And the professor who was at Tübingen, the boss, I worked on his private ward, I think he was very happy with my clinical service. So I went to him and saying, I want to do some research in the lab science. He says, you will not succeed. You're very good clinically you should do continue what you do good. 

And I thought, I don't believe him. So I wrote a grant to the German National Science Foundation. I got the money for two years. I was all set up to go to Sloan Kettering and about three months before my friend who was still in the lab said, don't go to Sloan Kettering. Go to USC because there is a laboratory which develops novel technologies. This was in 1990. They were already doing PCRs on genes from endoscopic biopsies. So I contacted them, read their research, and I knew this is the wave for me to go. Now we started doing this research on colon cancer and gastric cancer samples and that was for me the beginning to work on GI Oncology

Dr. Small [04:48] I’m going to go into a question that everyone is asking now, and that is early onset colorectal cancer. And you look at the data, if you look back in what, 1995, what about 11% of patients under 55 were diagnosed? Now you're up to 20%.

Dr. Lenz [05:05] Yes.

Dr. Small [05:06] Besides I guess more the sensitivity of diagnosis, what is it? Is it biology? Is it environmental? What is causing this increase?

Dr. Lenz [05:16] Yeah, I think this is still a mystery. There are a lot of research groups around the world working on it because it's not genetic or we know this is not a genetic predisposition leading to early onset because when you have a 20-year-old or 25-year-old or an 80-year-old patient coming in, you think it is a family inheritance, but it's not. And it's very interesting because certain ethnic groups have different onsets of early onsets. So Hispanics are by far the highest early onset incidents from any ethnic groups. Our patient population in LA County is 90% Hispanic. So we see that. We saw that many years ago that we already had young Hispanic patients with colon cancer. No one else saw and we didn't know why. We did always genetic testing. It was not it. Then we thought the tumors developing in young would be different, but there are no big differences.

Very small one would not explain the early onset. Now, one of the interesting aspects is that the patients I see in the early twenties look not high risk. They're not obese, they're often high school athletes. They are fit. 

They're not fitting a risk profile which we usually associate with colon cancer. There is a question if metabolic pathways are involved, the glucose and fructose metabolism in the colon is a very unique pathway, but it has not been proven yet. So we are looking is metabolic pathways responsible for early onset? Now there are also very interesting and new data because when it's not genetic, can it be epigenetic? Meaning there are no mutations, no genetic inheritance, but there are ways which can silence genes which may have the same effect as mutation. Now, epigenetic regulation could be done by outside factors or by behavior, by food, by exposures. And there are a lot of new risk features we now know. Very obvious is food and exercise and so on, but also plastic material.

Dr. Small [07:40] Is there a way to measure to see if there's something unique about that population? Was there a unique difference?

Dr. Lenz [07:45] So we have to be very unique to look, can we test for epigenetic regulation? And there are tests available called methylation. Methylation was not in pursuit even the data in the tumor genome atlas, but there are very little. So we are now doing a large study, the biggest ever done on whole genome sequencing, whole transcriptome analysis, DNA methylation from over 500 patients with Hispanic. We already have 260 and a third of us of these patients are early onset. We can estimate the exposure from environmental factors including PFAS, including work environment, inverting air pollution and so on. And we will capture with them with surveys and questionnaires, what they do, what they eat, how much they eat, how much exercise they do. There are all this information captured on exposure environment as well as the potential outside way in order the family history. Or when you look at coronary artery disease, we know when the parents have it, even the kids are not risk and obese at higher risk. That is considered epigenetic. So I think we're getting very close to better understand because this is an epidemic.

Dr. Small [09:08] So there's an increased risk in Hispanics, but also I was looking Native Americans as well as African-Americans are also disproportionately increasing with colorectal cancer. Do we know any reason why? Is it biology in that case or environmental?

Dr. Lenz [09:23] I think we already knew when we looked at all the different ethnic groups for patients with disease, the African Americans usually have the poorest prognosis and there are some genetic differences when they develop colon cancer compared to the white or the Asians because the Asians usually do the best followed by the Hispanics, followed by the Caucasians or whites followed by the African Americans. So we know there are biological differences. They have often genes in their tumor, which is more difficult to treat. They have less response to treatment, they have differential response to immunotherapy. So there are biological differences. I think at the end of the day, the goal of personalized medicine, forget the ethnicities, you need to treat individually the tumor, doesn't matter who has it that you have the most optimized treatment. For early onset, we don't know what the treatment would be or now there is a little bit move on the epigenetic regulation because the group in China who is very well established scientifically, they have tested a drug which modulates epigenetic regulation and combined it with immunotherapy and combined it with 

anti-VEGF treatment and showed incredible response rate. This is for me a proof that going down that road to change the genetic and epigenetic regulation with immunotherapy and anti-VEGF or bevacizumab treatment is, and this is an MSS tumors? Yes.

Dr. Small [11:03] Really?

Dr. Lenz [11:04] Yes. Now what we already know, the methylation stages of African-Americans versus Hispanic versus white is completely different. I mean it's almost black and white. You understand. Completely different. Can this explain the differential outcome? We don't know yet. We hopefully see it, but this is for the first time we do a methylation signature, which has not been done in any major patient population.

Dr. Small [11:32] So if we look at clusters, do you think we'll see a similar response beyond ethnicity?

Dr. Lenz [11:38] So I think if all this environmental factor really go through the epigenetic regulation, we would be able to identify these patients by the methylation signature. So I think when we find this link, it doesn't matter anymore how they got it. It is

Dr. Small [11:56] As long as they have it. Yes, yes. 

Dr. Small [12:04] So we know that. Now we've obviously lowered the age in terms of when one should get a colonoscopy. I had to get mine earlier than I planned, but now we looked at the data in terms of colonoscopy, what it’s like 90% sensitivity rate as well as specificity versus a stool DNA sample with Cologuard, I'm looking at the sensitivities about what 90% as well. However, the specificity is a little less. At what point do we say that it's okay to use Cologuard or those type of stool DNA approaches versus a colonoscopy?

Dr. Lenz [12:43] So I think first of all, colon cancer is the most preventable cancer of all because you have precursors, you have the polyps. The development of colon cancer takes five to 10 years, which is the reason the interval of the colonoscopy is 10 years because it takes so long. Or the exception is MSI high, they can develop within a year. That's the reason they get it yearly. So because you have all these precursors, you can prevent colon cancer a hundred percent today if they do colonoscopies. Because of the early onset we get down to 45, I still don't think this is…

Dr. Small [13:18] You think we need to go earlier?

Dr. Lenz [13:19] Yeah. And colonoscopy at the moment is the gold standard. Okay. Now there are certain populations, groups, religious issues to see, I don't want to do a colonoscopy because just the thought of that would be for them enough to say I will not do that.

Dr. Small [13:40] By the way, that means everyone here please get your colonoscopies.

Dr. Lenz [13:43] That's correct. We will do it afterwards. Okay. Is that the difficulty and that they should do like a Cologuard or something else, but there is a problem or because the specificity is not there and the reason is that polyps already have mutations which can mimic colon cancer. So that's the reason when you have a positive test, you need a colonoscopy. There's no way around it. It's a compromise. Even not the best. But because you miss, I think it's better than to do nothing. I try always to do colonoscopy because it's actually not so bad, you know? I mean the first thing is the prep. Prep. The prep…

Dr. Small [14:30] The prep. The prep is the worst.

Dr. Lenz [14:32] The colonoscopy is not. The prep is like the worst. Yes. I think they should develop something better. I mean we're flying to the moon and cannot have a good colon prep.

Dr. Small [14:40] Exactly.

Dr. Lenz [14:41] I mean…

Dr. Small [14:41] And then now even moving into colonoscopy and AI assisted colonoscopy, now that I'm excited about, I think they said there's about a 10 to 20% increase in pickup in adenomas. If that's the case, why have we not done more of it? Why are most academic centers not using AI guide?

Dr. Lenz [15:00] I think the AI system is not there yet because the intraluminal processes like a polyp or cancer are not easy to see on any imaging. That's the reason CT scan will not help. CT scan cannot detect colon cancer. So with AI, you need still the clearance, you need still the whole prep. Okay,

Dr. Small [15:21] The wonderful prep,

Dr. Lenz [15:22] Yes. So it does not change. And then the flat tumors you may not find and identify. So I think if AI doesn't change dramatically, I don't think that's a good substitute.

Dr. Small [15:41] So we know that with ctDNA, we're able to now detect these molecular, I mean even relapse months before imaging. And based on DYNAMIC we saw that you can actually use CT guided MRD to determine whether you're going to escalate or deescalate treatment. I guess at what point do we really start implementing ctDNA-based treatment decisions?

Dr. Lenz [16:06] I do it already. 

Dr. Small [16:07] You do, really? Actually this morning I was on a call with a physician. They saw a molecular relapse based on ctDNA imaging was still stable. So, there's still a lot of debate whether or not they trust or should you wait for imaging?

Dr. Lenz [16:22] Yes. So I think it's probably not as straightforward as it sounds, I think I do liquid biopsy for MRD minimal residual disease on all my patients after surgery, not only from the primary tumor but also resection of metastatic disease. Now in the setting of a primary tumor or when you get a positive liquid biopsy test, we do not know what the time interval is from a positive test to see the disease developed on imaging or visible on imaging. It could be three months, six months, nine months, 10 months. So the argument is would you do treatment early when 10 months nothing is visible and would you create and expose a patient to chemo he may not need at least as long. Now the argument against it that all the studies we have seen is that the conversion of a positive liquid biopsy to a negative one with chemo changes the prognostic outcome of this patient into a situation where it is the same prognosis as it would have been negative. So we know that there is a potential benefit, but there is always argument when do you start treatment with a positive or do you seek increasing? Now there's also one lesson we learned about 10 to 15% of liquid biopsy for MRD is false positive. So you don't want to treat a false positive. So when the number is low for the ctDNA count, I check it again four weeks later to make sure this is for real positive and it's going up. And then I discuss with the patient because there is no consensus that we should treat. Now there are clinical trials developed which look for MRD positive colon cancers after resection of the primary tumor to treat with novel treatments. What was a little bit of setback was at ASCO in the positive deescalation of treatment did not make a difference. The chemo is effective but not escalating because what do we call a positive liquid biopsy is this metastatic disease, but you cannot see it. We know that small minimal residual disease requires different treatments. When you look at the adjuvant setting, all the new drugs have failed. FOLFOX is the standard of care. They try to add bevacizumab, they add cetuximab, they try to do FOLFIRI, all failed in the adjuvant setting. Meaning if you have really not well established tumor volume, these treatments do not work as well. Now you and I know ATOMIC was presented, this is the first trial for MSI high in the adjuvant setting. But there are big problems with this trial, not with the trial itself, but the trial was developed before we had the IDEA trial, before we know about neoadjuvant immunotherapy for MSI high. So I think a lot of my colleagues including me struggle what to do in the adjuvant setting for MSI high. And I think the NCCN has also issues how to put it that we don't overtreat patients for wrong reason because these patients are resistant to chemo and here we would give six months. So I think however, the proof of principle is that the immuno component seemed to work in the adjuvant setting, but there is no doubt, I think that's the wrong approach. It has to be in the neoadjuvant setting.

Dr. Small [20:15] So let's talk about that and I want to get your thoughts on organ sparing type of treatment for neoadjuvant.

Dr. Lenz [20:19] I think there is a paradigm change.

Dr. Small [20:21] Yes.

Dr. Lenz [20:22] Okay. And it's happening everywhere. Okay. Because the first start was that with a chemo radiation chemo prior to surgery, we are now able to spare sphincter and preserving technologies. And this is amazing. But the future is beyond chemo and chemo radiation. And I think we will talk a little bit about MSI high, but we should also include MSS because in my opinion, everything will change for colorectal and colon cancer moving in the neoadjuvant setting. And not only MSI high but also MSS. The combination of immune checkpoint inhibitor with CTLA-4 and other immune checkpoint inhibitor will in the future become standard of care. With its efficacy, we will do less surgery, less radiation, and less chemotherapy. The challenges are can be stage a colon cancer, not imaging, but we colonoscopy. But this is all possible and feasible. We just need a better immune combination. Everyone will get neoadjuvant immuno and then evaluate if we need surgery or if we need radiation or we need chemotherapy. And the patients with rectal cancer have the biggest benefits because they don't need a really stoma placement, that can sphincter sparing. Now I think this is even underrated because when you don't need radiation of the pelvis, all your sexual function for the young patients is a big thing.

Dr. Small [22:04] Yes. Maybe you could take the listener through what the side effect is when you have surgery plus radiation.

Dr. Lenz [22:12] I think there is no doubt that radiation leaves scars or in the area of the radiation field, which includes the rectum, includes the vagina, includes the bladder. So you can have all irritation in these different organs massively lasting for a long, long time. So you don't want to do that if you really don't need to. And I think we need to learn better in order to really avoid radiation treatment. Now chemo is a little bit easier because you get sick, but it's getting better and has not often so long-lasting lifelong side effects. But I'm very optimistic with a new immunotherapy combination. We will replace many of these treatments, which is considered standard of care. We just need to advance.

Dr. Small [23:04] And the data are great for MSI high. Let me ask you, MSS, where do you think it's going in terms of neoadjuvant therapy?

Dr. Lenz [23:12] I think this will be possible personally. When you look at the metastatic refractory setting, look at the BOT/BOL data or the Adagene data, they see in extrahepatic disease, 40% response rate. You show me new adjuvant chemo radiation with 44%. So what I'm saying is it's not the end, but when this is used earlier, not in refractory setting, the efficacy should go up, not down

Dr. Small [23:45] And many people when they think about colorectal cancer, they don't realize how heterogeneous it is. And even learning this and understanding that the differences we're developing better targets. Again, if you think through immunotherapy, you saw the data, initially you'd look at a six month PFS, now you're looking at greater than 50-month progression-free survival. Tremendous.

Dr. Lenz [24:10] Yes. So I think we have come a long way or we have now molecular-defined subgroup where the treatment has changed, including since ASCO. We have the HER2 with the data of HER2-targeted treatments. So I think we have exhausted the targets within the tumor we've mentioned. I think the future will come from targeting metabolic pathways. All the, when you think about all this new information, exercise, and diet, it's a metabolic pathway. So what do we need to do to mimic what we achieve with this diets and exercise, or what can we modulate in the patient or impacting indirectly than the tumor and the sensitivity? I think that the immunotherapy basically enables the microenvironment to attack the cancer. It's not attacking directly. It goes to the immune cells, which are part of the tumor microenvironment. I think that we are only starting to understand where the resistant mechanisms are. We don't even know what the immunesuppressive natures are in the MSS tumors in liver. There are a lot of hypotheses, but we really don't know. I think these are the areas which would make the big impact because 90, 95% are MSS tumors. I think the biggest change in our view is can some of these treatments or some of these pathway we identify being used to prevent it in the first place, the treatment is very good, but this needs to move into

Dr. Small [26:04] Prevention.

Dr. Lenz [26:05] So do we will have a concept of diet and exercise. And I think that some people need medications, and I don't mean drugs, but some targeted medication to enhance that effect and prevent it. And when we identify patients at risk, we can easily identify if this works or not. So I think that in this situation that targeting metabolic pathways, targeting structures, we enhance or potentially inhibit development of cancer will be the next success. It will not be broccoli. It'll be not just fiber diet that is not good enough. This does not really reach the tumor microenvironment. Or it is local, it creates a little bit activity and make the bowel move faster and more often where you have less exposure. But we need something which really interferes with metabolic pathways or the changes of the tumor microenvironment really early on. There is the NIH network called HTAN, which I think is absolutely phenomenal because they look not at the tumor, they look at the normal tissues which will develop the tumor. What are the earliest changes? Molecular changes, pathway changes in order to develop drugs to prevent the sequence of pre-cancerous lesion going into cancerous lesion.

Dr. Small [27:42] So then let me even take you to treatment.

Dr. Lenz [27:45] Yes.

Dr. Small [27:46] Now when you and I spoke on the phone, one of the things you were adamant about was sequencing. You have a window of opportunity for maximum tumor vulnerability. Maybe you could take us through why sequencing is important, and what do you recommend?

Dr. Lenz [27:59] I was always convinced that the sequence of treatments you choose is absolutely critical for the outcome. You cannot save a successful treatment for later because sometimes we start a little bit here and then when we really need it.

Dr. Small [28:16] You want to reserve it.

Dr. Lenz [28:17] Yes, when you really need it.

Dr. Small [28:18] Yes.

Dr. Lenz [28:19] That does not work. The treatment pressure on tumors changes the biological makeup of the tumors which are resistant in a dramatic, specific way. And the sensitivity changes usually for the worst, or when you do first-line treatment, it's about 50, 60% in second-line, 10 to 20 and then to two or three. This is not because you do the wrong treatment, is that the tumors have cross-resistant pathways. So you need to make sure that you do the best treatment first. And we have learned that now recently in BREAKWATER, we know BAF mutant tumors have usually overall survival median about 12 to 15 months. And that's actually the standard of care arm. Now when you do the encorafenib cetuximab chemo, it's 30 months. It's as good as any normal tumor without this bad mutation. So this is the proof that you need always to give the first treatment and not save something for later. So that's one important lesson. Now, what I think is very unique, because we will also talk about immunotherapy, is that immunotherapy plays a significant impact on subsequent treatments, because immunotherapy remodels and changes the tumor microenvironment. And I know we will talk probably about it that we have almost exhausted our identification of targets on the tumor by sequencing to the death for certain mutations in the tumor and have completely neglected the microenvironment. 

Dr. Small [30:15] So maybe you could give an overarching view on the tumor microenvironment, what that is and why it's important, and then how do we leverage it to actually attack the tumor.

Dr. Lenz [30:25] So I think in the beginning of our research we were trying to avoid to have any normal cell or from the tumor in our sequencing tissue because it would have diluted it. We didn't realize that these cells are all very important. The tumor microenvironment depend where you are, the liver, the lung, the bone, the gut. When I throw you in the water, you're not still the same person, but your activity is different. 

Dr. Small [30:51] Yes.

Dr. Lenz [30:52] And the tumors is the same. When you throw it in a different environment. It will drive or drive faster or not as fast. But we now realize that there is significant communication networks in the microenvironment is blood vessels, there are fibroblasts, there are nerves, and there are immune cells. All these communicate directly with the tumor cells and with each other. It is an incredible network. Okay. So interfering with that will be the future of new treatments. So the cancer-associated fibroblasts play a big role in controlling inflammation and immune cell trafficking. The blood vessels are absolutely critical for the activation of certain immune cells. The nerves talk to the blood vessels, the nerves talk to the immune cells. So if we understand that communication network and how we interrupt it, that will be a new treatment option. And I'm convinced that will happen, because we now have the capacity to dissect out the microenvironment and better understand the role of these different functions. Now we all talked about the brain-gut connection. It's all nerves talking to each other in order to do the inflammation and do the blood vessel formation and so on. So it comes together at some point. But the microenvironment is the new frontier for cancer research, not the tumor.

Dr. Small [32:29] So this whole, I guess, gut-brain axis, a big discussion has been microbiomes and how do we modulate the microbiome since it is part of the tumor microenvironment. What are your thoughts on that and how do we do it well?

Dr. Lenz [32:42] So, I think there is, we are just a little bit scratching the surface on understanding what the microbiota in the gut does. Now we know when you have bad bacteria that they create a lot of inflammation, and inflammation is not good. Or when you have chronic inflammation, you can cause eventually cancer. Patients with ongoing colitis develop that. We know that very well. We have even identified the bacteria which are the worst one to create inflammation. The fusobacteria. And the fusobacteria were shown that they're not only sit in the gut, they can travel into the tumor, and these fusobacteria, high check cancer cells and travel to the liver. So they're part of the metastatic spread.

Dr. Small [33:35] Interesting.

Dr. Lenz [33:36] They're looked in a mouse model where this happened and then they're treated with antibiotics, and the tumors in the liver stopped growing. So I think it's all a little bit simplified. I think it's much more complicated because we tend to believe and we have bad bacteria, they're responsible for everything. Personally, I don't think that's the major story about it. Bacteria are natural and we all need, we have four or five pounds of bacteria in our gut. It’s not little, but these bacteria not only in the gut, we are dependent on them. Without them we would not survive. But some of these bacteria are also potentially communicating with cancer cells and they may in the tumor and we have some data showing that. And this bacteria communicate again in a very unique way with the tumor cells, but also the tumor microenvironment. We actually have started a collaboration with a microbiologist who does on focus on core cultures of bacteria with cancer cells. And I was shocked how sophisticated this bacteria communicate with cancer cells to two major pathways. One is metabolic and one is neurotransmitter. Yes, I had the same look on my face, thinking bacteria produce neurotransmitter? So there is very unique things. I think these are all things we have never thought about and just going to develop. So when you think about it, that neurotransmitter play a role, there are no drugs targeting neurotransmitter. Now we have done over the last probably four or five years, incredible research on neurotransmitter and tumors. There was a publication out in Cell many years ago. Because it was in a pancreas cancer model, and this pancreas cancer was not able to produce an essential amino acid. So it triggered a nerve cell from the spinal root to grow an exon into the tumor to produce this essential amino acid.

Dr. Small [35:59] So let me ask you this question. So, how do we then address it?

Dr. Lenz [36:02] So we don't know fully what these drugs do. So we did a very easy experiment, or we gave a mouse with colon cancer, dopamine like we treat Parkinson and the tumors decreased their growth in a significant way.

Dr. Small [36:20] Wait, sorry, you gave it dopamine and it decreased

Dr. Lenz [36:23] Yes.

Dr. Small [36:23] So we want to increase the release.

Dr. Lenz [36:26] Remember Parkinson is a lack of dopamine. We gave the dopamine like we treat Parkinson's medication, we gave medications which change the dopamine metabolic pathway and they have an antitumor effect. It doesn't melt away, but it is almost the opposite that you would think.

Dr. Small [36:47] But that's interesting. So basically if we modulate the release of dopamine is basically what we're saying, we may be able to actually help with

Dr. Lenz [36:57] I think right now there are potential values for treatment. But I think where this plays a big role is for prevention.

Dr. Small [37:05] Yeah. Yeah.

Dr. Lenz [37:07]  When we can understand the regulation of neurotransmitter, if Parkinson's patient or neurogenerative disease, it's not all dopamine, it's really protective. If we can create a pathway which mimics this without the side effects, we would prevent colon cancer. In the moment we are looking for a better target in the neurotransmitter network in order to have more effect. And we identified a overarching gene. We are working on this, but I think this is the frontier. This is where I think the future may have more promise than the classical treatments we are giving now, because at the end of the day, metastatic disease still has a median survival of 10% after five years. We need to do something different. Now I think what is very important for colon cancer discussion is we talked about always the best treatment first. Because if you shrink colon cancer metastases and it comes to a resectable stage, there is a curative attempt. You can cure some of these patients. That's not possible in breast cancer. Or if you're metastatic, you can't do anything anymore. In colon, you can. So the intervention in identifying to have a shrinkage or a significant shrinkage and you can resect, you see big differences in outcome.

Dr. Small [38:30] A lot of data have recently come out about fecal transplants, and we're seeing that, with fecal transplant, you have increased, you can have increased sensitivity to some therapies. What is your take on fecal transplant as you're talking about the whole tumor microenvironment and microbiome?

Dr. Lenz [38:50] So I don't use it in my clinic, but it's used for colitis patients very successfully. But I'm fully convinced I put all my patients on the probiotics and everybody says, what should I take? Or I don't need it. I eat yogurt. And it's interesting, the cheap yogurt has one bacteria. The middle yogurt has about two or three, and the expensive yogurts have six. When you count, you look at the ingredients, you see the diversity and the frequency of your acidophilus, the bifido, the thermophiles, and so on. So I recommend a probiotics which has at least 10 different species.

Dr. Small [39:34] Okay.

Dr. Lenz [39:34] To really look for calming down and controlling the inflammatory environment. So all my patients are on probiotics, with a big, high impact. It's not the 20 billion, it's the diversity which counts.

Dr. Small [39:47] Ah,

Dr. Lenz [39:48] Okay.

Dr. Small [39:49] Because I saw one with just one. To your point, even some 

Dr. Lenz [39:51] Don’t buy a yogurt with one.

Dr. Small [39:52] Now I'm learning that.

Dr. Lenz [39:54] Yes,

Dr. Small [39:56] It tastes good, though.

Dr. Lenz [39:57] No, the other one tastes much better. 

Dr. Small [40:05] So I know that challenge as well as SWOG. This ASCO’s presented data on exercise and eating anti-inflammatory diets.

Dr. Lenz [40:16] So interestingly, all these factors—inflammatory, anti-inflammatory diet, exercise—is all the microenvironment. You change not the tumor, but you change where the tumors, what environment the tumor lives, what the host is changing. So I'm a big believer. So we have now started with that. We actually give our patients information on anti-inflammatory diet. I tell all my patients not to eat red meat, to avoid refined sugars, to supplement diet with vitamin D3, to exercise, drink coffee, no cream tea. We try to guide them through in order to have a framework. I think knowing that this particular, the extent of exercise is not known or I think it's important that all my patients do some exercise. I say 20 minutes, 30 minutes a day is good. Or you can also not overdo it depending on chemo. You cannot run around and do a half-marathon when you get chemo, but you can't walk around the block twice a day, to walk about three, four miles. So I try to make sure that they do that. It's also good to get out and see something. Have sun. This is all important for your rhythm. I think for the food it's a little bit more complicated.

Dr. Small [41:42] Well, I've noticed many things had to be erased from my diet when it comes to anti-inflammatory.

Dr. Lenz [41:46] So we are working, actually, we have a little team who's working on potentially to have a better understanding what diet and what that would mean for the food you can eat and avoid. But I am a big believer in it because this is what you change the microenvironment. Now I tell you we did an incredible experiment. We work with our specialist, Dr. Cohen, from the school of gerontology. So aging. We took young mice and 1-year-old mice, which was a hard thing to get by. We put the same tumor in the young and old. And we gave them high-fat diet, regular diet and calorie restriction. And we looked at the stool microbiota, we looked at the cytokines in the blood, and we looked at the tumor, and the data are amazing. So young mice, the microbiota is angry, very inflammatory high cytokines. The high fat diet, these mice died within days. When they had calorie restriction, they lived much longer. Much longer. The young ones. The old ones, the stool was much nicer, diverse, not so inflammatory. The cytokines were lower and the diet did not make too much difference. A little bit if you had high-fat diet, a calorie restriction a little bit, but not even compared to young. And some you would have expected it and some you haven't. But then we looked at the tumor and here came the big surprise. The same tumor changed in the old versus the young. The tumor makeup and intratumoral thickening changed.

Dr. Small [43:40] Interesting. Interesting.

Dr. Lenz [43:42] The tumor. So the host,

Dr. Small [43:43] Based on the host

Dr. Lenz [43:44] Changed the tumor. That's what you do with your diet. And we identified the major pathway which changed. We identified the gene. And this gene is highly predictive and prognostic for outcome. So a host can change the tumor. So exercise, food, I'm

Dr. Small [44:04] Critical. Critical.

Dr. Lenz [44:04] In no doubt that it can do it because we can see it.

Dr. Small [44:09] So then in that case, as we think about prevention and those that are predisposed to colorectal cancer, should we be pushing those people to really make sure that they are, their diet is anti-inflammatory diet and all the lists that you

Dr. Lenz [44:24] Yes, absolutely.

Dr. Small [44:26] But, I mean, are people counseling them about this? Because I have not heard a lot about this until after you've been diagnosed.

Dr. Lenz [44:33] Yes. So I think we have always counseled them on healthy diet. We have never had a very specific diet for anti-inflammatory or pro-inflammatory, what to avoid. That's what we are at the moment changing in our counseling. I do the meat and on the alcohol.

Dr. Small [44:51] So if we look at other lifestyle behaviors that resulted in increased risk, curious to see what your lab had discovered.

Dr. Lenz [44:59] Yeah, so I think we have seen and that has been published that certain professions have higher risk, including pilots, night shift nurses, and it becomes very apparent that the disruption of regular night sleep is increasing risk for colon cancer. So the circadian clock, which regulates night and day shifts, is very poorly understood in cancer situations. So knowing that the administration schedule and knowing that certain professions who cannot sleep at night have a higher risk of colon cancer or different outcomes, we started looking at the regulation of the clock. We studied these genes in many phase three clinical trials, including 80405, FIRE-3, and you name it, in thousands of patients, since we have large clinical databases, molecular characterized, and the data were amazing. We were completely blown away because many of these circadian genes predicted efficacy of two targeted drugs, one immune checkpoint inhibitor and one the anti-VEGF bevacizumab-based treatment. We confirmed that in multiple trials. We even confirmed that in a Japanese cohort. So this is for real. So I thought, wow. 

Dr. Small [46:31] Yes.

Dr. Lenz [46:32] So is that an effect on the tumor? Is this effect on the tumor microenvironment? What is it all? So we did very simple tests all. So we knocked out the gene, we overexpressed it, okay. And it changed the growth pattern of the tumor cells dramatically. So at this point I wanted to know more about the mechanism and are there drugs available? And it happened to be that one of the pioneers of circadian clock, Dr. Steve Kay is at USC, and he's a metabolic guy, a plant biologist, nothing with cancer. So I showed him all this data, predictive and outcome and prognostic, and he was saying, oh my god, that is incredible. We should work together because I have a drug which targets the clock. He developed it for metabolic disorders. So after mechanistic knocking it out and knocking it in, we use this drug in our animal models. And combined it with immune checkpoint inhibitors and combine it with bevacizumab. And there was traumatic change in efficacy. So just a very non-toxic drug changed the efficacy of immune checkpoint inhibitor inhibitor significantly and increased the efficacy of bevacizumab I have never seen before. So it is the microenvironment which I think plays a bigger role, but we don't know for sure what the particular targets in the tumor microenvironment is. 

Dr. Small [48:19] I know as we start thinking, wrapping up, there's a couple of things I want to really pick your brain on. Crystal ball. If you look five to 10 years out, where do you think the field is going to go when it comes to colorectal cancer?

Dr. Lenz [48:34] I think we will cure much more patients. We will use less chemo, we'll use less surgery, less radiation treatment. We will optimize immunotherapies in a way that we will use it in most of the majority of the patients. I think that there will be new drugs developed, taking advantage of targets in the tumor microenvironment, which we just start to believe. I think that epigenetic treatments will be part of our treatment strategies, and I'm very optimistic that all this research will hopefully translate into better prevention drugs, which we have not seen. So I think these targets, which are now the new frontier, will hopefully translate into very effective prevention studies and treatments.

Dr. Small [49:22] What are three things you want the listeners to take away after listening to this show?

Dr. Lenz [49:27] First, colon cancer is preventable. Do the screening with any kind of unexplainable symptoms in a young patient. Don't wait because there are too many mistakes done thinking this is hemorrhoids, this is stomach upset and month and month go by without a colonoscopy. Second, do molecular testing on the tumor, if patients develop colon cancer. That will guide the best treatment options. Do it at the time of diagnosis, not later. Because with molecular-defined subgroups, now we have treatment options. We can completely change the outcome, including curative attempts. To miss an MSI high would be a crime, okay, because we can cure these patients. Third is you need to make sure you really watch for the sequence of your treatments. The best treatment first, and the future will lie in the tumor microenvironment as targets for novel treatment or novel treatment combinations. So I did four

Dr. Small [50:32] For the physicians starting out in their career who are now walking into GI oncology. Any advice?

Dr. Lenz [50:39] Yeah, I think listen and don't be shy to ask questions. Be curious, okay. Don't be shy to question decisions or ask why because only that way we find better answers, okay. And I think sometimes people think these are weird ideas and they are actually very interesting and they lead to novel questions. So work with your mentor, work with your professor, reach out to basic scientists, open up that communications. You will be very surprised how much more information you gain and you better understand why you're doing and why certain drugs work. I think sometimes we drown in the clinics because of clinical issues and we need to look beyond what we do, but better understand why this happens, what can be improved. So I think open-minded, listen, look and go to meetings and talk to others, particularly the basic scientists. It's not easy but it's very rewarding.

Dr. Small [51:45] And I remember when you were on the phone with me, you told me that as you were looking and seeing the differences, the question you asked is why? Now

Dr. Lenz [51:53] Yes. Yes.

Dr. Small [51:53] Let’s figure out the why because that's the root of everything.

Dr. Lenz [51:55] And I mean we stumbled really on the night shifts all, but take it from there and go back and thinking because I think what the basic scientists are missing to know what's happening in that clinic, what do we see different? What makes them different in the way? It was so funny because I think we talked on the phone about this. We stumbled on the location right versus left.

Dr. Small [52:21] Yes, yes.

Dr. Lenz [52:22] Okay. Because we had a postdoc and looking and I said, can you check out ER alpha and ER beta in colon because we know premenopausal women have less colon cancer, but only on the right, not on the left. So we started looking at ER beta, which is expressed only in colon, not ER alpha. And sadly we clearly see there is a difference. Postmenopausal woman, you prevent colon cancer on the right, not on the left. So now we knew and checked on the location as a predictive and prognostic marker, and it is, it's all in the guidelines. So the clinical observation follows biology because it's a different disease, midgut versus end gut that explains why the prognosis is different. This explains why certain drugs will not work. So be minded, be curious, ask why. I completely agree.

Dr. Small [53:22] Yeah. My old mentor used to say, there isn't a problem that we can't solve. You have to ask why and then go figure it out.

Dr. Lenz [53:29] I agree.

Dr. Small [53:30] Yeah.

Dr. Lenz [53:31] He's a smart man.

Dr. Small [53:33] So one of the things I like people to realize that the reason why this is so important is because there's always people behind this disease. There are people that we fight for. There's a reason why we cannot stop, why we have to continue to ask why and then try to seek the answer. So we all have people or that person that we are fighting for. Is there someone that you're fighting for or

Dr. Lenz [53:55] Yeah, I have wonderful patients. I love them all. I think one of the biggest rewards for me is that many of them go out and do communities and create national support groups, advocacy group, and they're doing an amazing job because I think physicians are all very busy in the clinic and cannot explain everything, and information about clinical trials is not so easy to communicate. The patient advocacy in the US is unparalleled in the world and what they do for our communities and our patients is completely underrated. They help so much to better show the patients what they need to do, what they have to ask, what clinical trials are out, please look for out for this. I am so impressed by them and that's what I'm fighting for, that they have all the information to share and be able and amplify what we know to make access to people who otherwise would not have access to that information.

Dr. Small [54:56] Yeah, I agree. In the US particularly, I mean this is a powerful group and we have to continue to support them.

Dr. Lenz [55:01] Yeah, I mean Colontown and Colon Cancer Alliance and WunderGlo Foundation, they have impacted so many patients and people around the world. I'm very minimal for my impact compared to them. I'm so impressed with that, that they are able to do that.

Dr. Small [55:19] Well thank you so much for your time and thank you for your fight and just to our listeners and remember always why we fight and who we're fighting for and ask why

Dr. Lenz [55:29] And fight on

Dr. Small [55:30] And fight on. Thank you so much. It's been such a pleasure. Such a pleasure. 

Dr. Lenz [55:37] It was a pleasure. My village, we were 90 people in the class. Okay. I'm the only one who went to university. I'm the first one in our family and I left to the university and I was just happy to made it. If you would have said I would become a physician and would study abroad and would be in the US in the major cancer center, I would say, are you nuts? Are you on medications? I just went whatever was fun.

Dr. Small [56:05] What makes your practice unique in LA?

Dr. Lenz [56:06] I think USC is an incredible university because we have the private practice, we have the rich and famous, and we have also a county hospital where people come who have no insurance, who are the underserved. And I love it to have my feet in both worlds. We make no differences how we treat patients. And that's the reason I stayed. The patients, the county, they are so lovely and so grateful. Just that you help them and you're there for them. Yes. I think it keeps you humble.

Dr. Small [56:39] You have one of the largest patient populations. I guess, samples in the US I'm curious to know.

Dr. Lenz [56:44] Over the last 20 years we had postdocs from different countries and the people who came to me wanted to do research. So I said, you can come, but bring me your clinical trial samples. Bring me your databases. And that's what they did. That makes a difference not only for them, but it has impact for patients everywhere or it's a global impact.

About Dr Heinz-Josef Lenz

Heinz-Josef Lenz, MD, is an award-winning trailblazer and mentor whose pioneering work in colorectal cancer gene regulation, drug resistance, early detection and surveillance has reshaped the field of oncology. He is the recipient of multiple prestigious honors, including the ASCO Young Investigator Award, Career Development Award and the USC Mentoring Award, celebrating his excellence in both research and mentorship. Dr Lenz also serves on national committees including SWOG, NCI Task Forces and advisory boards and has authored numerous peer-reviewed publications.

Dr Lenz is a professor of medicine, Preventive Medicine and Cancer Biology J Terrence Lanni chair in Cancer Research. He is also deputy Cancer Center director at USC Norris and co-director of USC Brown Center for Cancer Drug Development.

Dr. Heinz-Josef Lenz is a paid BMS consultant.  

00:09 [Dr. Small] Every day nearly 50,000 people around the world hear three words that change everything. You have cancer. One in two men. One in three women. Behind every number A life interrupted a story rewritten. This season we turn our focus to the fight of a lifetime cancer.

At ASCO 2025, I sat down with three of the most powerful voices in oncology. They have authored now over a thousand publications and are presidents of oncology's most outstanding professional organization. I'm truly honored to introduce you to Dr. Lillian Sue, the senior medical oncologist at Princess Margaret Cancer Center in Toronto. Dr. Howard Skip Burris, president of Sarah Canon Research Institute in Nashville and former ASCO president and Dr. Fabrice André, director of research at Gustav Rui Cancer campus in France. This is where science becomes action, where innovation meets impact. This is the future of cancer care. This is Doctors unscripted. Now let's get started.

Thank you everyone and thank you for coming. I'm going to ask you a question that's probably the hardest question for the day and it's about when you were in med school and you had those colleagues that you knew exactly what they were going to go into. What did your friends or colleagues believe you were going to go into and why did you choose oncology? And as you're telling us this, I would like you to introduce yourself. What do you do, your institution and then why? I'll start with you for Fabrice.

02:12 [Dr. André] My first thanks a lot for inviting me. So my name is Fabric André, I am a medical oncologist working in Paris, France. And so when I was in medical school, I was medical school in Grenoble. That is a city in the French Alps. I was doing ski racing. I really wanted to do sport medicine. I was fascinated by sport physiology. But then when you grow up in medical school, step by step you see the patient, you want to improve their situation. And also I became fascinated by molecular biology At that time it was growing. So then I switched to medical oncology.

02:50 [Dr. Tania Small] Got it. I thought now you did mention something about hematology as well.

02:55 [Dr. Fabrice André] Indeed. I love theology. I wanted to do hematology. I was doing some ski in New Zealand, so I asked a friend to take my fellowship and he ticked the medical oncology. It's okay. I owe him a lot of things.

03:13 [Dr. Small] No, thank you for that. What about you Lillian?

03:16 [Dr. ] First of all, thank you for having us here. It's going to be fun talking to friends. I'm Lillian Siu. I'm a medical oncologist at Princess Margaret Cancer Center in Toronto, Canada. I wanted to be an oncologist from the get-go, so I basically took all the rotations that everybody has in oncology and did it and trade off their other rotations with me. So it was pretty much a interest from the get go.

03:40 [Dr. Small ] Yeah. And what about you Skip?

03:41 [Dr. Burris ] So Skip Burris. I'm an oncologist at the Sarah Cannon Research Institute in Nashville, Tennessee. I came out of college at West Point with loving engineering, math and economics and went off to medical school and it was an exciting time for cardiac surgery. They were doing the initial bypass surgeries and transplantation and I traded some rotations to do more cardiac surgery. It was really exciting for a while. And then the lack of patient touch continuity bothered me and I was a little nervous about what I was going to end up picking. And as I went through the various rotations, I found that I love the oncology patients. I liked working with the oncologist, liked the oncology nurses. And I really picked oncology as a career because they say you want to go work with people that you love to work with. And that was a big part of the decision and sort of learn the science after the fact.

04:41 [Dr. André ] And you Tania, did you know which medical specialty you wanted to do when you were at medical school?

04:46 [Dr. Small ] You know what, I thought I was going to go into OB-GYN. I loved it. I was watching these babies being delivered and I wanted in. And I remember even during the third year of med school, I was like, I'm going to do all the deliveries. And then I realized that that's not the piece that I enjoyed. It was actually looking at life and the potential of life. So I quickly moved from enjoying deliveries to actually the humanity and the human being that I wanted to treat. And that's what moved me in to medicine and then oncology. 

05:24 [Dr. Small] So this year ASCO was filled with transformative data across the board. Out of all the sessions you attended, which data do you think is going to have the most impact over the next 12 months? And I'll start with you, skip.

05:37 [Dr. Burris] You're right. I mean there was data everywhere, exciting news everywhere, but this year, and it's not always the case, but this year the actual plenary session had presentations that are going to require our colleagues to go home and make a decision about how they're going to incorporate that information. The room was packed. I was joking. Even the bathroom lines were long like we were at some major sporting event. And yet as you went through the presentations, large trials randomized with answers that said, am I going to incorporate immunotherapy into the adjuvant, new adjuvant setting? Am I going to consider switch therapies in breast cancer? Am I going to do the biomarker and molecular profiling that we really should be doing for more patients at the time of their initial surgery to impact what my tribute decision will be? So I felt like all the presentations on that session, the oncologists around the world need to think about those results and there's not a right or wrong answer, but make a decision about how they're going to use that information to treat their patients.

06:43 [Dr. Small ] And so in that case, what do you think for you, because you're still in practice, what do you think you're going to take home and I guess incorporate?

06:52 [Dr. Burris ] So I have been beating the drum about not saving testing, not saving therapies where I've always believed better treatments, better testing, better therapies would come along. And so I'll go home and use this to continue to reiterate, what I believe is you ought to do the best testing and broadest testing on your patient as early as possible and you ought to consider utilizing those new therapies where there's data early on, not be a saver of a treatment.

07:24 [Dr. Small ] I completely agree. What about you Lilian?

07:25 [Dr. Siu ] I'm a head and neck medical oncologist. So there have been for the first time, two positive studies in head and neck cancer. One is keynote 6 89 that was presented in a CR and one is Nivo post-op that was just presented at ASCO. One is perioperative immunotherapy, one is essentially adjuvant immunotherapy. So I think when I go home we are going to actually literally have a meeting with multidisciplinary specialists, ENT surgeons, radiation oncologists, medical oncologists. We already planned that meeting on Friday coming up to discuss what are we going to do. I'm not sure we know the answer and it will be a very interesting discussion. I think the other abstract that I was very interested is the Canadian abstract, if I may showcase Canadian work is Chris Booth's study about exercise in patients with stage three and high risk stage two colorectal cancer, that it was able to reduce death by 30% in follow-up for these patients in addition to all the standard treatment that they have had. And it's a cancer specific survival that they actually did not die from their cancer as a result of an exercise program. So I guess the question is can we extrapolate this to all cancers if that works for one cancer? So I think those two things are going to possibly change my practice.

08:50 [Dr. Burris ] What you do in Canada, can it be incorporated into rest of the world, particularly the us? Will we be able to get folks to follow this advice?

08:59 [Dr. Siu] Well I think exercise is, I was going to say as easy as not easy, it's hard to make somebody exercise because you can do it for two weeks, you're going to do it for two years or 20 years and that kind. And that's why there was a coach involved in the study to actually have somebody supervise and encourage you. I'm not sure without one. It's that easy to implement. So we'll see.  You need to coach every person in America.

09:24 [Dr. Burris] Great idea.

09:25 [Dr. Small] But then also then how do you pay for that I guess is the other question. So we have now these different dietary changes as well as lifestyle changes, but then how do you incorporate that, ensure our insurance company's going to pay for it? How do we, that's a good question,

09:3 [Dr. André ] But I think Tania, there are ways to develop medical device on this topic. With digital medicine, wearable, maybe in the future the oncologist will check the acquisition of the data from a wearable of the patient with a kind of digital coach saying how much exercise the patient will do and has done. I think there are two questions that are really important in this is first, what type of physical exercise improve the outcome? I mean it's not all the same. Is it an Nairobi? Is it? And the second one is what is the mechanism? Because so if we understand the mechanism, well maybe we can also develop some drugs that will improve the outcome even better. So in fact, it's eye opener but it's also door opener. We are opening a totally new field. Maybe it's going to be about cancer metabolism, I don't know, but it's very important study I have to say. My first one was a head and neck presentation. The second one was the one on physical exercise. So in 30 seconds I had to find what was the third one? So I think I will select the one on trastuzumab Deruxtecan in patient with metastatic breast cancer with the overall express HER2 is the first line setting. The median PFS is around 40 months. And then I was discussing yesterday with colleagues said, well let's go back in the past 2001 with the New England Journal of Medicine, first randomized trial chemo versus chemo plus trastuzumab. The PFS was four months for chemotherapy. So it means that in around 20 years we move from four months progression-free survival disease control to 40 months. So it just tell us that with the knowledge of biology, the development of biotechnology where we can really have meaningful improvement for patient who are dealing with metastatic cancer. So when I was fellow metastatic cancer was meaning death in a few months. Now the first line disease control is around 40 months in some subset of breast cancer. I think the number impressed me a lot this 40 months.

11:58 [Dr. Small ] I completely agree. And even in terms of I'm going to switch now to diagnostics and I'm curious to get your thoughts and I'll start with you for breeze on all the data in terms of liquid biopsy and obviously we've been talking about it for years and years and years, but even leveraging CtDNA to determine prognosis as we saw with IFI data or in terms of switching as we saw with Serena6. So out of curiosity, what are your thoughts please

12:25 [Dr. André ] Circulating two more DNA meaning these are fragment of the DNA coming from the cancer cell that are released in the blood. So by a blood test we can detect this fragment of DNA coming from the cancer cell. Why it's important first because from the analysis of circulating tumor DNA, you can detect the mutation that can inform you on which treatment the patient should receive. Maybe we can agree that this is almost standard of care. I mean even in France we do it routinely for patient. The second application is early detection of cancer or early detection of relapse. And this is where I think we are going to have a discussion. Is it yes or not ready to be used? The third application is the opposite is when the patient has a cancer, whether there is a clearance of the ctDNA and if there is a clearance it means the outcome is good and maybe we can decrease the burden of therapy. There was a fantastic study in colon cancer where they could show that after surgery and local therapy and adjuvant therapy and before a joint therapy, there is no ctDNA it's possible to deescalate and to reduce the amount of treatment. So that are the three use case. I think it's level one evidence for detecting mutation. There are some very convincing randomized trial in colon cancer to deescalate treatments meaning no adjuvant chemotherapy. There is no CtDNA. And the question today is if we detect CtDNA rising CtDNA before the relapse of the cancer is detected by imaging, is it useful or not? I think that the reason that we're presented are promising. I think maybe it's a little bit early to conclude from my opinion that the detection of ctDNA before relapse on imaging really improve the outcome of patient. The drug that was tested in this trial called Serena six, that can be the strong Estrogen receptor degrader is effective. It's not the discussion. The discussion here is its CT detection before relapse on imaging useful for the patient. I can see SKIP is ready to make sure you get a chance

14:58 [Dr. Burris ] You took the eight hours and condensed it down and I was leaning in because the idea of saying so much with fewer words is impressive and I think you outlined it into very nice segments. So no reason to repeat that. I think the challenges that I see in my world at Sarah Cannon communicating and working with community oncologist is justifying how often to do it that gets into the price, but we need to get it to a place where we can do it frequently. I think the other part which is a little bit of a hurdle is handling the information and then being forced to make that decision oncologists want and a get this result, do this therapy sort of thing. Getting some rhythm and guidelines on how often to do it is where we need to go next. But great overview summary.

15:52 [Dr. Siu ] I want to interject too, I think have three points. One is I think the assay matters. Not every assay is made the same and not everybody understands it out there that if your assay is not sensitive, even if it's negative, it does not mean you have no residual cancer. So I think the assay is very important. And looking at the dynamic study in the colorectal cancer, the de-escalation seems to be a possible way forward, but de-escalation is much more difficult because obviously in that study dynamic three they escalated by adding a more intense chemotherapy. But probably it didn't help because there's cross resistance and the drugs matter. What you're going to do when you have the positive CtDNA result really is important. So I think if we think that one size fits all, just because you detect MRD, you add more drugs, it will work. I think that's a fallacy. It's not going to work. So I think these are the nuances that we have to think about when we think about ctDNA molecular residual disease switch therapy. I think there's still a lot to be learned.

17:07 [Dr. André ] A lot of people think that the future transformation of oncology is going to come from early detection of cancer by blood tests. If this happens, I mean the life of patients is going to be dramatically transformed. Maybe we'll be able to early detect pancreatic cancer, liver cancer, highly little cancer. So probably the next two years we will have results of very important studies on this field that can potentially transform oncology and the life of millions of patients per year. So we are really looking forward for this.

17:43 [Dr. Burris ] I just want to add one thought to that and I'm aligned. We've done a lot of work at Sarah Canon with those various clinical trials and they've been attractive and people are interested and Fabrice said a key thing about the highly lethal cancers. I think we've got to focus there. If you can pick up a pancreatic cancer early people get focused on breast and prostate that are slower growing and we've got more treatment options. And does early detection really make a difference, which I still think it does, but the early endpoint on highly lethal cancer should be where we really judge those tests.

18:15 [Dr. Small ] But then, okay, so let's talk about that. So if you think through to your point pancreatic cancer, who do you know to create, how do you implement something like that?

18:22 [Dr. Burris ] You describe a great challenge and in participating in the trials, we've had some great anecdotes of picking up a few patients and went to early surgery. But the fact is upper socioeconomic folks are who's using the test commercially right now. So we don't have the answer to your very good question.

18:43 [Dr. Small ] I think that was one of the things I want to explore as well. We look at our different environments and we talk about liquid biopsy and if that's the future, how do get it implemented for you and more the rural community for you across the lower and middle income countries and which is a big focus of yours, how do we get that implemented within our communities?

19:00 [Dr. André ] Well I think in Europe, Tania in Europe, the biggest problem here is the lack of market for diagnostic tests. If there is no market, there is no private investment. So there is no new device. So I think the next step for Europe in this topic of pretrial medicine is recreating a market for diagnostic companies.

19:21 [Dr. Burris ] The only thought I'll add to it, and you alluded to it earlier, Tania, is this is a place to bring the payers to the table because treating earlier should be certainly much more cost effective. Exactly. So having them participate in this will be key.

19:45 [Dr. Small ] I mean we can pull out all the economic models to show, right, if you can do much more preventative care or start or diagnose early, treat early, you're saving a lot of money in the backend. And one of the things I was thinking about is are these early studies, if you think through phase ones, there's been a lot of discussion about, obviously we've been doing a lot of adaptive designs, but how do we move fast? and shave off a lot more time, especially during this time, but yet hold true to the scientific rigor. So curious to get your thoughts.

20:13 [Dr. Siu ] Yeah, I think obviously there's a competitive market where when you do your trial you want to not share that data until you're finished. And I think when your study is finished in early phase, I think that data should be shareable because it's sort of the hopefully post competitive phase that you are able to actually learn from each other and how many drug X targeting target Y out there. Many. And we know that for example, companies all have very similar pipelines and yet by the time we hear of five of them or six of them fail, you still have four or five of them going on and that data is not shared, that data is not learned. And I think it is a pity that we're not able to do a lot of iterative learning on negative data. I understand positive data is hard to share. I think negative data can be shared that will eliminate us not wasting our time, our resources and obviously our patient's time to go into studies that probably has a very, very little chance of succeeding. And I think one of the area I'm very interested is how we can actually leverage preclinical published sound lines models, AI, whatever it be on clinical trials and real life evidence and post clinical trials, real life evidence and keep learning as a model. Maybe we can do more federated learning. You don't send it out but you can train your model locally and then feed it to the world. I think that's the only way we can actually learn quickly together.

21:55 [Dr. André ] I think the way you can also accelerate things is through cancer classification. Our cancer classification have been done for local treatments. Now we are in the era of molecular oncology, meaning any drug is targeting a specific protein specific molecule. Specific process for me does not make any sense. We say look, we start with melanoma two years after we do kidney cancer two years after we do lung cancer because the molecular determinants of drug sensitivity are the same in lot of cancer. So we should really move in addition to organ based classification to have molecular based classification going pan cancer or multi cancer. I think that could dramatically accelerate drug development. If we look at anti PD 1 for example, it took more than 10 years before some group of patients defined by a disease defined by an organ got access to anti PD-1. But again, the molecular determinants of sensitivity of anti-PD-1 one were exactly the same as the melanoma or kidney and cell lung cancer. So I think that could dramatically accelerate drug access.

23:12 [Dr. Small ] How do we change that? Because most of us are focused on a particular tumor type even in terms of practice. So how do you make that paradigm shift?

23:21 [Dr. André ] I think this is the work of scientific societies, ASCO. I mean these are very strong stakeholders. So if tomorrow this organization are saying, look, in addition to the conventional way of classifying cancer, we can agree on another way to classify cancer based on molecular alteration. And of course ACR can be a major player on this question as well. That can really change the defeat dramatically and accelerate and of course regulatory agency have to be involved in this switch of classification. But in our analysis we think it's a major challenge for drug development.

24:03 [Dr. Siu ] A lot of the problem is that it's not funded in many jurisdictions. NGS is just not available on every patient. So it's challenging. I completely agree with Fabrice that we need to learn not just on histology, we need to learn about the biology and yet NGS is not available so you only have half of the equation and it's hard to contribute data when you don't have the second half. And I think that's something that perhaps the funders and the payers need to think about how to actually make it more available perhaps especially in cancers where there are actionable targets. Right?

24:36 [Dr. Burris ] Going back to what we were all saying, if you're going to fail, fail fast and that helps everybody stays resources. Patients don't go on effective therapies. The other thing I comment on going to the NGS piece, if I'm a pharma biotech with my drug, I want to know everything I can about that patient so that I can then, and this is where AI and other analysis can come in, why didn't it work in those groups? So people say, well give me an example. I mean go back to many years ago if we treated trastuzumab with for everybody, it wouldn't have gotten approved if we hadn't found the subset. Cetuximab struggled till we realized that there's a whole group of colon patients with K-ras that weren't going to respond. So there's simple examples like that and now that we're with better agents, better targets, better understanding, it should even be more relevant. We should have dozens of those examples and we probably do.

25:34 [Dr. Small ] And that's why I was going to ask next because obviously there's been a lot of companies talking about AI and leveraging AI to do better predictive modeling, to understand resistance much better. Who are your responders who won't respond? How can we start using AI to develop better studies, to develop better drugs?

25:52 [Dr. Siu ] I mean AI is such a buzzword. Everything is like AI is like everything tastes better with bacon on it, everything that looks better when you have AI in your design and your model. And I think we're still at the learning stage of how to leverage AI and yet the learning curve has to be really steep. To be honest. I think it's a good time because we have technology and biology really both side by side each other and they're racing to be who is which one is more relevant and they both are. And I think we have so much data that we can feed into these models and the important thing is to really understand when the output is correct or not. And I worry about hallucinations. I think the future is very exciting with these digital pathology AI models, generative AI models, but we just need to be a bit cautious in the output.

26:44 [Dr. Burris ] So on the AI front though diving in, but I have our molecular team continually provide me slides that are called the perfect patient. So I'll give you two quick examples that I just gave at a recent lecture. The perfect pancreatic cancer patient for a trial, they had a very specific KAS mutation that this biotech company desperately wanted. At the same time they were mtap deficient. So they were the perfect patient for the PRMT five. And so with trial to put 'em on and both those companies are going to judge in a silo or a vacuum. So then fabrice, I had a patient classic estrogen positive breast cancer patient. Then our molecular team pulled out from one of the sites who had a TMB over a hundred. So we don't give immunotherapy to an estrogen receptor positive breast cancer patient. But with a TMB greater than a hundred, she was the perfect patient for several IO trials. So what is it about the, you're going to need AI to understand a

27:43 [Dr. Siu ] Combination.

27:44 [Dr. Burris ] AI has got to hopefully help me, help us figure out that all these patients we've proven with NGS that every patient really is unique.

27:56 [Dr. Small ] So as we were talking about AI and one of the things that I'm really curious about is how do we leverage AI to even understand our responders versus non-responders and use that much more to predict. So how do we leverage AI to get smarter about that?

28:12 [Dr. Siu ]  So it has to be taught and the only way it can learn is we give it data from experience, real world negative trials, positive trials. And it keeps go on to an iterative cycle of teaching and learning. And I think this is why this kind of process of having data sharing is really important in my view

28:31 [Dr. André ] Tania, this is going to become a major role for academic institution. That is the issue with AI  that they need large number of high quality data and this can only be delivered by institution who are committed to provide data or very high quality. So this work of generating data is going to be more and more important. Then I think about AI of course is going to probably to transform oncology still we need to be realistic. We still need brain to invent, discover what is a new dimension of biology that is important, being able to design the experiment on the way that the AI will not be able to do it. So I think I'm very optimistic about AI is only thing that we need to rethink the role of academic institution in this new era. Plus we all have to realize the most important predictor dimension of biology is the one that has not been discovered yet. And this is still in the hands of the human.

29:41 [Dr. Burris ] And I'll just add the one hope I would have for AI is if we think about novel endpoints, we're at a place now with some diseases, there'll be continued fights of do you have to show overall survival? But with certain mutated cancers where people are going to do well for years or even thinking about tumor classifications like CLL or some of the bone only prostate breast, it's just not realistic for us to wait on advance for survival. We've got to have other endpoints there. And the other point I would bring up is the parts of the human condition that are affecting these therapies. The fact that patients that are overweight seem to do better with some of the immunotherapies, there's other biologic characteristics that we need to accumulate all that data and hopefully AI can sort out what some of those issues are as to why people do better or not. 

30:46 [Dr. Small ] Since you went into overweight healthy living, I want to actually talk about that because like I said, that was a big focus for ASCO and we know that weight gain smoking, we know sanitary lifestyle all contribute to your increased risk of cancer. What do we know about lifestyle and its association with cancer and what should we be doing as healthcare providers?

31:09 [Dr. Siu ] Well I think that the obvious ones are the ones we already know. Smoking is bad for you and drinking a lot is not good for you. I mean for the cancers that we already know. But I think for the new areas, exercise seems intuitive but the mechanism like Fabrice said is not clear. It is not because they become healthier just because they stopped drinking and doing good things because their cardiac risk has not changed, for example. Or it's similar between the two groups. So I think we have a lot to learn. For example, my psychiatrist in my hospitals are interested in people in distress. Their psychological condition affect their response to immunotherapy, what's happening to your cytokines and all your enzymatic metabolic systems. These are complete unknowns to us and we spend so much time on tissues, blood and everything else. We forget about some of these other areas that are probably much more challenging to be honest, to measure. And I think they do factor in terms of treatment and responses and resistance.

32:16 [Dr. André ] Absolutely. I think Tania, I think maybe two point on this topic. First a major component is social determinants of outcome. We have a French epidemiology study has been fascinated because each time we address a question, we always see social determinant of outcome coming first to predict toxicity, quality of life, deterioration of quality of life, et cetera, et cetera. So this is a very serious issue that for oncologists we don't have this in the radar, so we need to create awareness on this question of social determinants of outcome. The second thing I wanted to mention is all the work from Qlik Institute about the role of macrophages on cancer promotion. This can be transformative on the way we even perceive the cancer because maybe we can modulate this by blocking IL one or different other mechanism. So this is very important but also maybe we can predict, but more importantly is going to totally change the way we, again we classify disease. Tomorrow we'll see everyone or you have high level of chronic inflammation, you are predicted to develop cancer, cardiac disease, neurogenerative disease, et cetera, et cetera. So probably the trunk of the disease is going to be shared between many disease. So these things of mild with cell macrophages as a determinant of and predictor of further disease is going to be something very important for the next decade.

34:05 [Dr. Small ] And you're right because I think every therapeutic area is exploring that. And as you guys know, I did a show before on Alzheimer's, you're going to hear us talk a lot about that and inflammation is prediction and its prognosis when it comes to Alzheimer's.

34:17 [Dr. Siu ] I want to ask you with obesity, do you think GLP one agonist is going to have a big role in cancer reduction, cancer mortality change?

34:25 [Dr. Burris ] So with the dramatic uptake of those drugs, we should be able to have an answer in the very near term. And you would think that that's a place where AI could help if we can aggregate the data quickly as to have that level. And then the next step of that, I was going to comment on a minute ago, is part of that success going to be reducing the markers of inflammation and is it going to be reductions in stress and being able to measure that? Because a common question I keep getting asked by colleagues and friends outside the profession is younger individuals getting cancer. And I think we used to consider that anecdotal, but now it seems to be clearly a prevalent issue. And so environment diets are part of that, but much of the tools we have now allow us to lead pretty sedentary lives. And then it also feels like stress is higher than it's ever been. And so measuring how those are part of the impact has got to be part of the story.

35:22 [Dr. Small ] And even as we continue to talk about health, there's a big discussion about microbiomes and I know there's some recent data was shown that even with when it comes to resistance of for example, PD ones and once you change the microbiome, once you change the environment, you get better sensitivity. What are your thoughts on this?

35:44 [Dr. Burris ] So a shout out to my wife and I gift though a young investigator award every year and we've had one of Lillian's outstanding researchers be a recipient and this year our award winner is a researcher out of California who's studying exactly that, and we don't pick the project the review committee does, but she's studying the fecal microbiome. The tissue microenvironment from patients who relapsed on the neoadjuvant checkpoint inhibitor trials that did pretty well. But what was it about that group that didn't get the success? And she's got some information suggesting that the microbiome there might really be a factor to a key point we've got to study.

36:31 [Dr. André ] But I think Tania, I agree it's interesting. What we are missing still is a large randomized trials. If I do fecal transplantation, I change the outcome of the patient and the day we have it suddenly it's going to attract a lot of attention, lot of investment, new clinical trials and then it's going to grow dramatically. Today it's a little bit looping a little bit. So we have a lot of retrospective studies. There is something happening, but it's difficult to de exactly which bacteria is important, which network of bacteria. So I think we still miss this bigger data showing clinical utility and then things will go very fast and very broad.

37:14 [Dr. Small ] And maybe someone just for our listeners, if someone wants to explain what the fecal transplant is

37:20 [Dr. Siu ] There are different ways to do it. You can take stool from patients who are very good respondents from one immunotherapy drug and give it through colonoscopy to another patient who is going to receive immunotherapy in the hope that you're going to directly transfer group organisms into their gut so that they can actually have a higher chance of responding to immunotherapy. As you said, there are oral formulations that can do the same either in the form of bacteria or encapsulated stools or different formats.

37:51 [Dr. Small ]  Thank you for that. No, that's a fascinating area. So we're going to talk about disruption. So when we think about disruptors in the field, we are looking at different modalities, whether it is ADCs, bispecific, tri specifics, protein, degraders, radioligand therapies, there's a lot happening in this field. What excites you the most and where do you think the field is going to go next?

38:16 [Dr. Burris ] Lilian, I'll let you go first.

38:17 [r. Siu ] Okay. It's hard to predict which one will, it's probably going to be combinations thereof. I'm excited about vaccines because I'm interested in the molecular residual disease space. So I think in that group it's hard to give somebody who has molecular residual disease, prolonged intense toxic therapy. So I think the attractiveness of having a personalized therapeutic vaccine is very exciting. And obviously we already have preliminary data from some diseases, pancreatic cancer, kidney cancer, that perhaps we are able to trigger enough of immune response to perhaps eradicate an intercept in those patients with high risk disease that we just talked about with detectable ctDNA. So I think I'm very excited in that and that data still needs to be matured through randomized trials. It's still a bit early, but certainly I'm very interested in following that path.

39:12 [Dr. Small ] Yeah, no, completely agree. What about you Skip?

39:13 [Dr. Burris ] I would echo the sentiment on the vaccines. I think we had some early starts that were too broad. It's going to get more specific and going to minimal residual disease, early adjuvant therapy, that's going to be the place to really study those. I'll throw in that I've been amazed by how quickly the bispecifics and now you're hearing about tri specifics Bispecifics bi functionals and having had some experience with those and seeing those therapies overcome resistance to traditional therapies. I have great hope for that. I have great hope for it's that ultimate combination of science and engineering. One of our common mentors, Dan Von always said that he thought engineering would play a big part in curing cancers. And I think he's going to be proven correct again that the engineering is going to help us have the better molecules there.

40:07 [Dr. André ] I fully agree what has been said, I think biotechnology, are going to change cancer care, but we all have to keep in mind, and as Skipp was saying, we can improve drugs only if we understand the failure and the mechanism of action. So that put all the academic colleagues at the center of the research, we need to understand from patient sample what's wrong, what's right to go next step. Maybe that two point first, I've been quite impressed by radiotherapeutics. I think it's going to grow. We still don't know how it's going to be implemented, a lot of work, but it's here, it's going to grow. And then the second thing, because you talk about disruptive, it's something that we would like to do since five years, we don't know how to move it forward. There's no more and more we are going to a situation where we can really model the biology of cancer in each patient. The logical next step will be to create a drug per patient. So If you understand the mechanism, you understand the protein. We have AI to design drug. We are not so far to create one pill, one antibody, one complex drug for patient and the only issue is the time and the price it would cause. But I think as a concept we should start working on this.

41:24 [Dr. Burris ] Do you think on the radioligand front there's enough targets that are going to be suitable, meaning tumor specific not found on normal tissue?

41:38 [Dr. André ] Oh, I think so. First, there are a lot of work on this topic, so I don't think we have a clear answer to date. I think biggest institution in the world are working on what they call surface. So discovering new protein that are specific to cancer and maybe we'll have some surprise, maybe some proteins from a retrovirus over expressed in cancer. Then the question you're asking is very interesting question from a pharmacology perspective, what do we call a normal tissue? And finally, do we need to compare the protein of the cancer to any normal tissue or should we just spare the most important tissue like heart, kidney, brain? And I think this question for me is also, but it's a crucial question. If we want to discover new cancer specific target, I don't think we should compare to any normal tissue. I think we should limit to the tissue where if you target this organ is going to create major toxicity 

42:38 [Dr. Siu ] I mean that's going to be relevant for ADCs, it's going to be relevant for CAR-T’s. I mean I presume knowing what is expressed on the surface, what internalizes, which one's functional, which one's not functional and all the normal versus non-normal distribution.

42:55 [Dr. Burris ] I guess I didn't clarify my question. That was a great answer and I agree with it and I feel better hearing you say that. And when I think about an A DC, you think about off target chemotherapy effect that will go away as opposed to we always think of with radiation that once we've done it, it's done. So is there going to be a different level of concern? But I certainly share your sentiments and I think you get to a key point about there's organs we must protect. 

42:22 [Dr. Siu ] Well that's why the payload in these drugs are going to be very important, whether they're going to have very short distance and not damage your deep organs and The half life, right?  Yes. 

42:36 [Dr. Small ] Throughout this discussion, we've been talking a lot about sharing data, understanding both from an academic standpoint, from a society standpoint, from even a pharma standpoint. How do we work together? We understand obviously the environment has changed and let's be clear there's less funding for research as well. How do we work together so that we don't drop the ball and we continue to move research forward?

43:59 [Dr. Siu ] Yeah, I mean if you think about it, patients want to share their data a hundred percent. Physicians want to share their data for sure, because we all want to learn to see what is going on and we don't want the field to move very quickly. We wouldn't want it to stall. So what are the barriers? I think a large part of it is legal. And I think we need to work on how do we overcome the legal concerns and legal barriers. Of course we want to provide privacy. That's completely understandable. But at the same time, there are many ways we can do this kind of sharing without breaking these privacy concerns or similar concerns. And I think this is where we really need to work that framework that everybody feels comfortable and yet we can move the field much more faster than we are now.

44:46 [Dr. Burris ] Agree that we've got to empower the patient. There needs to be some standardization of when you're moving into the situation for the first time with your physician, that you agree to share your data with the appropriate provisions to protect privacy. I mean the data is the patients, there's intellectual property on drug development and those factors be brought in, but it's the patient's data. They're going to benefit from sharing with each other and we've got to continue to push that initiative.

45:19 [Dr. André ] I think Tania, I fully agree of course regulation especially in Europe is a major buyer to share the data. But I wanted to add something else. We should also add in the evaluation of academics, whether they have contributed to large database, how many download, et cetera, et cetera. Myself, I had my team evaluated, well a few time ago. We have added in our evaluation how many times our data were download by external teams. And the evaluation committee was very happy with this. So I think it's also about leadership of organization, institutions and society to reward people who share really the data.

46:09 [Dr. Small ] Now I'm going to shift to something that I think is near and dear to all of our hearts, and that is looking at access and looking at access for patients. Because obviously no matter what kind of innovation we bring forward, no matter what kind of breakthroughs we bring forward, if it's not reaching patients, then eventually it's for Naugh. How do we work to improve access? And I'll start with you, skip, since I know that again, you work in a lot of rural communities. How do we ensure that our medicines are reaching the patients? Our studies are reaching the patients.

46:39 [Dr. Burris ] It's a critical issue, democratization of care, access to care, and it goes beyond even race and socioeconomics. I mean sometimes it's geography, sometimes it's social support system that the patient has. All those factors play together. So we've got to recognize that. And certainly with all the modern delivery techniques and technology, there should be no barriers anymore with regard to geography. And we can't expect individuals to travel to the great institutions, but they can't get to those cities. I think the other part goes back to the data issue, understanding and having those patients aggregated in so that we can look at populations of patients that might benefit. And that's another part of the futility success analysis. And then I'll shout out for asco. I think one thing that ASCO's taking very seriously is this idea of getting rid of the copays and the patient participation in paying for their cancer care. Yeah,

47:40 [Dr. Small ] Couldn't agree more. 

47:43 [Dr. André ] I think Tania, from my perspective, first, the first step was to be aware of this problem. When we are aware of the prem, well it means that we can start working on that. So I think the first step has been done. I see two direction on this topic. First is short duration therapy. Part of the pre is that the fact that treatment have become too complex, too long. So I think when a patient is presenting a cancer that is highly sensitive to a drug, we need to be sure we reduce the duration of therapy because by reducing automatically, we reduce dramatically the cost of the treatment and we make it more accessible. So this is a major effort that we must do in the field of academics about deescalation therapy. The second one, and Skip mentioned that is about technology. We are discussing about AI. Probably AI is going to revolutionize access to treatment in low medium income country because when we apply AI to images, or maybe we can detect microsatellite and stability, maybe we can detect no, all this feature that define very high sensitivity to treatment. So I think for me the two pillars, the two solutions are short duration therapy and moving easily accessible technology to where some country where there is some issue of access.

49:11 [Dr. Small ] How close do you think we are to being able to implement that or how receptive our treaters and researchers?

49:21 [Dr. André ] From my experience in the few project we did, I mean we have a lot of engagement from everyone and I think everyone want to go in this direction and we have really good feedback from many stakeholder including startup companies working on the field of AI, including government, including pharmaceutical companies. So I think everyone want to do something. You know why? Because there is a major ethical issue behind. The major ethical issue is I give you the example of Immunotherapeutics to patient with MSI. It has become a major ethical issue that some patient in the world don't have access to this. This is a curative treatment for patient with highly little cancer. So we go beyond the general political question, it has become an ethical, ethical issue. So it's becoming very, very serious.

50:13 [Dr. Small ] Yeah, no, I couldn't agree more with your thoughts, Lilian.

50:17 [Dr. Siu ] Yeah, I guess I'll go more to the trial level. For every clinical trial, I think it'd be good for us to think about who are we recruiting? Do we need to have, for example, patient navigators and patient advocates and to really understand how to make the trial easier and more implementable. Of course, we want pharmacokinetics every day for the rest of their treatment cycles forever and ever. But are they needed? And do we need every visit to come down to the cancer center? Can some be actually being more local? And I think navigators can help with a lot of that. And obviously patient voices need to be heard and sometimes when we review protocols, we think it's easy, but it's not. And I think having that kind of patient engagement and patient advocacy for every protocol would be very helpful.

51:09 [Dr. Small ] I mean to your point, sometimes when you look at a protocol, so much of it's just copied and pasted, right? Totally. And then you haven't asked yourself the question, how much of this do you really need? Or even having discussions with the regulators to say, do you really need all this PK data? Do you need all of this? Because now your patients are excluded of that.

51:29 [Dr. Siu ] Yeah, absolutely. 

51:31 [Dr. Small ] So I'm going to do a quick round robin for final question. We have, again, this is really focused on HCPs, but we also have a lot of younger HCPs, whether they're fellows, residents, or just starting their career in oncology. May I start with you? Skip to go around any advice that you have for them, something that someone told you or something that you picked up throughout your years?

51:57 [Dr. Burris ] Fabulous question I'm worth thinking about. To me, the idea of finding that person who you really trust and looking around and interviewing the elders in your group. And they don't have to be a lot older as to who you think is really going to be a mentor for you or a sponsor for you. They're subtly different, but I think it's worthwhile just not taking that person who might be in your tumor type or in your disease area. I've been very fortunate with those folks who've helped me, but that's got to be a two-way street. And I think it is worth really being diligent about thinking who do you want to be that advocate to work with you? Yes.

52:40 [Dr. Siu ] I would say while we want our early career investigators to focus, it's also important for them to also think out of the box sometimes to learn something that you would not normally feel comfortable to sit in a lecture for or read a book on or read a paper on. Just sometimes it helps you stimulate that part of the brain that you haven't used because you haven't been thinking about that at all. And it could be applied back to where you want to focus. I think just more, what's the word? Disruptive, transformative, more out of the box.

53:13 [Dr. Small ] There's something that I usually say to people and especially to students, if it has been done, then we can do it. But if it hasn't been done, then we must create it. And to me as oncologists, we have to continue to push the boundaries, be disruptive, ask the questions, and actually if there's no response, come up, find the answer and continue to pursue it. So can agree more. What about you?

53:34 [Dr. André ] No, me. I think Tanya, I would really encourage young colleagues to go oncology because I think it's really a specialty that can transform you as a man or woman because you are really, I mean at the center, at the core of what is humanity, I mean you are dealing with patient, some of them are going to die. So you really learn what is the most simple but most important thing of human beings. So I think it's, for me, it's real, especially that has really transformed myself. So I really encourage colleagues to go in that direction. We know in this era where there is ai, complicated things, sophisticated, going back to the most simple and important thing that is human being, life, death, family, et cetera. I mean, we all need to go back to all these things now.

54:23 [Dr. Small ] And with that, thank you so much. This has been fantastic. So I mean, again, just thank you all for being here. And obviously we have, to me, the giants in the field that have moved the needle, seeing where you have moved the needle for patients, for people, for humanity, is exceptional. So thank you so much for everything and thank you for being here. Thank you for speaking and teaching and sharing your knowledge with the HCPs that will listen. I appreciate all of you, so thank you.

54:49 [Dr. Siu ] Thank you for having us.

00:00:04:07  [Tania]  Welcome to doctors Unscripted. I'm Doctor Tania Small, and I'm here to bring you into a different kind of conversation with some of the brightest minds in medicine and research.

Today I'm joined by Doctor John Kane, an internationally acclaimed psychiatrist renowned for his pioneering research in early psychosis and patient centered innovation, and with over 900 peer reviewed publications. Doctor Kane is redefining mental health care. We'll explore what drew him to psychiatry, unravel the biology of schizophrenia, decode the triad of symptoms, examine breakthroughs challenging the dopamine dogma, and discover how patient driven science and partnerships are shaping the future.

Now let's get started.

Doctor Kane, thank you so much for joining us in downtown New York City for our first episode of Doctors Unscripted.

00:01:11:09 [Dr. Kane] Thank you. My pleasure. Thanks for the opportunity.

00:01:14:03   [Tania] I have a few questions for you today. But I'm starting off with the hardest one, and that is, do you remember when you were med school and you were trying to figure out what you wanted to do? Most of us were trying to figure out at least what we wanted to do, what fields we wanted to practice in.

And a lot of times, most of our colleagues could guess what fields we were going to. For example, my colleagues figured I was either going to go into ob/gyn or onc, and I ended up going into onc. What did your colleagues believe you were going to go into, and what inspired you to go in to psych?

00:01:49:02   [Dr. Kane] So they didn't have to guess because I told them. I knew when I went to medical school that I wanted to go into psychiatry, and it had been something that I was interested in ever since high school. And rather than just studying psychology, I wanted the medical degree to be able to really have a, you know, a medical perspective on mental illness.

But I think as a teenager, I was reading novels and got very interested in trying to understand, why did people act a certain way and what determined their behavior, and why were people so different? And I became fascinated with, sort of the human mind and behavior and, and then trying to understand mental illness.

00:02:32:15  [Tania] Since high school.

00:02:34:01  [Dr. Kane] It was high school.

00:02:35:13  [Tania] Was there anything that really stuck with you while you were in med school or even in residency that really changed your [perspective]?

00:02:41:13  [Dr. Kane] Well, I remember the first time in medical school that I actually interviewed a young man with schizophrenia, and he was pretty much my age and had his first episode of schizophrenia, in the recent past. And I saw him at Bellevue Hospital and, it was a pretty powerful experience because I think I was trying to understand the way he was thinking, and he was quite delusional.

And I was asking myself, is it is it possible that he really believes these things?

00:03:18:16  [Tania] Yeah.

00:03:19:20  [Dr. Kane] And then I also met with his parents and I saw the anxiety and the devastation that they were feeling at that time. And it was for me, it would be it would be great if we could figure this out and understand why. Why does this happen? You know, this is a young person with a lot of a lot of promise that becomes psychotic and develops an illness that's really can be quite disabling.

00:03:47:04 -00:04:48:19 [Tania] I remember, when I was learning a lot more about schizophrenia, when I started working in pharma, I learned a lot more about schizophrenia and someone explained it to me this way because, as a pediatric hematologist oncologist, a lot of times you just have so much hope for these kids, and your goal is to get them through it so that they can really fulfill the life that they're meant to live.

And someone told me you could imagine a newly diagnosed person with schizophrenia, and sometimes immediately it can look like lights out, and their goal is to turn on that light. And I guess my question is like, I know one of the things that you focus on is really early psychosis. And, how did the families actually, feel about it?

How did the patients get through it in the beginning?

00:04:48:21 - 00:05:48:04  [Dr. Kane] It's very hard., We had a grant application for the RAISE Project, but, I had never used a quote from a poem in a grant application. A lot of my colleagues thought that that was not such a good idea. But the quote was, tread softly because you tread on my dreams.

That's a quote from Yeats. And I thought that really kind of summed up what we're trying to do here is that, you've got a young person, you've got a family, lots of hope, lots of potential. Parents are always worried. But, you know, you see something like this develop unexpectedly and, it turns out to be a pretty serious illness, and it's devastating, you know?

So this led us also to understanding the importance of early intervention. And, you know, can we diagnose this condition early, can we intervene rapidly and try to get it under control?

00:05:48:06 - 00:05:52:07 [Tania] Yeah. About what age are people with schizophrenia diagnosed?

00:05:52:10 - 00:06:19:20 [Dr. Kane] So the median is in the early 20s. It's usually late teens, early 20s. And, you know, it's occurring at a time, which is really critical in people's development, whether it's educational or psychosocial. And so it has a tremendous influence, tremendous impact on what people can do subsequently.

00:06:19:22 - 00:06:31:11 [Tania] And let's talk about that and talk about the biology, because I know a lot of times, again, people hear schizophrenia. They think it's just a homogeneous disease and can't put their finger on it. What do we know about the biology so far?

00:06:31:11 - 00:08:18:07  [Dr. Kane] So it is very heterogeneous. I mean there's a very strong hereditary factor, but we don't understand the genetic the dynamics of the genetic influence. There have been many, many genes that have been implicated, but all with very small effect size. So we don't we don't have a major gene or genes that we can point to and say, this is the reason I think I would say that schizophrenia is probably not one illness that right now, we approach it with this sort of diagnosis, but I think it probably includes what we will one day learn are multiple different phenomena with different etiologies and different pathophysiology, so that we're trying to do research and understand this illness. We don't have great tools yet to really stratify people into different categories. But there is hope with genetics and brain imaging etc. that will come to understand it better. I mean, up until now, we've sort of had the dopamine hypothesis of schizophrenia, the idea that there's too much dopamine being produced in certain brain areas.

And so we tried to block that with medication and to some extent it's been effective. And we can treat the acute signs and symptoms of schizophrenia with medication. And it often works pretty well. And then the other problem we get into is people need to take medication on an ongoing basis to prevent a recurrence or a relapse. And I think nonadherence is a challenge in any chronic illness, whether it's hypertension and diabetes or epilepsy or asthma.

But in mental illness it's perhaps even more of a challenge with and people with schizophrenia also have cognitive dysfunction. And, that that can make it even more difficult.

00:08:18:08 - 00:08:31:08 [Tania] You spoke about the different pathways. You spoke about dopamine and blocking dopamine. Is that where we landed now or do we know a lot more about schizophrenia?

00:08:31:11 - 00:09:19:23 [Dr. Kane] Yeah, I think we've learned a lot more. For example, the notion has been that, it's excessive dopamine release, presynapticly, and the way we've been treating it up until now is to block the postsynaptic receptor. So, you know, I think there has been a better understanding of some of the pathways and new approaches to treating the illness.

But I think we were left with, as we said before, a very, very, heterogeneous phenomenon. And there may be people who have different mechanism of action. It may be we see the interaction between genetics and environmental factors. And we need to better understand in which category people fall into.

00:09:20:01 - 00:09:24:02 [Tania] Are there any biomarkers on the horizon so that we can understand this better?

00:09:24:08 -  00:10:25:00 [Dr. Kane] There's certainly excitement about genetics and about neuroimaging and even electroencephalography. But we don't at this point have biomarkers that are useful at the clinic level, to help better understand which treatment to use or which treatment might work or to predict the prognosis of that person. So we're really trying the best we can to take advantage of different treatment modalities.

We know that medication can be very helpful. We also know that psychosocial interventions are very important. And ideally we want to combine the two. Even though we consider this a biological illness or a brain disease, we know that psychosocial interventions, therapy, family therapy, family psychoeducation can also be very important in helping people achieve better outcomes.

00:10:25:02 - 00:10:35:07 [Tania] Doctor Kane, I want to ask you a little bit about the different symptoms. Can you explain the difference between positive, negative and cognition and how do we manage those symptoms?

00:10:35:08 - 00:13:10:19 [Dr. Kane]  Well, positive symptoms are things like delusions, which are fixed false beliefs, hallucinations, hearing a voice when no one is speaking, having difficulty communicating in a logical fashion. Negative symptoms involve no motivation, diminished affect, diminished expression, lack of involvement with day-to-day activities. Seeing friends, hobbies, socialization, sometimes poor self-care, and then cognitive dysfunction, which really is a core feature of schizophrenia and affects probably 80% of patients, involves things like, difficulty with attention, with verbal memory.

So remembering things like, if I give you a phone number, will you remember it long enough for you to actually dial the number? Attention obviously is very important. And then social cognition, which is how do we understand social interactions? Can I read someone's facial expression in a way that's meaningful? Do I understand my own emotions?

So these are all problems that people with schizophrenia have to deal with. And our understanding is that the cognitive dysfunction actually begins long before the other signs and symptoms. And so it really is a core phenomena. The negative symptoms also, which affect at least 50% of patients, also often begin before the positive symptoms. But once when someone gets to a point where the diagnosis of schizophrenia is actually made, we'll often see all three of those things.

One of the challenges is that the medications we have had up until now work mostly for the positive symptoms. They don't really help the negative symptoms as much as we'd like, and they don't help the cognitive dysfunction as much as we'd like. So we're very eager for new treatments to be available that can help patients in those particular domains and even positive symptoms.

Although medications can often be quite effective, they're not 100% effective. And then in terms of preventing subsequent episodes, medicine is very important, prophylactically. So even when someone improves from their acute episode, they're at risk for having another episode. Could be six months later, could be a year later. It could be two years later. The medicine is very, very effective in reducing the risk of a subsequent relapse.

But many people have trouble taking the medicines.

00:13:10:21 - 00:13:16:23 [Tania] And why is that? Is it because of the disease itself? Is it because of the side effect profile of the medication?

00:13:17:04 - 00:13:18:00 [Dr. Kane] It’s all of the above. Okay.

So the disease itself, I mean, sometimes people don't fully appreciate what's wrong and they can't really kind of wrap their heads around it. Sometimes people feel better once the medicine has worked for the acute symptoms, they feel better or they're out of the hospital. They're not having those delusions anymore or not hearing voices. So they feel, well, maybe I don't really need to take medicine anymore.

Nobody wants to take medicine on a long-term basis. Side effects. I mean, all of these things. And then I think it's human nature to have difficulty taking medicines too long. Whether you have diabetes or hypertension or epilepsy or asthma, it's a challenge. So the cognitive dysfunction maybe adds to that as well. Because I'm not as well organized as I could be. And remembering to do something. So yeah, it's many, many factors. But it's a huge problem. And you know half of our patients have difficulty with adherence. There was one study that was done in Finland, where they followed 2500 patients who were hospitalized for the first time with schizophrenia.

And within 60 days of leaving the hospital, they weren't getting their medicine. So it's a big challenge.

00:14:31:09 - 00:14:43:01 [Tania]  And I want to go into two pieces that you said you spoke about. The first symptom tends to be cognitive dysfunction. Is there a way or is there anything that allows us to diagnose it at that time?

00:14:43:03 - 00:15:12:17 [Dr. Kane]  It's hard. It's hard because when someone has cognitive dysfunction, unless it's really, really severe, you don't necessarily recognize it because you don't know where they should have been or where they sorted out if there's been a decrement. I think we are getting better at that. And now there's a lot of research going on in what's called the clinical, high risk, population, where we do see that cognitive dysfunction may be a predictor of somebody actually developing schizophrenia.

So there's a lot of research going on in these domains looking for early signs so that we can intervene earlier.

00:15:25:05 - 00:15:38:05 [Tania] You spoke about the research as well. You said that even getting patients on clinical trials sometimes can be challenging. Why is that and what can we do to improve that to get those answers?

00:15:38:08 - 00:16:07:19 [Dr. Kane]  Well it's interesting. You came from an oncology background. And I think if you look at, the clinical trials that go on in oncology, it's like many people participate in that because that's something that's brought to their attention very early in their treatment history and psychiatry. That doesn't happen. And I think it would be great if we could develop, you know, more clinical trial and clinical trial networks so that when people come into a hospital, they're offered opportunities to participate in some kind of research.

We could do research about anything. It could be access, how did you how did you get here? Who referred you? How long did it take you to realize that something was wrong? How did your parents react? Or it could be a treatment trial. It could be a registry, a long-term study.

There's so many things that we could learn from, but the average patient is not participating in research in psychiatry. And I think we need to do a better job of making research available to people explaining to them why it's important. A lot of people think, oh, I don't want to be a guinea pig.

You know, that's really not what it's all about. This is how medicine progresses, right? We have to learn from each other.

00:16:47:19 - 00:17:06:08 [Tania] I want to learn more about that because, when practitioners are treating patients, they see patients day in and day out. And there's a lot of research that's there. But how do you manage your time to learn all the new information, continue to see your patients and then apply it? Is that a challenge?

Is it too much information that needs to be distilled? What do you think is the real challenge, when it comes to that education?

00:17:13:00 - 00:17:32:05 [Dr. Kane]  I think that's a big part of it. I think there is so much - people are just deluged with information. You know, where attention is a challenge, right? What do I pay attention to? So I think we have to help clinicians. We have to synthesize data and present it to them in a way that's meaningful to them.

They often react to studies and say, but does that apply to my patient? So we have to do research that's really generalizable, that's real world to help clinicians understand, how does that apply to my patient. That means sometimes being more inclusive in our clinical trials so that we understand the impact of treatment in general.

I think we are getting better at these things, but we still have a ways to go.

00:18:01:08 - 00:18:23:22 [Tania] So you opened another door because I want to walk through and that is inclusivity. When it comes to clinical trials and even just beyond clinical trials, we know that there's still disparities when it comes to health care, particularly in this patient population. Where are we with that? And then I want to go into how do we make our trials more inclusive.

00:18:24:00 - 00:18:47:12 [Dr. Kane]  So I think we've made progress. We still have a ways to go, obviously. The US is very diverse. I think people struggle with, who can I trust? And I think we need to make sure that we have people working with us who who can talk in a meaningful way to anyone who's afflicted by a mental illness.

I think peer counselors can be very helpful. The idea of having someone else with the same lived experience, but who speaks your language, who comes from your culture, who understands what you're going through on a personal level. I think I think that can be very powerful. I don't think we use that often enough.

But we're making progress in that direction, too. I think more people are being trained as peer counselors. I think we're we recognize how important that is. I think there's been more emphasis on including people with lived experience when we design our clinical trials, when we execute our clinical trials to make sure that we're really hearing the patient perspective. Patient reported outcomes are very important.

But again, the diversity issue, we need to make sure that all of these things are available to everyone.

00:19:41:05 - 00:20:05:05 [Tania] You know, I was speaking to a colleague of mine, and one of the things, again, that he put in perspective for me was, when someone is diagnosed, for example, with cancer, what do we do? We go in and we say, how are you dealing with things? Are you okay? And all of a sudden you have this empathy, more sympathy, at least towards them.

And then one of the things he told me, though, is what happens when you meet someone who was diagnosed with schizophrenia instead of leaning in, you tend to lean out because of all that is associated with that. So I just wonder, as a health care community, how do we get more people to lean in? Is it a lack of understanding?

Is it a is it a fear factor? But what can we do?

00:20:28:23 - 00:20:51:16 [Dr. Kane] I think it's all of the above, in a sense. There is a fear factor. I think people tend to be afraid of what they don't understand. But we have to recognize that mental illness is an illness like any other illness. We have to treat it the same way, with the same kind of understanding, appreciation and consideration.

I think in schizophrenia. We also need to do research and we need people to participate in research and benefit from the research also to make sure that we get the support that we need. I don't think enough funding goes into research on mental illness, for example. I mean, everyone is sympathetic to oncology or to heart disease.

But the reality is mental illnesses account for a tremendous amount of disability, not to mention personal suffering and family burden and even shortened lifespan.

00:21:25:20 - 00:21:50:15 [Tania] There's something that I like to call patient-driven science. And that is where we develop our drugs for patients. So we move from a product-centered drug development to a patient-centered drug development. And in pharma we create the technology. As a physician, you have the expertise and patients, they understand - they're living their disease.

How do we come together to really develop the best drugs for patients?

00:21:55:09 - 00:22:22:11 [Dr. Kane] So we need to really have ongoing communication between the federal agencies in the US, whether it's NIH or the FDA and industry and academia and clinicians in the field and patients and families all working together for a common goal. Everyone has their role to play in that process. But it's really a collaborative process.

00:22:22:13 - 00:22:40:13 [Tania] And I'll say this, one of the things I tell my team all at the time is even though you may not be touching a patient at this time, you are still a part of this treatment team. And the outcome of that patient is still our responsibility collectively, as part of the health care community.

00:22:40:13 - 00:23:01:14 [Dr. Kane]  And it's really true. I mean, everybody, when we're doing, a clinical trial or we're doing research, the study coordinator or the person working on recruiting has to understand the critical role they play. Everybody plays a critical role. I mean, I think that's true across the board that we need to understand that everybody's important and they need to they need to recognize that.

00:23:02:11 - 00:23:19:19 [Tania] But that's so important because I think we forget that. And so how do we all hold hands and make sure that we all feel that responsibility for that human that we are treating?

What are you most excited about when it comes to innovation for patients living with schizophrenia?

00:23:27:01 - 00:23:48:03 [Dr. Kane] Well, I am excited about what we were discussing earlier, which is the evolution of new thinking about how we might manage the dopamine dysfunction that exists in schizophrenia. The development of muscarinic agonists I think is very exciting. There are half a dozen companies now that are involved in developing such drugs. So I think that's very welcome.

I think other innovations we're seeing more and more, in brain imaging; trying to understand neural networks and problems in connectivity in various brain regions. It's great to see the innovation that's going on now there. You know, there's been a lot of interest now in a in a new way of looking at the control of dopamine in the brain.

00:24:11:18 - 00:24:19:15 [Tania] You spoke about muscarinic receptors. And that's a new mechanism that I know there's been a lot of discussions about. Can you tell us a little bit more about it?

00:24:19:17 - 00:24:39:20 [Dr. Kane]  There's been interest in muscarinic receptors for years and years, but I think now we're getting a lot closer to fruition. And a sense of what we've seen is that by influencing some of the muscarinic systems, if you will, we can have an influence on that presynaptic release of dopamine.

And importantly in the brain areas that are critical to the development of schizophrenia.

00:24:45:13 - 00:24:53:21 [Tania] What advice do you have for us in order to improve the patient experience together for those living with schizophrenia?

00:24:53:23 - 00:25:22:06 [Dr. Kane] People have to understand what mental illness is, how common it is, how it affects people, how it affects individuals, families. And then, as we were talking earlier, the right collaboration between all the stakeholders. And that means the patients, the families, the pharmaceutical industry, academia, federal agencies, etc., to really go after this problem in a major way and it is getting more attention.

I think there's more awareness of mental illness. I think during the pandemic and after the pandemic, there seemed to be kind of an emergence of a better appreciation of mental illness. But, we still have a long way to go.

00:25:35:23 - 00:25:47:01 [Tania] Well, I think all of us are ready to lean in to this together. And I just want to thank you for your time. Thank you for your expertise. Looking forward again to continue to move this field forward.

00:25:47:02 - 00:26:00:04 [Dr. Kane] My pleasure. Thank you so much for this opportunity.

00:26:00:06 - 00:26:04:18 [Tania] What was that novel that you read initially?

00:26:04:20 - 00:26:16:05 [Dr. Kane]  Well, probably just the Crime and Punishment novels are not necessarily all fiction, right? I mean, a lot of it is actually based on lived experience that people have had. It took me a while to realize.

Tania [00:01] Welcome to Doctors Unscripted. I'm Dr. Tania Small, and I'm here to bring you into a different kind of conversation with some of the brightest minds in medicine and research. In part two, I sit down with world renowned geriatric psychiatrist, Dr. George Grossberg. We delve into the exciting world of emerging targets, the hidden crisis of Alzheimer's psychosis, and the science that's shifting this disease from something we manage to something we delay and eventually prevent. So join us as we shatter outdated paradigms because the future of Alzheimer's care is being rewritten. Now, let's get started. Can you take me through when someone is diagnosed with Alzheimer's, what are the different spectrum of mood disorders that can be associated with it?

Dr. Grossberg [00:58] Yeah, so there's a spectrum of mood disorders and a spectrum of behavioral disorders. Everything from major or clinically significant depression early on and later on as well, as well as more of a situational or reactive depression, which may actually respond very well to interactive psychotherapy, but also very common throughout the disease. I had a patient recently who heard and saw and very much believed that there was a family with small children living in her basement, and she tried to convince her adult children that this family's here, they're living in my basement and they're not supposed to be there. And of course, every time they would go down to the basement, they didn't see the family, and then she would say, well, they must have snuck out because they knew you guys were coming, and so on. So psychotic symptoms are also not rare. So there's a spectrum of what we call neuropsychiatric symptoms that can accompany Alzheimer's disease from the earliest stages to the middle or moderate stage, and then also in the more advanced or severe dementia stage.

Tania [02:01] Is there an early sign that these patients may develop these types of psychosis or any kind of mood disorder?

Dr. Grossberg [02:09] That’s a really good question. So I'm not sure that we can predict that, But what we do know is that people who early on develop these neuropsychiatric symptoms, whether it's agitation or psychosis or depression, the spectrum of behavioral symptomatology, they don't tend to do as well as people who don't have them. They tend to progress more rapidly. They may end up institutionalized more earlier or more frequently than those that don't have them, but we don't really have a good way to predict who's going to have them. Now, of course, if someone has, you mentioned depression before, if they have a history of recurrent depression and now they're diagnosed with Alzheimer's disease, they're going to be at greater risk of developing depression down the road. But as far as the other neuropsychiatric symptoms, they're very hard to predict.

Tania [03:01] How do we recognize psychosis in Alzheimer's and how is it different than other different mood disorders?

Dr. Grossberg [03:08] Yeah, those are important issues. So when we treat patients with Alzheimer's disease, we're not just looking at the cognitive aspects, although the newer medications for Alzheimer's disease have been developed with that kind of focus, including the disease modifying kind of therapies that are now becoming available, we're also thinking about the associated, what I call neuropsychiatric symptoms of Alzheimer's disease. And there are several, the most common actually, but not necessarily the most disabling, is apathy or a lack of motivation being kind of a serious couch potato, serious couch potatoes. They don't cause a lot of trouble. So often it's not paid attention to, people are apathetic about apathy, but the ones that you can't be apathetic about, the ones that are really, really impactful are agitation, even overtly aggressive behaviors and psychosis. So psychosis in Alzheimer's disease is very common. To your question, maybe 50% of patients have psychotic symptoms sometime during the course of the disease. Most often it's going to be delusions kind of firm, false beliefs that a patient has that don't jive with our sense of reality. They could be, for example, accusatory or paranoid a patient recently in the long-term care environment who started believing that the nurses were out to get her and that her food and medicine was actually poisoned. So if she refused to eat, she refused to take her medication. I had another patient recently that had visual hallucinations that were very frightening. There were these frightening creatures coming through the window and people would see her shaking and she would try to describe what she was seeing, but it was very hard to kind of follow her in the more advanced stages of dementia. Patients can't tell you what's going on, but they can't have psychotic symptoms. They can have visual hallucinations, and an evidence of that might be that they're picking at things that nobody else sees. I had a patient recently also in the assisted living memory care environment with Alzheimer's disease where the nurse's assistant was walking into her room to clean the room or clean her sheets, whatever, and the patient was facing the corner of the room and carrying on an animated conversation with someone that wasn't there. So you can assume that she may be hearing voices and maybe having auditory hallucinations, maybe even visual as well as a manifestation of psychosis. So psychosis, agitation, they can often come together, can be very, very disabling as can depression. So depression is very common throughout Alzheimer's disease, and if we don't recognize it and don't treat it, it can accelerate disease progression. We know that all of these neuropsychiatric symptoms when they occur in Alzheimer's disease, especially early on, are a bad sign because even if we treat them appropriately, there can be more rapid disease progression. And of course, if we don't treat them appropriately and they remain uncontrolled, the family can no longer take care of that kind of individual, and they often end up having to place them in a nursing home or in a long-term care environment. So these are ancillary symptoms beyond the cognitive disturbances that we see in Alzheimer's disease that are just as impactful, if not more so for patients and family than the cognitive disarray that they see with the disease. But in all patients, there are just a whole range of different risk factors for Alzheimer's disease that are modifiable. So we need to do a much better job educating middle, middle-aged individuals that are moving into their later years to basically try to avoid or to manage and treat these risk factors so that we can decrease the rate of Alzheimer's disease later on or delay the onset of Alzheimer's disease, everything from smoking to obesity to high lipids, cholesterol. I mean, there are many different modifiable risk factors, and the earlier we get them under control, the better one's going to be as far as their risk of Alzheimer's disease later.

Tania [07:45] So our audience that listens, they're mostly HCPs, and so I would love you to take us through what should we be doing to manage these symptoms or different diseases to delay?

Dr. Grossberg [07:59] So that's a very important topic. I talk about lifestyle modification.

Tania [08:03] Yes,

Dr. Grossberg [08:04] And I always start with the cardiovascular because there's this saying that what's good for the heart is good for the brain. So anything that's going to be decreasing, the risk of heart disease, heart attacks and so on. Things like high blood pressure, hypertension, diabetes, hyperlipidemia, obesity, lack of exercise and so on, and the better those are controlled, the better it's going to be not just for your heart, your cardiovascular system, but also for your brain. Then we talk about habits, things like smoking, things like alcohol, especially in excess, which may be problematic. That leads us to dietary alterations and changes. We now recommend very, very highly what's called the MIND diet, which is a combination of the Mediterranean diet with low sodium or low salt, which is the dash diet for hypertension.

Tania [08:59] Even though the Mediterranean does come with wine

Dr. Grossberg [09:02] Mediterranean very limited amounts of wine. That's true. We are learning now that alcohol is a kind of a two-edged sword, that there may be some benefits of very modest drinking, but there may be other liabilities even of modest drinking. So alcohol is very controversial right now, but what we do know is in my older patients who are having cognitive issues, the best amount of alcohol to take is zero. Once you start to have memory problems, we talk about activity, the importance of activity, and I talk about activity in four spheres, all important talk about physical activity, 150 minutes a week or more of walking or some kind of exercise, more is better. Mental activity, challenge your brain, keep your brain active. Social activity, don't be a hermit or a couch potato spiritual activity, whether it's religious activity or things like meditation, mindfulness, yoga, all four are very, very important, and we want to make sure that you're doing those on a regular or day-to-day basis. There can be other things that we want to keep people active in, so people considering retirement, sometimes we'll ask 'em if they have hobbies or other activities to get into. If they don't, maybe you should reconsider retirement. Obviously, depression, if it's recognized, needs to be kind of treated promptly. There are many different risk factors. Hearing vision, if you have hearing loss, get hearing aids, if you have visual issues, get that fixed. All of those are risk factors for Alzheimer's disease if they're not recognized and not addressed. So there are many different risk factors that are modifiable and the more of those that we kind of work on and employ the microbiome. So we do recommend either fermented foods like cultured yogurts and things like that, or a probiotic to introduce good bacteria into the system. That's part of lifestyle modification. If it's not part of your lifestyle, you need to make it part of that together with the mind diet. But the bottom line is the more of these things that we do, the better the likelihood of either delaying or decreasing the risk, even if you have genetic loading, that's very recent data showing that you can even overcome the genetic loading by doing more and more of these lifestyle modification approaches utilizing more of these approaches.

Tania [11:38] So what do we say to the non-believers? Because we've, there's a lot of discussions talking about the brain, gut connection, health and access, and there's still a lot of non-believers and a lot of physicians still don't believe in it. Can you share a little bit more of the data and how do we convince them? 

Dr. Grossberg [11:54] It's interesting because I'm actually working with one of our super bright fourth year medical students. We're putting together a presentation on the relationship between dysbiosis, bad bacteria in the gut and how they may actually get into the bloodstream and cross the blood brain barrier and maybe contribute to cell death or inflammation of neurons, which is part of Alzheimer's disease and other brain diseases. But there's really quite a bit of evidence that what happens that bacteria in the gut may actually have systemic effects or benefits or may have deleterious effects on brain functioning. One of the areas that to me also has been always very fascinating is the relationship between gum disease. As people get older, they often have inflammatory changes of their gums. They may lose teeth because of that. So gum disease is caused by a specific bacteria that actually has been found at autopsy in close proximity to the plaques and tangles in all Alzheimer's disease, and we think may contribute to inflammation and cell death. And there is, in fact, one of the risk factors for Alzheimer's disease is periodontal disease, especially if it's not properly and effectively treated. So that's one evidence or one area of evidence. We also know that there are diseases that are caused by certain bacteria that affect the gastrointestinal system, where if you can introduce healthy bacteria into the GI tract, it pretty much wipes out the pathology. H pylori is the example of that. So there are many little pieces of evidence that kind of show us or are beginning to show us that what happens relative to bacteria in the GI tract may have systemic effects and specific effects on the central nervous system. And we think introducing good bacteria addressing this dysbiosis is what's called maybe beneficial, and it's so easy to do.

Tania [14:11] Let's talk about microbiomes

Dr. Grossberg [14:13] The microbiome. Another hot topic.

Tania [14:15] Yes.

Dr. Grossberg [14:16] So we do recommend either taking a probiotic capsule or eating fermented foods like the cultured Greek yogurts. Things like kimchi and sauerkraut and kombucha and things of that nature can introduce good bacteria into the system and may have benefits. Yeah,

Tania [14:36] There's data, and this is separate in oncology that shows your point that bacteria can increase resistance to certain medications, and so there's a lot of studies happening out there.

Dr. Grossberg [14:47] Yeah, no, that's a really exciting area and kind of an emerging area. A lot of people don't know much about it. Some of the earliest data actually was in some posters at the international Alzheimer's meetings where some scientists from Asia actually examined bacteria in stool and patients who had Alzheimer's disease versus non Alzheimer's age match sex, match whatever controls and found a lot more of the bad bacteria with Alzheimer's patients versus the good bacteria in those that didn't have it. So that began this inquiry into the importance of the gut bacteria, a microbiota,

Tania [15:38] So biologically what is happening when it comes to different types of psychosis.

Dr. Grossberg [15:42] So we think that there are similar phenomena to what we see with psychosis and other neuropsychiatric diseases, maybe related to dopamine, maybe related to the nicotinic system and nicotinic receptors as well that trigger the symptoms of psychosis. And we do know that the current generation of anti-psychotic medications can be helpful for psychosis in Alzheimer's disease. The problem is, and they all work very similarly in that they basically block excessive amounts of dopamine And older patients, whether with or without Alzheimer's disease, are much more sensitive to the common side effects. They develop the Parkinsonian side effects more readily. We worry about the metabolic side effects, effects on blood sugar and so on. Lipids, high lipids, they already have problems with that. Some of them are too sedating, some of them drop blood pressure, which can increase the risk of falls, which is huge in this patient population. But in many other areas of medicine, we're starting to learn that what we learned at medical school isn't what we now know at the present time. So what I learned in medical school was that psychosis was basically too much dopamine be manufactured and you block the dopamine with one of the older or newer kind of antipsychotics, and you're going to help with the positive symptoms of psychosis in any disease that has those kind of manifestations. It's only been more recently that we realize that there may be other very important players that precede the excessive amounts of dopamine being secreted, and that would relate to the nicotinic receptors, particularly the M1 M four receptors. You're preceding the excessive synthesis, and these drugs work in the regions of the brain that are most affected not just by psychotic symptoms, but also cognitive symptoms. The M1 receptors can be more involved in the cognitive arena and the M four decreasing the excitatory changes that are triggered by glutamate in the glutamatergic system, and we're looking at parts of the brain like the hippocampus, for example, which are the seed of memory and cognition. So that's a new understanding and I think potentially a big breakthrough.

Tania [18:18] We spoke about the psychosis piece. I can only imagine the toll that it also takes on a family. I mentioned that my grandfather was diagnosed with Alzheimer's, and I spoke to you about certain behaviors he had, such as thinking someone stole his money and which

Dr. Grossberg [18:44] Is very common,

Tania [18:46] And you look at patients who were sometimes head of households and head of families now with Alzheimer's disease plus the added psychosis to it, how do you counsel families, because you spoke about earlier also it's the community, it's the family. How do you manage, help them manage

Dr. Grossberg [19:09] Through? Those are great questions, and I think it's particularly important because a lot of families are even embarrassed and reluctant to talk about these neuropsychiatric symptoms, whether it's accusatory behaviors or agitation. They don't understand that these are common important parts of the disease. So unless we as healthcare providers ask about, so one of the things I've been advocating is that if you're a primary healthcare provider that's taking care of an older patient, working with them in the family that maybe has a dementia like Alzheimer's disease at every visit, at every visit, you should ask them and ask the family, has there been any behavior change? Has there been any personality change? Is there something going on other than just the memory and cognitive arenas that we need to be aware of? Recognizing that it's these behavior or neuropsychiatric symptom type changes, whether it's agitation, psychosis, depression and so on, that really are most stressful to families. They're the number one reason within Alzheimer's disease where families finally just give up, throw in the towel and say, I just can't take care of mom or dad anymore. And they think about institutionalization right now in the US the number one reason for ending up in an institutional setting like a nursing home is false. Number one is false. So when the family can no longer guarantee safety of their loved one, they start thinking about long-term care. But number two, running neck and neck, right behind that are the neuropsychiatric symptoms like psychosis, agitation against a background of a dementia like Alzheimer's disease. Those are the most distressing, much more so than forgetfulness or some of the cognitive changes. So it's very important to recognize them, to diagnose them and to obviously offer treatment and to educate the family that whenever you go see your doctor or your healthcare provider, make sure you tell them about these kinds of changes. Very common and they're very impactful.

Tania [21:17] So there's something along that line that we call patient driven science. We talk about it all the time on this show, and it's really making sure that we're developing the medicines for patients. So it's not a product-centered drug development process. It's a patient-centered and really following the needs of those patients. With that in mind, because there's a lot of new studies coming forward when it comes to Alzheimer's, yet it's so many have failed, what do you recommend when we're thinking about designing the right medicines, the right studies for patients? And I'm going to start with clinical endpoints. What is most relevant to families, to patients when we're designing these studies?

Dr. Grossberg [21:59] So we always have to think about patient and family as being one entity, and then of course, they together with us are part of the therapeutic alliance. There's no doubt about that. But we also want to keep in mind that we want to focus on clinically relevant and impactful symptoms. I like the word impact, and we're not just talking about impact on the patient, but also impact on the care partner.

Tania [22:31] What, in your opinion, are truly impactful clinical endpoints that we should be looking at? Yeah.

Dr. Grossberg [22:36] Well, behaviors are clinically impactful. There's no doubt that our focus has been primarily on two areas. Cognition and activities of daily living and of the two activities of daily living to me are much more impactful than just memory or cognitive functions. So knowing about how independent or dependent a patient might be, those need to be increasing areas of focus. And we talk about activities of daily living, two different groups, basic and more instrumental activities of daily living, the basic activities of daily living, and we ask about those is how independent is the person in things like dressing and bathing and grooming and feeding themselves and hygiene and so on. Those are not lost until the more advanced stages of Alzheimer's disease. But there's also what are called the instrumental activities of daily living. Those would be things like being able to go to a grocery store and pick up some items that you need, being able to drive, maybe being able to balance a checkbook or being able to participate in healthcare decisions or financial decisions to even decide what you want to order at a restaurant on a menu rather than depending on someone else to kind of order for you. Those are important and points that often are not paid as much attention to because we're focused on memory and cognitive arenas. And then the other area is what we've been talking about. Another important endpoint is what impact can we have on behaviors that are going to be very distressing to the family, to the care partners, whether it's psychosis, whether it's agitation, whether it's depression, anxiety, irritability, and so on. So those can be built into clinical trials as well and move higher up the totem pole than just looking at what evidence we have that this new treatment might stabilize memory or maybe slow down some of the cognitive changes. Those have been generally considered secondary endpoints, but it would be nice to move them further up the totem pole.

Tania [24:46] So let's talk about what's new, what's next in this world of Alzheimer's disease as well as Alzheimer's and psychosis?

Dr. Grossberg [24:53] Yeah, it's very, very exciting, I think, and you talk about it in two arenas. We're talking about the disease itself and then the neuropsychiatric symptoms, and we focused on a couple of the neuropsychiatric symptoms, psychosis, which is very common and very impactful, impacting quality of life of both the patient as well as the family, the care partners. But let's talk about the disease itself. So up until two years ago, we've been treating Alzheimer's disease once it's diagnosed, and we mentioned we're making a lot of headway and biomarkers and more accurately diagnosing Alzheimer's disease, but we've had what are called the symptomatic therapies. Those have been beneficial and may still be useful, but we haven't been able to really make an impact on disease progression up until almost two years ago when the first of the NOW two disease modifying therapies became FDA approved, and a lot of us are combining the symptomatic approach with the disease modifying therapies in a similar way that you and I were talking about the field of oncology. Oncology, yes, often combines drugs of different mechanisms to better control various neoplastic kind of disorders. So we're using that as a model in Alzheimer's disease. The other exciting, I think, futuristic model for Alzheimer's disease, and these are being tested now, is to see if the disease modifying therapies, which we are giving to people very, very early in Alzheimer's disease, what if we give them to at risk individuals? Can they over time decrease the risk of developing Alzheimer's disease or maybe delay it together with the very, very important disease, very, very important lifestyle modification approaches to Alzheimer's disease. And as you and I were talking, I personally believe that lifestyle modification is as robust a treatment as any medications. And when you combine lifestyle modification with some of the new and up and coming promising medications, that may have a major impact on the prevalence of the disease as far as onset and maybe even potentially delaying it in individuals who are genetically vulnerable. Similarly, in looking at the neuropsychiatric symptoms now, we talked a lot about how our old thinking about psychosis is now very different. We now have for the first time an FDA approved treatment for agitation specifically in Alzheimer's disease, but we didn't have before. So I think the future looks very bright both as far as potentially prevention and or delay. We're already at a much better diagnostic kind of sensitivity arena than we were before. And the future looks very bright as far as being able to treat the neuropsychiatric symptoms in a tolerable fashion, specifically psychosis and conditions like agitation,

Tania [28:01] Especially, I mean, you talk about the combination piece and obviously in oncology that is what we do. We do double. It's triplets sometimes quads,

Dr. Grossberg [28:08] Exactly. We're also worried about drug drug interactions, and we want a medication that's relatively clean in that regard, recognizing that our older patients, they're often on several different medicines that are needed to control their blood pressure or control their diabetes. Now, you had brought up earlier this other exciting future area of the GLP one agonists. They seem to have anti-inflammatory effects in the central nervous system.

Tania [28:35] So you talked a little bit about prevention. I want to kind of poke at that because I mean, imagine if we could get to the point where we can prevent, not just slow down, but prevent someone from converting to true Alzheimer's disease. Do you think that's in the future?

Dr. Grossberg [28:50] I hope so. A number of years ago, someone asked me about how long I thought it was going to be before we had a cure. I don't know what that means, but a cure for Alzheimer's disease. And I went out on a limb and I said, well, maybe in the next couple of decades. That was, I think a couple decades ago, we haven't had a cure yet, but we're moving in the direction of prevention. If a combination of different things together may be able to either delay significantly, delay onset, or perhaps decrease the risk even in individuals who are genetically vulnerable. A recent study, which we haven't talked about was in genetically vulnerable individuals, those that had a first degree relative that was diagnosed, specifically diagnosed with Alzheimer's disease, and now we're looking at the progeny. So it's an adult son or daughter with a mom or dad diagnosed with Alzheimer's disease. Strict lifestyle modification approaches have been shown to be beneficial even in those individuals as well as those that already have the early stage of Alzheimer's disease to maybe significantly slow it down. So one of the areas that I like to emphasize is the power of lifestyle modification in addition to the new pharmacotherapies that are being developed, which are pretty amazing.

Tania [30:11] Yeah. So what advice do you have for healthcare providers in this field?

Dr. Grossberg [30:16] One of the pieces of advice that I have for treating healthcare providers, whether it's physicians or PAs or advanced practice nurses who are on the front lines, is the importance of always involving the family is the importance that anytime you see an older patient in your office and there's a concern on the part of a family member about that person having issues with memory or cognitive change, that that needs to be taken seriously and should be promptly, thoroughly evaluated. So we can remedy reversible factors and identify individuals that can benefit from the new treatment approaches to Alzheimer's disease.

Tania [30:59] Thanks for all the work you're doing and all the work you've done to move this field forward. Sometimes it's hard to see within our generation the big changes that have been made, but from the time you've started until now, you've seen the growth in the field and a lot of it has to do with you and the work you've done. So thank you much.

Dr. Grossberg [31:17] I won't take the credit, but thank you,

Tania [31:24] Dr. Grossberg. Now, let's go back in time. What would you tell your 1980’s self if you could?

Dr. Grossberg [31:31] I would pretty much tell myself to do what I've done, which is pursue what you really, really have a passion for doing. And for me, the passion wasn't just in taking care of patients and families, but in also educating the next generation, because that can be as meaningful as all the hopefully good help that we're providing to our patients and their families.

Tania [31:53] In other words, you wouldn't change a thing?

Dr. Grossberg [31:56] Well, no. I really like it the way it was, and I hope to influence young doctors in training to do what I do and have a passion for what they do, and particularly a passion for working with older adults and their families who are so needy and can really benefit from our health.

About Dr. George Grossberg
 

George Grossberg, MD, is a trailblazer, educator, and a clinical psychiatrist who provides comprehensive psychiatric services for patients ages 65 and older.  Dr. Grossberg is the Henry & Amelia Nasrallah professor in the Division of Geriatric Psychiatry in the Department of Psychiatry and Behavioral Neuroscience at Saint Louis University School of Medicine, Missouri. He's also the past president of the American Association for Geriatric Psychiatry and of the International Psychogeriatric Association.

Dr. Grossberg is a paid consultant for BMS.

00:00:01:13 - 00:01:32:14 [Tania] Welcome to Doctors Unscripted. I'm Dr. Tania Small, and I'm here to bring you into a different kind of conversation with some of the brightest minds in medicine and research. 

How do we respond when a person diagnosed with schizophrenia commits a crime during a psychotic break? Do we see a criminal or a human being worthy of treatment, dignity, and a second chance at life?

Our guest today, Dr. Ilan Melnick, is challenging every assumption we’ve held about severe mental illness, justice, and rehabilitation, with a 90% reintegration success rate and 0% recidivism. Today, we'll explore psychosis on trial, rehabilitation and evidence-based care, rights reclaimed, and compassion on locks. We'll step inside Passageways, the largest forensic reintegration facility in the US, a pioneering model built not on confinement but on trust, empathy, and comprehensive care.

And here's the remarkable part. There are no locks on the doors. That's right. No locks. Dr. Melnick will show us why these individuals don't just need care; they deserve to be seen, treated, and unlocked. Now let's get started.

Thank you so much for joining us here at Doctors Unscripted.

00:01:32:14 - 00:01:35:12 [Dr. Melnick] Thank you so much for inviting me. I really appreciate it.

00:01:35:14 - 00:01:51:07 [Tania] So I have a lot that I want to get from you. 

00:01:51:09 - 00:03:00:18 [Dr. Melnick] Talk to me. 

The first question is when you were in med school…actually, let me take a step back. When did you know you wanted to be a psychiatrist?

Great question. So, my path really didn't start with psychiatry. When I was in medical school, I loved working with my hands, I thought it was just really cool to be in a controlled environment, and really thought surgery. Actually went and started a residency in surgery and ophthalmology at Harvard, at Mass Eye & Ear.

And, after about 2 months, realized that it was something I really hated doing. At the end, I was stuck doing refraction a lot and not something I really enjoyed. One of my mom's friends was head of Jackson Memorial Hospital Crisis, and he invited me to come and see what he did. And day one, I walk in and we’re, like, tackling people to give Haldol and Ativan to people.

And I thought this was so much cooler. Really loved it. Loved every moment of it. And realized quickly that this is - this was a better fit. Quit my residency in surgery and ended up starting at the University of Miami.

00:03:00:20 - 00:03:04:19 [Tania] Usually in med school, we can typically predict what people are going to be.

00:03:04:19 - 00:03:05:21 [Dr. Melnick] Yes.

00:03:05:23 - 00:03:08:11 [Tania] What did people assume you are going to be?

00:03:08:13 - 00:04:14:08 [Dr. Melnick] Gosh. A dropout, I think, was what they were…No, in med school, I was, you know, growing up with dyslexia was always very difficult for me to kind of imagine myself doing anything that had to do with reading a lot and managing those kind of patients. So I think surgery was where people really thought I was going to do well.

It is something that really that I learned early on when doing psychiatry that my ability to recognize patterns really was helpful in being able to become a better psychiatrist. Being able to recognize how people think and realizing that neurotransmitters do play a role in that, and being able to figure out what neurotransmitters were either too high or too low, and being able to manage it was something I thought was so cool.

And so, although, yes, surgery was something that I really thought I loved a lot, I realized that this is really my true calling.

00:04:14:10 - 00:04:21:14 [Tania] So talk about a little bit what kind of psychiatrist are you. I know you — I learned a little bit about forensic psychiatry. Can you tell us a little bit about that?

00:04:21:14 - 00:05:04:04 [Dr. Melnick] Yeah, sure. So, I'm one of these — I have a lot of different types of practices. So although I do work in forensics, and forensic psychiatry is not what you see on TV. A lot of it has to do with testifying. A lot of it has to do with recognition of patients that maybe are found either incompetent to proceed or are not guilty by reason of insanity.

But the other half of my practice is working with celebrities, models, and athletes in a concierge psychiatric practice. So I get the balance of working with the, you know, the very sick who don't think they're sick and the not so sick who think they're desperately ill and pretty much everywhere in between.

00:05:04:06 - 00:05:11:16 [Tania] What led you there in terms of forensic psychiatry? And then, what exactly does that mean, and how does that translate to the patients that you see?

00:05:11:16 - 00:05:53:19 [Dr. Melnick] So I came into forensic psychiatry kind of by accident. I was doing a lot of, a lot of testifying in court. I was, talking to different types of patients. And I realized that this was a very difficult-to-treat population, but gave me a lot of challenge. And I was asked to cover for a forensic psychiatrist at a program and I thought that was kind of cool. And, when I had the opportunity, they asked me if I would join in, and, as the chief medical officer. And at the time we only had, like, 25 patients. And then we managed to escalate it now. I've been there since 2008, and now we have about 130 patients there.

00:05:53:19 - 00:05:59:16 [Tania] So take me through the process. You're in court, so a patient is found.

00:05:59:18 - 00:06:03:02 [Dr. Melnick] Well, let's put it this way: A patient goes and they commit a crime.

00:06:03:06 - 00:06:04:12 [Tania] Okay. Start there.

00:06:04:14 - 00:06:11:14 [Dr. Melnick] So they commit a crime. At that point, either they're competent to proceed to trial or incompetent to proceed to trial.

00:06:11:20 - 00:06:12:02 [Tania] Okay.

00:06:12:06 - 00:06:36:20 [Dr. Melnick] If they're competent, then they go through the normal court system. If they're incompetent, they have to restore competency within a forensic psychiatric facility, where they give them classes to understand the criminal justice system. And some of those patients are restorable and where they're able to become competent, and some are considered nonrestorable, where they're not able to regain competency.

00:06:36:20 - 00:06:39:21 [Tania] And how do you determine if a patient is nonrestorable?

00:06:39:22 - 00:06:49:11 [Dr. Melnick] So it's usually about 5 years. So if a patient after 5 years is not able to become restorable, they kind of drop all their charges.

00:06:49:12 - 00:06:50:03 [Tania] Interesting.

00:06:50:04 - 00:06:51:01 [Dr. Melnick] Yeah.

00:06:51:03 - 00:07:04:02 [Tania] And you said at one point, which I found fascinating, you can tell whether someone is, I guess, faking versus truly, truly not guilty due to reasons of insanity. How can you tell?

00:07:04:04 - 00:07:48:08 [Dr. Melnick] Yeah, it all has to do with the patterns. Patients who are illogical are consistently illogical. So, usually when patients start changing from becoming illogical to logical within conversations, we normally think very linearly, where we think in a straight line. And what happens is that, as, you know, patients who have psychosis and they're having delusional thoughts, they may become circumstantial and sometimes even tangential. With a, you know, when you're dealing with patients and, and asking them questions, I usually will start asking things very quickly to try to get them off beat, to see whether or not the illogical becomes logical within their, their thought process.

00:07:48:09 - 00:07:49:20 [Tania] Give me an example.

00:07:49:22 - 00:08:47:11 [Dr. Melnick] I will say things like, you know, ask questions in rapid successions. You know, what's your name? Where are you from? You know, where did you go to high school? And then start going into more theoretical questions and start changing topics. And people who are illogical will continue in the illogical thought. People who are logical will start thinking, why is he asking me all these questions in different orders?

And, and oftentimes that shows me that the patient is, you know, not able, it is not really telling the full truth of things. We also look at body reactions, body tone. If they are very comfortable in the way that they're talking, even though they're talking about some illogical things, compared to people that, let's say, are trying to come up with ideas, what you'll see is that they'll start stuttering things won't make sense. You know, things they say at the beginning differ from things that they say at the end. The story isn't fully developed.

00:08:47:12 - 00:08:56:04 [Tania] Let's talk about the illogical. First, it starts illogical or not straight. And then what is your end game, is it to get them to… 

00:08:56:05 - 00:10:40:19 [Dr. Melnick] Basically the, the laws in the United States say that you cannot try somebody or someone who doesn't understand what they're being tried for, or whether the court system, that they understand the court system at all. Reasons why we can't, you know, people with severe mental retardation, you can't bring them to court for certain, you know, crimes that they commit.

Once they were able regain competency, then all of that changes; they are able to come out with, they're able to then understand what the court system is all about, you know, why they're there, what the seriousness of their charges are, what are the consequences of the, of the charges that they had. In that way, we’re able to restore competency.

So once you restore competency, then they go to trial. And either they're found guilty or they're found not guilty. Now, if they're guilty, then they go to jail, whatever it might be for whatever crime they committed. If they're considered not guilty, then you have either they're not guilty because they get let go or they're not guilty because at the time of their crime, they didn't understand what was right and wrong, they didn't understand what was happening within that, that moment because of their mental illness. So patients with schizophrenia who hear voices that say, the people on the bus are, you know, aliens, and it's my job as a citizen to kill all the aliens on the bus, and so that may happen. It didn't mean that they were killing them with the idea of, of just killing people for, you know, fun; it was really because of the delusional thought process that they were having. Once they get better in their delusional thought process, these people would probably not have killed those people on the bus.

00:10:40:21 - 00:11:07:01 [Tania] So then let me ask you this question because, how do you reconcile, I guess, the ethical dilemma between knowing that this patient did not know what they were doing and really couldn't control their actions, versus to the actual crime being committed? Like, like, do you ever walk into this ethical dilemma when it comes to that? Because you're seeing families who may have lost a loved one versus a patient?

00:11:07:03 - 00:12:13:06 [Dr. Melnick] So oftentimes in our forensic facility, it's usually directed at family members themselves. So it's, usually it's their parents, it could be their children, it could be, you know, spouses. The idea is, is that usually the ones that do it because of insanity, do it because not, there's no secondary gain or any, any secondary gain to, to do the crime.

I'll give you an example of an arson. We have a patient that was cold one winter, and he lit a, a little can on fire, just to kind of heat himself up. And it caught a dumpster on fire, which then caught a building on fire. And it wasn't, you know, he was a person with chronic paranoid schizophrenia, and he ended up having to go to prison because of that.

But, you know, when he was then found, you know, when he went out and was found not guilty by reason of insanity, he became a part of our program. And we've now been able to rehabilitate him to the point where, it's not like he was trying to hurt somebody, it was just accidental that this happened.

00:12:13:08 - 00:12:17:16 [Tania] And did he understand what he had done over time?

00:12:17:17 - 00:12:35:05 [Dr. Melnick] Yeah. So at the moment, he was just trying to get warm. It had no bearing on, you know, what was going on. And if it wasn't for his mental illness, not being able to cognitively come up with good ideas or, or really rationalize the consequences of what was going on, then he probably would have never done, lit the original can on fire.

00:12:37:11 - 00:12:57:10 [Tania] So these patients that you, I guess, come across, is it, do you come across them once they get into the court system, or do you have patients that haven't been to court and yet they're still part of your facility?

00:12:57:12 - 00:13:16:03 [Dr. Melnick] Yeah, so, to come to our facility, these people are usually found not guilty by reason of insanity. And they are then committed to a forensic psychiatric facility, usually about 3 to 4 years, while they stabilize. And after they stabilize them, then at that point they can apply to come into our program.

00:13:16:03 - 00:13:34:17 [Tania] At your facility, I saw those paintings, and again, just fascinating taking us through, I guess, the process of this patient's mind, you know, that you were able to see visually. Can you just tell us a little bit about the step process that it took to get her there?

00:13:34:23 - 00:14:10:01 [Dr. Melnick] Yeah. When she first came to us, she was very psychotic. And you start seeing the disorganization of thought. And she heard voices at the time. And then, you start seeing that when she's finally comes into our facility, she starts learning coping skills, life skills, she's able to kind of manage herself a little better. And once her brain starts getting more organized and the paranoia starts going away, the focus of the art changes to something much more organized, about people, about caring, versus the disorganization and the paranoia that you saw in the previous paintings.

00:14:10:03 - 00:14:24:17 [Tania] Now, how frequently can you get a patient going from that level of, of disorganization to, to actually have an empathy, to have an insight? Because from what I understood, that is the hardest piece to get to.

00:14:24:18 - 00:15:12:13 [Dr. Melnick] Yeah. So in our facility we're, we're close to 90%. I mean, part of what we do in our psychoeducational groups is to understand the seriousness of the crimes and how their actions impacted others and why, maybe they aren't, you know, they, they don't call every week to see how they're doing. Despite the fact that, in their minds, a lot of them didn't know that what they did was wrong. So what we're seeing here is we're seeing that change, and we're starting to incorporate empathy, and how they respond to others is a big component of their wellness. So as they move through the levels, that's one of the things that we look into is how they're able to, how they're able to empathize with the seriousness of the crime, despite the fact that they were considered not guilty due to it.

00:15:12:14 - 00:15:27:14 [Tania] You said a lot of the way this works was based on trust. You say, sometimes they, they leave your facility and become outpatients. How do they continue on their medication? How do they continue on the regimen when they're now outpatient, not being watched?

00:15:27:18 - 00:15:33:19 [Dr. Melnick] So the first level, when they're in the outreach, in their second phase of our program, they actually come in to take their medicines every day.

00:15:33:19 - 00:15:35:00 [Tania] Okay, okay.

00:15:35:00 - 00:16:01:03 [Dr. Melnick] And then as they kind of go and show that they're able to do things, we take away their morning, they can take their night doses at home, but they have to call in every single day to tell the staff that they took their medicines. And usually those patients are in there with somebody who's much more seasoned. And that person also monitors their pills. So there's a 360-degree view of what happens with the individual patients.

00:16:01:05 - 00:16:25:10 [Tania] So when, you know, again, maybe you can educate me and whoever's listening, from what I understood, a lot of the medications that are out there do not, do not really treat cognition; they treat, to your point earlier, they treat mostly positive symptoms. But yet, what you're telling me, these patients are becoming, the cognition starts to improve, insight starts to improve. Is that the medication? Is that the, the, like, what, like, like what do you think is allowing that to happen?

00:16:33:23 - 00:17:20:11 [Dr. Melnick] There's a certain part, you know, when the psychosis is gone, patients are able to think a lot clearer. But also the psychoeducational groups that we go through actually help improve cognition. Everything we do has a purpose. And so they'll, they'll do puzzles and they will do, as part of their psychoeducation they'll do word finding, they’ll, you know, and, depending on what level they're at, in terms of their functioning, we're able to kind of go and find ways to challenge them mentally. So we have them come up with ideas, we have them work in groups, we have them, you know, do things together to try to find if, you know, ways that they can think in a group. And that way we’re able to kind of get them a little bit more of a cognitive recharge.

00:17:20:14 - 00:17:21:06 [Tania] Yes.

00:17:21:08 - 00:17:24:03 [Dr. Melnick] More than it is just the medicine itself.

00:17:24:05 - 00:17:29:10 [Tania] You know, what I hear is also group thinking is also, it’s very interesting. So they do it in a group, not just individually.

00:17:29:10 - 00:17:33:05 [Dr. Melnick] Correct. Yeah. They do projects together.

00:17:33:07 - 00:17:42:05 [Tania] Now I'm very curious about a prison system. And how many patients do you believe are actually misdiagnosed that are in the prison system?

00:17:42:05 - 00:18:17:05 [Dr. Melnick] Vast majority. You know, it's, the Twin Towers in Los Angeles is the largest psychiatric facility in the United States. Here in Miami Dade County, same thing; it's one of the largest psychiatric facilities in the United States. The prisons have become the new forensic psychiatric facilities. And it's really sad because these patients, when they're in the prison system, don't get the services that they really need or the help that they need, as the money is usually funneled into taking care of the guards and the people that are staffing the prison versus the patients that really need the help.

00:18:17:07 - 00:18:22:14 [Tania] How do we get into the system and get these patients better diagnosed?

00:18:22:16 - 00:18:46:20 [Dr. Melnick] Yeah, it's unfortunate, but that happens quite a bit. I wish, better training, I guess would be the first. You know, the, the reality is, is there's not enough space. Psychiatric facilities have been closing down, not opening up. When they open up new ones, they're fractionally the size of what they were, the hospitals that they replaced. And unfortunately, the money just isn't coming in to the people who need it.

00:18:46:22 - 00:18:53:09 [Tania] What you do needs to be replicated, and we need to figure out how to support such type of program to really expand it.

00:18:53:15 - 00:18:54:14 [Dr. Melnick] Yeah.

00:18:54:15 - 00:19:08:23 [Tania] We talk about rehabilitation and that's exactly what you have done. So again, going back to the question asked about the end goal, what does success look like for you? And then I will have to then talk about how do, how do you get there.

00:19:09:03 - 00:19:47:08 [Dr. Melnick] Yeah. So success for me is really trying to do what I can to help as many patients as possible. You know, I've always, you know, I went into medicine to really be a patient advocate. Not only finding the right medicine for the patient and doing it in a successful way, but the other piece here is keeping them out of hospitals, keeping their brains healthy, keeping their physical, you know, well-being intact, and being able to teach them those life skills and coping skills so that they can go out in the community to be members of society rather than just the outcast that we've all trained them to be.

00:19:47:10 - 00:20:04:22 [Tania] You and I spoke about clinical trials, and a lot of it being done in academia. But then you have the hands-on experience, and each patient, I think, as we spoke about before, gets more of a personalized approach. How do you do that? Like how do you know what's the optimal treatment for each patient?

00:20:05:00 - 00:21:19:09 [Dr. Melnick] Yeah, I mean, I got to tell you, it's, it has a lot to do with understanding the pattern of behavior and what they're doing and how they think and how early they are into the disease state. The earlier into the disease state, the better outcomes we're going to look at, right? So when you're looking at medicines, and you're trying to get a patient stable, you know, we're trained to use some of the older medicines which tend to hit a lot of off-target receptors.

And what we see now with some of the newer medicines is that they're very guided, very, you know, they're, they're, they're very much targeted, exactly, to this, to these receptors. And by doing so, doesn't hit the off-target receptors, which can give us some effects that maybe we weren't counting on. And so hopefully that way we're able to not only get them better, but keep them well on the medicine for a longer period of time.

And we've been able to successfully manage our patients in a way that's not only good for their mental health, but by keeping them out of the hospital, preventing relapses, our patients actually do better in a healthier way long-term. Medicines that have less side effects, in that are newer; the way I describe it is a laser beam versus a shotgun approach to medicines.

00:21:19:11 - 00:21:35:18 [Tania] You know, it’s funny, I think about it as I think through chemotherapy versus targeted therapy, same thing in oncology where I usually tell people chemo is like putting a blindfold on and just shooting, right. You're just knocking down everything versus getting very specific to get on-target effect and less get off target.

00:21:35:18 - 00:21:36:12 [Dr. Melnick] Exactly.

00:21:36:18 - 00:22:00:02 [Tania] So let's talk about relapses. I watched a program that you spoke on, and you explained that every time a patient relapse, you know, it gets worse and worse and worse. So my assumption is to go then to, I guess to your point, get the ideal treatment early, prevent the relapse, and therefore you can actually keep their brain as healthy as possible. Like what is, what is the, I guess, the method to this. 

00:22:00:04 - 00:22:48:22 [Dr. Melnick] Yeah, it's exactly what you said. I mean, the earlier the intervention, the longer that they've been on medicines that help them stay stable and out of the hospital and prevent relapses, the more intact they are not just cognitively but functionally. And there are multiple studies that have shown how we're able to kind of manage those patients successfully and keep them out of the hospital, but also give them the cognitive reserve that they deserve as time goes on. We know that patients that have early psychotic symptoms have worse prognosis. We know that people that break later on have, have better prognosis. But what if we were able to get those patients stable and not have any more episodes? Well, then at that point, we're able to keep their cognitive reserve intact and be able to get them to become more functional members of society.

00:22:49:00 - 00:23:01:12 [Tania] You took us through the patients that you treat, which were really, I guess I'm, I guess we assume are pretty severe to get to that point. How do we get ahead of it? How do we get, how do we prevent that from happening?

00:23:01:14 - 00:23:53:19 [Dr. Melnick] Great question. Early recognition is vital. You know, we tend to, we tend to use medicines that are, that, that really don't allow our patients to really show their wellness over time. We know that some of the typical antipsychotics, which are still being used quite a bit, especially in psychiatric facilities, are neurotoxic, as per Dr. Henry Nasrallah.

And, you know, we're seeing how the newer generation of medicines are not only able to get our patients stable today and to treating their positive symptoms, but also, long-term, minimize the chances of having some of the movement disorders, cardiovascular issues, diabetes, and waking. And as we're able to get these patients better, we're able to keep them better for long-term.

00:23:53:21 - 00:24:04:15 [Tania] You've seen the change in medicine over the last 10 years. Where do you see it going over the next 10 years when it comes to treating patients with severe mental illness?

00:24:04:16 - 00:24:28:20 [Dr. Melnick] Yeah, I mean, there needs to be an approach that's done beyond just giving somebody medicine and sending them home. There needs to be a, you know, biopsychosocial formulation to every patient that walks through your door. This is not a cookie-cutter disease, unfortunately.

00:24:28:22 - 00:24:53:06 [Tania] In terms of stigma, even when people have family members diagnosed with this, people get afraid, and they’re embarrassed and they're ashamed. How do we unwind that and, and get people to understand that this is a disease that, that deserves a chance, it deserves people, it deserves empathy, deserves care. How do we, how do we, change that around?

00:24:53:06 - 00:25:58:20 [Dr. Melnick] For many years, people with schizophrenia were just thrown into hospitals. You know, they were mistreated, they were locked in dungeons, they were put on insulin. They were, you know, frozen, given seizures. I mean, so many different ways that they were mistreated. We finally have resources, and we need to start changing our way of thinking. The stigma is our creation, not theirs.

And we need to start doing what we can to bring these patients out into the community, which is what we've done at Passageways: being able to give patients their lives back even though they've had mental illness, even though they've committed serious crimes. The fact that we're able to get them into community and be able to become functional members of society is something that needs to be taught and educated about. That these people are not people we just throw away into a hospital or into a hole like we used to do, but actually are able to be rehabilitated. Maybe not all, but the ones that can and the ones that want to, we got to give them that opportunity.

00:25:58:22 - 00:26:57:13 [Tania] So I'm going to switch gears a bit because, you know, most of our listeners will be practitioners. And as we spoke about before, what you have done, to me, is remarkable. And, I mean, for those who don't know, when I first heard you speak, I had a whole list of questions I wanted to ask, which got thrown away because I was so fascinated by what you did. I mean, coming into medicine, you're, our, our goal is to make a difference in patients’ lives. Our goal is, is, is to turn things around. And, and when you hear about patients who have committed such crimes being rehabilitated in a way that most people think is impossible, I mean, it was, I'm fascinated, I'm touched. It is the way, to me, medicine should be practiced.

What advice, what knowledge can you impart on people seeing patients that want to rehabilitate, that want to get them better and just don't know how to do it.

00:26:57:15 - 00:27:29:18 [Dr. Melnick] I mean, first is, I tell my residents, don't ever follow the same rut that everybody has laid down. You know, everybody tries to follow the same path. And what we need to start doing is creating new paths. You know, and when you come up against a wall, don't just stand there and expect the wall to move down. Go around the wall; figure out new ways.

We need to start thinking outside the box, and we need to start changing our mindset and putting our patients first, which we really haven't been doing for many years.

00:27:29:20 - 00:27:35:21 [Tania] So then, with that, what is your proudest moment?

00:27:35:23 - 00:28:38:13 [Dr. Melnick] My proudest moment professionally is, is really seeing patients get out of from underneath a hole, underneath a rock, be able to kind of come out and be able to see the light at the end of that tunnel by rejoining society, being able to move into their own apartment, being able to keep it clean, being able to, you know, start dating.

We have patients that have started to date, we've had 2 that have gotten married. The idea is, is that where before our limits were just the fact that, well, they have schizophrenia, we're going to have to take care of them. But we've been able to show that that's not the way this works. We're able to get some of those patients back into society and be able to become functional.

And my proudest moment are the days that these patients graduate high school, they learn how to read and write, which before they were not able to do so, are able to get jobs, are able to go out and really start making something more than just a patient with schizophrenia.

00:28:38:15 - 00:28:51:02 [Tania] Yeah. And last question. What advice do you have to give to all of us, whether we're in pharma or treating practitioners? Any advice?

00:28:51:04 - 00:29:37:09 [Dr. Melnick] Yeah. Again, follow your own drum. You know, don't allow others to tell you what has to happen. If you feel a medicine is the one that's right for your patient, fight for them. Be a patient advocate. We all went into psychiatry to be patient advocates. We didn't do it for the money. So it's important for us to find ways to be able to go out and be able to manage those patients appropriately so that they can be successful patients in society.

And my advice is don't allow people to tell you no, don't allow people to say you have to do this, this, and this. Follow your heart, follow your brain, follow your own path to be able to get to what you feel is important for your patients.

00:29:37:11 - 00:29:44:01 [Tania] I've learned a lot from you. You've given me optimism on what we can do, what you've done. Imagine if this can be replicated.

00:29:44:03 - 00:29:45:01 [Dr. Melnick] I hope it will be.

00:29:45:04 - 00:29:59:01 [Tania] And thank you now for taking the time to go through this experience with us. Thank you for taking us through your center. Thank you for sitting with us. This has been quite, I would say, an inspiring discussion.

00:29:59:01 - 00:31:06:21 [Dr. Melnick]  Thank you.

Some of our patients really respond to art pretty well. What we start learning from them is that when they're more psychotic that they are, you start seeing some of those things come through the art. This is one of our patients. This is a woman who ended up killing her husband. And while killing her husband, you see in the top, you see a machete going through a heart. You see the x’s through the heart, and you see her underneath it, holding the heart up. But what you also see within the heart are the different faces that she was. You see the white face at the bottom of the heart. But you also see at the upper right hand side a teal face as well. This was in ‘89, right after she committed her crime.

You see here in 2008, 2009, much more organized in her thought process. You start seeing that there's organization within the paintings and much less of the paranoia that comes out, less psychosis. So same person painting in different ways. Showing the wellness of her after we ended up treating her in 2009. Part of what our program does is teaching empathy, teaching the remorse.

Dr. Melnick directs a dignity-first program that blends comprehensive psychiatric treatment, cognitive-restoration therapy, trauma-informed support, and structured community re-entry. The outcomes are extraordinary: 0 percent recidivism and 90 percent sustained reintegration — results that upend long-held assumptions about severe mental illness, justice, and what true healing can look like.

Together, Drs. Small and Melnick unpack how this model works, why it succeeds, and how clinicians can begin adapting its principles today. This conversation reveals what becomes possible when we treat the person behind the psychosis — with dignity, rigorous care, and a roadmap for real-world impact.

About Dr. Ilan Melnick

Ilan Melnick, MD, is the primary psychiatrist in two outpatient clinics in the Miami, Florida area, as well as a staff psychiatrist and chief medical officer at Passageway Residences of Miami-Dade County. In addition, Dr. Melnick is a staff psychiatrist and medical director for Jewish Community Services and performs independent medical and psychiatric evaluations for Miami-Dade County police, fire, transit and aviation departments.

Dr. Melnick received his medical degree in Bayamon, Puerto Rico and went on to do his residency in psychiatry and fellowship in geriatric psychiatry at the University of Miami/Jackson Memorial Hospital. He continues to be involved in education as an assistant professor at Florida International University School of Medicine and through his role giving grand rounds at major universities and hospitals around the world.

Dr. Melnick is a paid consultant for BMS.

00:00:04:07 - 00:01:11:08 [Tania]  Welcome to doctors Unscripted. I'm Doctor Tania Small, and I'm here to bring you into a different kind of conversation with some of the brightest minds in medicine and research.

Today I'm joined by Doctor John Kane, an internationally acclaimed psychiatrist renowned for his pioneering research in early psychosis and patient centered innovation, and with over 900 peer reviewed publications. Doctor Kane is redefining mental health care. We'll explore what drew him to psychiatry, unravel the biology of schizophrenia, decode the triad of symptoms, examine breakthroughs challenging the dopamine dogma, and discover how patient driven science and partnerships are shaping the future.

Now let's get started.

Doctor Kane, thank you so much for joining us in downtown New York City for our first episode of Doctors Unscripted.

00:01:11:09 - 00:01:14:01 [Dr. Kane] Thank you. My pleasure. Thanks for the opportunity.

00:01:14:03 - 00:01:49:02  [Tania] I have a few questions for you today. But I'm starting off with the hardest one, and that is, do you remember when you were med school and you were trying to figure out what you wanted to do? Most of us were trying to figure out at least what we wanted to do, what fields we wanted to practice in.

And a lot of times, most of our colleagues could guess what fields we were going to. For example, my colleagues figured I was either going to go into ob/gyn or onc, and I ended up going into onc. What did your colleagues believe you were going to go into, and what inspired you to go in to psych?

00:01:49:02 - 00:02:32:13  [Dr. Kane] So they didn't have to guess because I told them. I knew when I went to medical school that I wanted to go into psychiatry, and it had been something that I was interested in ever since high school. And rather than just studying psychology, I wanted the medical degree to be able to really have a, you know, a medical perspective on mental illness.

But I think as a teenager, I was reading novels and got very interested in trying to understand, why did people act a certain way and what determined their behavior, and why were people so different? And I became fascinated with, sort of the human mind and behavior and, and then trying to understand mental illness.

00:02:32:15 - 00:02:33:23 [Tania] Since high school.

00:02:34:01 - 00:02:35:11 [Dr. Kane] It was high school.

00:02:35:13 - 00:02:41:12 [Tania] Was there anything that really stuck with you while you were in med school or even in residency that really changed your [perspective]?

00:02:41:13 -  00:03:18:14 [Dr. Kane] Well, I remember the first time in medical school that I actually interviewed a young man with schizophrenia, and he was pretty much my age and had his first episode of schizophrenia, in the recent past. And I saw him at Bellevue Hospital and, it was a pretty powerful experience because I think I was trying to understand the way he was thinking, and he was quite delusional.

And I was asking myself, is it is it possible that he really believes these things?

00:03:18:16 - 00:03:19:18 [Tania] Yeah.

00:03:19:20 - 00:03:47:02 [Dr. Kane] And then I also met with his parents and I saw the anxiety and the devastation that they were feeling at that time. And it was for me, it would be it would be great if we could figure this out and understand why. Why does this happen? You know, this is a young person with a lot of a lot of promise that becomes psychotic and develops an illness that's really can be quite disabling.

00:03:47:04 -00:04:48:19 [Tania] I remember, when I was learning a lot more about schizophrenia, when I started working in pharma, I learned a lot more about schizophrenia and someone explained it to me this way because, as a pediatric hematologist oncologist, a lot of times you just have so much hope for these kids, and your goal is to get them through it so that they can really fulfill the life that they're meant to live.

And someone told me you could imagine a newly diagnosed person with schizophrenia, and sometimes immediately it can look like lights out, and their goal is to turn on that light. And I guess my question is like, I know one of the things that you focus on is really early psychosis. And, how did the families actually, feel about it?

How did the patients get through it in the beginning?

00:04:48:21 - 00:05:48:04  [Dr. Kane] It's very hard., We had a grant application for the RAISE Project, but, I had never used a quote from a poem in a grant application. A lot of my colleagues thought that that was not such a good idea. But the quote was, tread softly because you tread on my dreams.

That's a quote from Yeats. And I thought that really kind of summed up what we're trying to do here is that, you've got a young person, you've got a family, lots of hope, lots of potential. Parents are always worried. But, you know, you see something like this develop unexpectedly and, it turns out to be a pretty serious illness, and it's devastating, you know?

So this led us also to understanding the importance of early intervention. And, you know, can we diagnose this condition early, can we intervene rapidly and try to get it under control?

00:05:48:06 - 00:05:52:07 [Tania] Yeah. About what age are people with schizophrenia diagnosed?

00:05:52:10 - 00:06:19:20 [Dr. Kane] So the median is in the early 20s. It's usually late teens, early 20s. And, you know, it's occurring at a time, which is really critical in people's development, whether it's educational or psychosocial. And so it has a tremendous influence, tremendous impact on what people can do subsequently.

00:06:19:22 - 00:06:31:11 [Tania] And let's talk about that and talk about the biology, because I know a lot of times, again, people hear schizophrenia. They think it's just a homogeneous disease and can't put their finger on it. What do we know about the biology so far?

00:06:31:11 - 00:08:18:07  [Dr. Kane] So it is very heterogeneous. I mean there's a very strong hereditary factor, but we don't understand the genetic the dynamics of the genetic influence. There have been many, many genes that have been implicated, but all with very small effect size. So we don't we don't have a major gene or genes that we can point to and say, this is the reason I think I would say that schizophrenia is probably not one illness that right now, we approach it with this sort of diagnosis, but I think it probably includes what we will one day learn are multiple different phenomena with different etiologies and different pathophysiology, so that we're trying to do research and understand this illness. We don't have great tools yet to really stratify people into different categories. But there is hope with genetics and brain imaging etc. that will come to understand it better. I mean, up until now, we've sort of had the dopamine hypothesis of schizophrenia, the idea that there's too much dopamine being produced in certain brain areas.

And so we tried to block that with medication and to some extent it's been effective. And we can treat the acute signs and symptoms of schizophrenia with medication. And it often works pretty well. And then the other problem we get into is people need to take medication on an ongoing basis to prevent a recurrence or a relapse. And I think nonadherence is a challenge in any chronic illness, whether it's hypertension and diabetes or epilepsy or asthma.

But in mental illness it's perhaps even more of a challenge with and people with schizophrenia also have cognitive dysfunction. And, that that can make it even more difficult.

00:08:18:08 - 00:08:31:08 [Tania] You spoke about the different pathways. You spoke about dopamine and blocking dopamine. Is that where we landed now or do we know a lot more about schizophrenia?

00:08:31:11 - 00:09:19:23 [Dr. Kane] Yeah, I think we've learned a lot more. For example, the notion has been that, it's excessive dopamine release, presynapticly, and the way we've been treating it up until now is to block the postsynaptic receptor. So, you know, I think there has been a better understanding of some of the pathways and new approaches to treating the illness.

But I think we were left with, as we said before, a very, very, heterogeneous phenomenon. And there may be people who have different mechanism of action. It may be we see the interaction between genetics and environmental factors. And we need to better understand in which category people fall into.

00:09:20:01 - 00:09:24:02 [Tania] Are there any biomarkers on the horizon so that we can understand this better?

00:09:24:08 -  00:10:25:00 [Dr. Kane] There's certainly excitement about genetics and about neuroimaging and even electroencephalography. But we don't at this point have biomarkers that are useful at the clinic level, to help better understand which treatment to use or which treatment might work or to predict the prognosis of that person. So we're really trying the best we can to take advantage of different treatment modalities.

We know that medication can be very helpful. We also know that psychosocial interventions are very important. And ideally we want to combine the two. Even though we consider this a biological illness or a brain disease, we know that psychosocial interventions, therapy, family therapy, family psychoeducation can also be very important in helping people achieve better outcomes.

00:10:25:02 - 00:10:35:07 [Tania] Doctor Kane, I want to ask you a little bit about the different symptoms. Can you explain the difference between positive, negative and cognition and how do we manage those symptoms?

00:10:35:08 - 00:13:10:19 [Dr. Kane]  Well, positive symptoms are things like delusions, which are fixed false beliefs, hallucinations, hearing a voice when no one is speaking, having difficulty communicating in a logical fashion. Negative symptoms involve no motivation, diminished affect, diminished expression, lack of involvement with day-to-day activities. Seeing friends, hobbies, socialization, sometimes poor self-care, and then cognitive dysfunction, which really is a core feature of schizophrenia and affects probably 80% of patients, involves things like, difficulty with attention, with verbal memory.

So remembering things like, if I give you a phone number, will you remember it long enough for you to actually dial the number? Attention obviously is very important. And then social cognition, which is how do we understand social interactions? Can I read someone's facial expression in a way that's meaningful? Do I understand my own emotions?

So these are all problems that people with schizophrenia have to deal with. And our understanding is that the cognitive dysfunction actually begins long before the other signs and symptoms. And so it really is a core phenomena. The negative symptoms also, which affect at least 50% of patients, also often begin before the positive symptoms. But once when someone gets to a point where the diagnosis of schizophrenia is actually made, we'll often see all three of those things.

One of the challenges is that the medications we have had up until now work mostly for the positive symptoms. They don't really help the negative symptoms as much as we'd like, and they don't help the cognitive dysfunction as much as we'd like. So we're very eager for new treatments to be available that can help patients in those particular domains and even positive symptoms.

Although medications can often be quite effective, they're not 100% effective. And then in terms of preventing subsequent episodes, medicine is very important, prophylactically. So even when someone improves from their acute episode, they're at risk for having another episode. Could be six months later, could be a year later. It could be two years later. The medicine is very, very effective in reducing the risk of a subsequent relapse.

But many people have trouble taking the medicines.

00:13:10:21 - 00:13:16:23 [Tania] And why is that? Is it because of the disease itself? Is it because of the side effect profile of the medication?

00:13:17:04 - 00:13:18:00 [Dr. Kane] It’s all of the above. Okay.

So the disease itself, I mean, sometimes people don't fully appreciate what's wrong and they can't really kind of wrap their heads around it. Sometimes people feel better once the medicine has worked for the acute symptoms, they feel better or they're out of the hospital. They're not having those delusions anymore or not hearing voices. So they feel, well, maybe I don't really need to take medicine anymore.

Nobody wants to take medicine on a long-term basis. Side effects. I mean, all of these things. And then I think it's human nature to have difficulty taking medicines too long. Whether you have diabetes or hypertension or epilepsy or asthma, it's a challenge. So the cognitive dysfunction maybe adds to that as well. Because I'm not as well organized as I could be. And remembering to do something. So yeah, it's many, many factors. But it's a huge problem. And you know half of our patients have difficulty with adherence. There was one study that was done in Finland, where they followed 2500 patients who were hospitalized for the first time with schizophrenia.

And within 60 days of leaving the hospital, they weren't getting their medicine. So it's a big challenge.

00:14:31:09 - 00:14:43:01 [Tania]  And I want to go into two pieces that you said you spoke about. The first symptom tends to be cognitive dysfunction. Is there a way or is there anything that allows us to diagnose it at that time?

00:14:43:03 - 00:15:12:17 [Dr. Kane]  It's hard. It's hard because when someone has cognitive dysfunction, unless it's really, really severe, you don't necessarily recognize it because you don't know where they should have been or where they sorted out if there's been a decrement. I think we are getting better at that. And now there's a lot of research going on in what's called the clinical, high risk, population, where we do see that cognitive dysfunction may be a predictor of somebody actually developing schizophrenia.

So there's a lot of research going on in these domains looking for early signs so that we can intervene earlier.

00:15:25:05 - 00:15:38:05 [Tania] You spoke about the research as well. You said that even getting patients on clinical trials sometimes can be challenging. Why is that and what can we do to improve that to get those answers?

00:15:38:08 - 00:16:07:19 [Dr. Kane]  Well it's interesting. You came from an oncology background. And I think if you look at, the clinical trials that go on in oncology, it's like many people participate in that because that's something that's brought to their attention very early in their treatment history and psychiatry. That doesn't happen. And I think it would be great if we could develop, you know, more clinical trial and clinical trial networks so that when people come into a hospital, they're offered opportunities to participate in some kind of research.

We could do research about anything. It could be access, how did you how did you get here? Who referred you? How long did it take you to realize that something was wrong? How did your parents react? Or it could be a treatment trial. It could be a registry, a long-term study.

There's so many things that we could learn from, but the average patient is not participating in research in psychiatry. And I think we need to do a better job of making research available to people explaining to them why it's important. A lot of people think, oh, I don't want to be a guinea pig.

You know, that's really not what it's all about. This is how medicine progresses, right? We have to learn from each other.

00:16:47:19 - 00:17:06:08 [Tania] I want to learn more about that because, when practitioners are treating patients, they see patients day in and day out. And there's a lot of research that's there. But how do you manage your time to learn all the new information, continue to see your patients and then apply it? Is that a challenge?

Is it too much information that needs to be distilled? What do you think is the real challenge, when it comes to that education?

00:17:13:00 - 00:17:32:05 [Dr. Kane]  I think that's a big part of it. I think there is so much - people are just deluged with information. You know, where attention is a challenge, right? What do I pay attention to? So I think we have to help clinicians. We have to synthesize data and present it to them in a way that's meaningful to them.

They often react to studies and say, but does that apply to my patient? So we have to do research that's really generalizable, that's real world to help clinicians understand, how does that apply to my patient. That means sometimes being more inclusive in our clinical trials so that we understand the impact of treatment in general.

I think we are getting better at these things, but we still have a ways to go.

00:18:01:08 - 00:18:23:22 [Tania] So you opened another door because I want to walk through and that is inclusivity. When it comes to clinical trials and even just beyond clinical trials, we know that there's still disparities when it comes to health care, particularly in this patient population. Where are we with that? And then I want to go into how do we make our trials more inclusive.

00:18:24:00 - 00:18:47:12 [Dr. Kane]  So I think we've made progress. We still have a ways to go, obviously. The US is very diverse. I think people struggle with, who can I trust? And I think we need to make sure that we have people working with us who who can talk in a meaningful way to anyone who's afflicted by a mental illness.

I think peer counselors can be very helpful. The idea of having someone else with the same lived experience, but who speaks your language, who comes from your culture, who understands what you're going through on a personal level. I think I think that can be very powerful. I don't think we use that often enough.

But we're making progress in that direction, too. I think more people are being trained as peer counselors. I think we're we recognize how important that is. I think there's been more emphasis on including people with lived experience when we design our clinical trials, when we execute our clinical trials to make sure that we're really hearing the patient perspective. Patient reported outcomes are very important.

But again, the diversity issue, we need to make sure that all of these things are available to everyone.

00:19:41:05 - 00:20:05:05 [Tania] You know, I was speaking to a colleague of mine, and one of the things, again, that he put in perspective for me was, when someone is diagnosed, for example, with cancer, what do we do? We go in and we say, how are you dealing with things? Are you okay? And all of a sudden you have this empathy, more sympathy, at least towards them.

And then one of the things he told me, though, is what happens when you meet someone who was diagnosed with schizophrenia instead of leaning in, you tend to lean out because of all that is associated with that. So I just wonder, as a health care community, how do we get more people to lean in? Is it a lack of understanding?

Is it a is it a fear factor? But what can we do?

00:20:28:23 - 00:20:51:16 [Dr. Kane] I think it's all of the above, in a sense. There is a fear factor. I think people tend to be afraid of what they don't understand. But we have to recognize that mental illness is an illness like any other illness. We have to treat it the same way, with the same kind of understanding, appreciation and consideration.

I think in schizophrenia. We also need to do research and we need people to participate in research and benefit from the research also to make sure that we get the support that we need. I don't think enough funding goes into research on mental illness, for example. I mean, everyone is sympathetic to oncology or to heart disease.

But the reality is mental illnesses account for a tremendous amount of disability, not to mention personal suffering and family burden and even shortened lifespan.

00:21:25:20 - 00:21:50:15 [Tania] There's something that I like to call patient-driven science. And that is where we develop our drugs for patients. So we move from a product-centered drug development to a patient-centered drug development. And in pharma we create the technology. As a physician, you have the expertise and patients, they understand - they're living their disease.

How do we come together to really develop the best drugs for patients?

00:21:55:09 - 00:22:22:11 [Dr. Kane] So we need to really have ongoing communication between the federal agencies in the US, whether it's NIH or the FDA and industry and academia and clinicians in the field and patients and families all working together for a common goal. Everyone has their role to play in that process. But it's really a collaborative process.

00:22:22:13 - 00:22:40:13 [Tania] And I'll say this, one of the things I tell my team all at the time is even though you may not be touching a patient at this time, you are still a part of this treatment team. And the outcome of that patient is still our responsibility collectively, as part of the health care community.

00:22:40:13 - 00:23:01:14 [Dr. Kane]  And it's really true. I mean, everybody, when we're doing, a clinical trial or we're doing research, the study coordinator or the person working on recruiting has to understand the critical role they play. Everybody plays a critical role. I mean, I think that's true across the board that we need to understand that everybody's important and they need to they need to recognize that.

00:23:02:11 - 00:23:19:19 [Tania] But that's so important because I think we forget that. And so how do we all hold hands and make sure that we all feel that responsibility for that human that we are treating?

What are you most excited about when it comes to innovation for patients living with schizophrenia?

00:23:27:01 - 00:23:48:03 [Dr. Kane] Well, I am excited about what we were discussing earlier, which is the evolution of new thinking about how we might manage the dopamine dysfunction that exists in schizophrenia. The development of muscarinic agonists I think is very exciting. There are half a dozen companies now that are involved in developing such drugs. So I think that's very welcome.

I think other innovations we're seeing more and more, in brain imaging; trying to understand neural networks and problems in connectivity in various brain regions. It's great to see the innovation that's going on now there. You know, there's been a lot of interest now in a in a new way of looking at the control of dopamine in the brain.

00:24:11:18 - 00:24:19:15 [Tania] You spoke about muscarinic receptors. And that's a new mechanism that I know there's been a lot of discussions about. Can you tell us a little bit more about it?

00:24:19:17 - 00:24:39:20 [Dr. Kane]  There's been interest in muscarinic receptors for years and years, but I think now we're getting a lot closer to fruition. And a sense of what we've seen is that by influencing some of the muscarinic systems, if you will, we can have an influence on that presynaptic release of dopamine.

And importantly in the brain areas that are critical to the development of schizophrenia.

00:24:45:13 - 00:24:53:21 [Tania] What advice do you have for us in order to improve the patient experience together for those living with schizophrenia?

00:24:53:23 - 00:25:22:06 [Dr. Kane] People have to understand what mental illness is, how common it is, how it affects people, how it affects individuals, families. And then, as we were talking earlier, the right collaboration between all the stakeholders. And that means the patients, the families, the pharmaceutical industry, academia, federal agencies, etc., to really go after this problem in a major way and it is getting more attention.

I think there's more awareness of mental illness. I think during the pandemic and after the pandemic, there seemed to be kind of an emergence of a better appreciation of mental illness. But, we still have a long way to go.

00:25:35:23 - 00:25:47:01 [Tania] Well, I think all of us are ready to lean in to this together. And I just want to thank you for your time. Thank you for your expertise. Looking forward again to continue to move this field forward.

00:25:47:02 - 00:26:00:04 [Dr. Kane] My pleasure. Thank you so much for this opportunity.

00:26:00:06 - 00:26:04:18 [Tania] What was that novel that you read initially?

00:26:04:20 - 00:26:16:05 [Dr. Kane]  Well, probably just the Crime and Punishment novels are not necessarily all fiction, right? I mean, a lot of it is actually based on lived experience that people have had. It took me a while to realize.

Abour Dr. Jane Kane

Dr. Kane is an internationally recognized expert in the treatment and study of schizophrenia, with over four decades of leadership in academic psychiatry and clinical research. He serves as senior vice president for Behavioral Health Services at Northwell Health and chairman of psychiatry at the Zucker Hillside Hospital. He is also Professor and chair of psychiatry at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell. Dr. Kane has authored more than 900 peer-reviewed papers and led numerous landmark studies focused on early intervention, treatment adherence and relapse prevention in schizophrenia. His work has helped redefine how we understand the illness and how we care for those living with it.

Dr. Kane is a paid consultant for BMS.