Total Health Oncology: Best of Heme 2025 Session 3

[00:00] I'd like to welcome my good friend Andrew Yee from Mass General who's going to be talking to us about emerging therapies in myeloma. Please be sure to laugh at his jokes. Thank you, Betsy, and I'd like to thank the organizers and total health and the

[00:20] sponsors for inviting me and for helping to make this wonderful event happen. So I can't believe it's taking all this more until they get to the main event, which is a talk about multiple-mile OMR, right? I mean, I mean, there might be some fans out there, but I know. Because I think we spent all this time talking about

[00:40] lymphoma, leukemia, but now we're going to talk about myeloma for a change of pace. All right, these are my disclosures. And, you know, when I think about, so my task was to talk about emerging therapies in 15 minutes and like just to take a step in a different direction. We can talk a little bit briefly about the therapies that have emerged.

[01:00] We have to think about therapies that were emerging, but now they're like fully emerged. So I think about four drug regimens and multiple myeloma. We think about the anti-B-C made by specific antibodies, the anti-G-PERS, C, D, 5D, talkinumab, as well as the CAR T cell therapies. At one point they were emerging, but now I think they're fully fleshed out and emerged.

[01:20] And then I had all these different emerging therapies I could choose from, right? And it's kind of a daunting list, like which ones do I pick? And to take it to the next level, instead of emerging therapies, we can even talk about submerging therapies, though it's supposed to be kind of funny. But obviously it's falling flat. But I think,

[01:40] upon, but I think it is an important concept to think about because as we heard earlier today from Dr. Jane about, you know, in CLL, there's, you know, a fixed duration of therapy is being important, and I think the next wave in myeloma therapy will be to identify a fixed duration of therapy, you know, therapies where we can have a fixed duration using MRD to better God.

[02:00] guide therapy, but that's for a different time. So I'm just going to, for the interest of time, I'll just talk about these topics which revolve around BCMA. First topic would be bilatibamafidotin. So just as a refresher, bilatibamafidotin is an antibody drug conjugate that takes out a blood pressure treatment.

[02:20] the naked antibody bilantime and combines it with the toxin methadotin. Now this is different than vidotin. This is methadotin. And you might be scratching your heads thinking, look, didn't I hear about this drug before? You know, is it some kind of one-hit wonder or something? Because it received accelerated approval in 2020.

[02:40] And then 2022 just disappeared, right? And then why am I talking about it again? Well, I'm talking about it again because it's one of the emerging therapies. So just to provide some background is the Dream 2 study, which led to the approval of bactamafidotin. So this was a study that looked at triple class exposure.

[03:00] patients and as a single agent it showed an overall response rate of about 31%. Now I know in the context of other therapies that doesn't, it sounds relatively modest, but again this was as a single agent and I just wanted to provide some background in terms of some of these other studies. Now if you think about like Dara Tumman

[03:20] You know, back then, daratumumab and isotuxumab showed an overall response rate of around, you know, 30% in patients who were, you know, primarily linalidamide or bertesmab-exposed. But then, bolantimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimimim

[03:40] has a bit more, has some potential extra juice to it. So, bileanthemum methadone received accelerated approval in 2020, but there was a DREAM3 study. And in DREAM3, you know, bileanthemum methadone received accelerated approval in 2020, but you have to do the confirmatory study to afte-

[04:00] phase 3 to confirm the findings. So in dream 3 it randomized patients to belamaf versus pombilinimideximethosone and while it was statistic, I'm sorry, while numerically the progression-free survival is better, it was not statistically significant. So because dream 3 did not

[04:20] reach its primary endpoint, the drug was essentially withdrawn from the market in 2022.

[04:40] Why do I show this scene from Shaw's Shakespeare Defect? So essentially, there are a couple other examples in the myeloma field. I'm sure in other disease settings we have other examples. But Dream III is a negative study, so the withdrawal was the approval of the withdrawal. I know I'm speaking really fast because it's only 15 minutes, but maybe I should slow it down.

[05:00] down a little bit, right, Betsy? Okay. But, and then, you know, Ocean, again, similarly was a negative study. So, but I like to think of this, I showed this thing because I think about it as, we can think of it as the bella math redemption, right, because, because it turns out that they had two random

[05:20] myself. Do you guys remember the scene? Well, actually I would feel bad because I'm giving away the movie now. But there's a scene, right, where this is a scene where he's escaping the prison. And that's because there are two randomized phase three studies which showed pretty significantly positive results. So based on the results of DREAM's

[05:40] And potentially Dream 8, we potentially may see this drug back on the market and approved in the summer of 2025. Okay. So and we- There we go. There we go. Okay. All right. Thank you. So to talk about Dream 7, a lot of myeloma trials, they're sort of rigged where you know that the-

[06:00] investigational arm is going to win because you have like three versus two or four versus three or so of course if you have more drugs, germsick majority of the time you're gonna have a better outcome. But I think what makes Dream 7 unique it's a head-to-head. You guys recognize this movie? Rocky 4. Oh okay well

[06:20] And I didn't even get Betsy, I didn't even prime Betsy on this one. So, Iraqi Ford, mid-1980s. So again, it's a head-to-head study. Most companies, they want to take the conservator, we do, four versus three versus three versus two.

[06:40] if we're doing a head-to-head mono-to-head mono study. So we have the same background of bertesib and dexamethasone, but then we're directly comparing bella-maff, maffidodin with daratumin-maff. So in DREAM7, it combines bella-maff, and daratumin.

[07:00] Bortezobethasone versus Darratumabortezobethasone, and this is for patients with one prior line of therapy. And then after completion of eight cycles, you go on to receive it as a monotherapy. Now the key finding here is that you can see kind of a whopping PFS benefit of about 37 months versus 13 months. Again, a direct head-to-head comparison.

[07:20] comparison, you see significant improvement in progression-free survival. And similarly, you also see this also corresponds with deep-end response, including emberly-negative responses. Now we'll point out that in this study, this patient population was a little bit—not your typical patient population.

[07:40] because half of patients were lentilinamide-naive. Now in the US patient population, virtually everybody has lentilinamide exposure. But in the lentilinamide refractory subset, again, you do see significant improvement in PFS. And not only do you see improvement overall, let's look at the high risk subsets. So the patient

[08:00] Since with high risk cytogenetics, like say, 4, 14, 14, 16, or deletion 17P, these are traditionally the hardest to treat patients. And what is really impressive to see is that this drug can potentially overcome high risk cytogenetics. And then moreover, DREAIN7 showed improvement in over

[08:20] overall survival. So again, an impressive, and I think, just wanted to, I think to be able to show improvement to overall survival is very, is a high bar to clear, at least in myeloma because a lot of our myeloma therapies, to take for example like the anti-CD-38 antibodies, you know the anti-CD-38 antibodies have been one of the core

[08:40] foundational drugs that we use in myeloma. But interestingly, in relapse disease, the pombolinamide and carfilzamine, it turns out that you haven't actually seen a statistically significant overall survival improvement. So I think this just illustrates the power of targeting BCMA.

[09:00] And during the other studies using bollantimafidotin, I think the major limitation with bollantimafidotin is the ocular toxicity. And it's not because of BCMA. I think there's probably something intrinsic to the payload of using mafidotin. So mafidotin

[09:20] Actually, it turns out there are other drugs which use methadone as the palae which also show corneal toxicities. And with bileptomyotidone, the majority of patients will have some with, will have blurry vision, but at the same time, nearly all patients will have recovery of the blurry vision. So I think, I know that it's perceived as

[09:40] potential obstacle, but I think with appropriate education and supportive care, I think it will be key to be more effectively deploying this drug in practice. So then in addition to Dream 7, there's also Dream 8. In Dream 8, again, was another randomized study of a triplet versus a triplet.

[10:00] is bollantimatidylpamylidamide dexamethasone versus pamvelle dex. And again, this was including one prilodinotherapy, and it had to include lindolytamide. And in that study, we also showed significant improvement in progression-free survival. So I spend all this time talking about it because this is a drug that could

[10:20] potentially be back on the market and available for use. So I'm just thinking for people in the audience to see patients, this is something that could be available to use and if these other therapies like for that CAR-T cell therapy or bispecific antibodies, the bileptomatheidone is relatively easier to deploy and that you can use it.

[10:40] can give in the community, you don't have to worry about risk of CRS and neurotoxicity. I mean, for a car T-cell therapy, you don't have to, you know, you have to go to like a major medical center like MD Anderson or etc., right? But this is something that could potentially be more convenient for patients closer to where they live. Now, another theme to emphasize is that, you know, in dreamsept,

[11:00] The doses of bileptomycin that they use, they're the approved doses, so to speak. So when you hear about this drug, they're going to talk about using it at 2.5 every three weeks. But I think the theme, that's something to emphasize that myeloma therapy, the drugs, and this is true for other disease types, the dosing that was initially

[11:20] presented isn't the dose that's actually used in current practice. So we see multiple examples of this. Like we went from twice a week IV Velcade to once a week Velcade. And Betsy played a pivotal role in the RVD-like study, for example. But the point is that with better dose modifications, you can reduce the risk of toxicity.

[11:40] So I think the anticipation is that if this drug were to be available and you were to use it in combinations, I would suggest, you know, think about using it at a lower dose. Think about instead of every three weeks, every four weeks, even every eight weeks. Or you can space it even further. So because when you're giving it in combinations, you don't necessarily need to use the dose as tightly together.

[12:00] other at such a high dose. Okay so we spent a lot of time talking about CAR T cells, you know, lymphoma, leukemia, and of course in myeloma we have two CAR T cell products approved and recently in April there was a recent update to the approval. So for ita cells was approved in patients with two prior lines of therapy and then for

[12:20] For silt to cell, it was for one prilinotherapy, which significantly expands the potential patients who may be eligible for a CAR T cell therapy. And this is a pretty busy table, but this was just to show in the initial pivotal studies, you know, with isosiltosale, with siltosale in patients who've had

[12:40] medium to six parallans of therapy, you can see an amazing PFS of 34.9 months.

[13:00] respond back to me and say, well, in lymphoma, there's actually a plateau in the curve so where presumably patients could be cured, whereas in myeloma you don't see that plateau in the curve, so that's a fair response back. But with those amazing responses in patients who've had a median of six prior lines of therapy, why not try using it in patients?

[13:20] earlier in their disease setting when potentially their lymphocytes could be healthier and the patients themselves could be in better shape to tolerate the potential toxicities of therapy. So we have the Cardiutatid 4 study which looked at patients with 1 to 3 prilolines of therapy, including a proteasome inhibitor, and they had to be lentilidamide refractory.

[13:40] And I think what was really impressive to see in Cardiut 4 was a significant PFS benefit, you know, hazard ratio of 0.29. And I mean, these, I mean, the separation is pretty substantial. Now, one potential thing to think about would be, okay, what about the control arm? Was the control arm something that you would use in your practice? So they used darapam dei.

[14:00] or pomblodum and valcade decks. And what if you used carfilzumib instead as a potential? So I just wanted to point this out that, for example, in Ichema in the combination of isotoxamib, carfilzumib, and dexamethasone, the PFS was about 36 months. Granted, there weren't 100% lindelidamide refractory.

[14:20] What was impressive to see was they recently showed updated data from Cardi Tute-4 showing significant improvement in overall survival. So again, I was talking about how overall survival is a high bar to clear. So we can see with using silt-to-cell in this patient population showed improvement in overall survival. Now, I think what is interesting to see

[14:40] was this was across the whole cartotid-4 patient population. And what percentage of patients have had prior daritumimab? Because in current practice, now that we have Perseus, Cepheus, Amraz, GNG, and MGHD7, using anti-CD and theortic antibodies, moving to the front line.

[15:00] So, in current practice in 2025, moving forward, the majority and more patients will have CD30 antibody exposure. So here, I just wanted to point out that in patients with triple class-exposed, at PFS, it wasn't 35 months. It's only around 21 to 24 months. And for me, this is always

[15:20] been kind of a head scratcher. How do you go from 35 months and six median prior lines to something shorter? And I wonder if there's something different about a patient whose triple class exposed after only one to three prior lines suggests that that patient might have a different type of disease that might be more aggressive.

[15:40] to point out with using CAR T cell therapy, we hear about CRS, we hear about Icans, but there is something that might be relatively unique to myeloma CAR T cells and potentially more specific with siltacil is this delayed neurotoxicity. And I think in particular is this Parkinson's, about 5% of patients

[16:00] patients in the silt of cell had Parkinson's and when that shows up it's a major showstopper in terms of patients have personality changes, gait instability, difficulties with gait. And on the other hand, card to four is only a small proportion, only 0.6%. So there's probably something different about the different patient populations.

[16:20] I mean, we're better about using bridging therapy, reducing high burden disease. But I just wanted to share that as another emerging therapy, is that we're also getting potentially better at treating this toxicity. So I just wanted to, this was actually something from our institution. And actually, this was actually my patient. So this patient, so my patient.

[16:40] had, around day 20, had personality changes. His gait used to be a really, you could, you know, very jovial person, but after the treatment, you can see his personality kind of made these subtle changes. And his gait started to resemble more like Parkinson's. And with that treatment, with, I'm sorry, and then we gave

[17:00] He got a pulse of cyclophosphamide. And with the pulse of cyclophosphamide that completely mitigated the Parkinsonism. And I talked to him a couple months ago, two years, actually it was maybe earlier, maybe last month, gait changes. His Parkinson's is a respondent. He remains free of disease. So I just bring this up.

[17:20] Because the PARC is a major adverse event to reconcile with siltacil, but we have better ways of coping with it. And then there are two randomized studies to better look at siltacil in newly diagnosed patients. So these trials are ongoing. So I just want to conclude quick. Well, I don't know. Okay. So I just want to talk about

[17:40] be made by specific antibodies. So people talk about cross trial comparisons and people always say, oh, don't like to do cross trial comparisons, but I love doing cross trial comparisons. Because these therapies, they don't occur in a vacuum. It's not like you're going to compare the meal we had at one restaurant.

[18:00] restaurant, they had a different restaurant, right? It's only obvious. But at the same time, I realized that with these cross-truck comparisons, so I'm not sure if you guys remember this episode. Like, Homer Simpson loves Duff beer, right? And he goes to, like, this temple, like the factory. And the guy there is talking about all the different beer varieties. But it turns out

[18:20] It's all coming from the same spigot, right? It's all the same thing. So we spent all this time talking about the differences between one therapy versus another therapy, but in reality, they're probably more similar than different. And I've written it up because I think about, we have two anti-besemate bispecific antibodies, and now we were just hearing about all the besemate bispecifics and lymphoma. But they showed up.

[18:40] These are common themes where you have a PFS of about one year, but generally speaking, you have CRS rates of around 60% and about 20 to 30% patients are managed with tosalizum F, and there is a relatively high degree of infections when you target BCMA. So do the risk of CRS and neurotoxicity.

[19:00] There is this step-up dosing for these two where they talk about required to be in the hospital and you have to do this gradual step-up process. Now what does the efficacy of having a PFS of about one year or more mean? So if you do this real-world comparison, you can see that it represents a significant benefit comparison.

[19:20] compared to the choices you would have available at that time. And then there are two other anti-bismaid bispecifics that are currently in development, and these are something to be aware of. And I think something to point out is at Limvo Sultamab, I mean, the PFS of 12 months at 9—of 70 percent is probably the highest we've seen. And then with AVIs, AVI 383,

[19:40] One distinguishing feature about this is that there's no stepped-up dosing, and the dosing is about once every four weeks. Right? With the other biceps specific antibodies, it's about once a week. So with infection, when you target B-C-may, B-C-may is on the surface of plasma cells. There's a lot of hypogamma, gliobulanemia. And B-C-may is not only on plasma cells, it's on other cells.

[20:00] upstream of plasma cells. So infection is very common. So when we think about to Toclistumab, they had a really high rate in the majestic one where over 50% of patients had grade three to four infection and there were over 10% death rates from infection. But if you think about when the study was done, is it done in 2020?

[20:20] else also was going on in 2020, right? It was COVID, right? So the majority of patients, you know, weren't, they didn't have, you know, this, vaccines weren't available, etc., etc. And you can imagine that in 2025 when the majority, when COVID-19, there's near universal exposure and or vaccination.

[20:40] vaccination to it is probably less of an issue. So in real world practice it's significantly less. And key to making sure that to key, I think a key thing to point out is using IVIG is key to the success of using anti-besium by specific. So this is just one example from in Amsterdam.

[21:00] And moreover, so this kind of summarizes, you know, using IVIG as key as well as prophyloxis for VZV and PJP. Now, spacing out dosing is also another way, another emerging practice. And here we can see, I think one thing we appreciate is we're using bispecificase.

[21:20] antibodies is how durable the responses can be and that affords you the ability to space out the dosing. And moreover, right, so in February it was just to prove that you can space out the dosing, but more of when you space out the dosing you also reduce the risk of infection as well. And another thing that recently emerged from

[21:40] the ash is that what happens if you have this longer interval between patients? If you go into every two weeks or every four weeks, do you have to? What happens if you're two months out? Do you have to restart all over again? So it turns out that when this was looked at, the risk of CRS is very low. So they just updated the dosing where you have a nine-week interval.

[22:00] have to restart from scratch. And then how do we make this more user-friendly? Because it's the notion of using tosylism as prophylaxis. So instead of reacting to it, you can use it as prophylaxis. And presumably this could help with outpatient initiation by a specific ask, because you really reduce the risk of CRS. So one example, it was

[22:20] was only like 14% as opposed to 60%. And so this was just in the NCCN guidelines. So I just have two more slides left. Okay. So one is in just a couple. So this is in relapse patients for prilinoxid therapy, but now we can think about newly diagnosed patients. So here I just want to show just whopping responses.

[22:40] impressive progression-free survival. And then also when you look at combining with, in transplant-eligible patients, or with Bortez, you can see practically 100% MRD negativity rate. And this is only after three cycles of treatment, as opposed to in the PERCIA study, which looked at DarrRVD after stem cell transplant.

[23:00] And, you know, the ember B negative tibia rate was 60% after all that. And whereas if you just do using a bispecific antibody after three cycles, you have an ember B negative, which I think is—so I think in the future this could be the next standard of care. So, so I think I spent a lot of time talking about bileptomyotidin. I think this is something that can be become available I think using common

[23:20] will be key. I think CAR T cells are going to be moving forward, as well as anti-beast may buy specific antibodies. I think the future looks bright and I'm excited to see what the future unfolds. And sorry, I probably spent too much time explaining the jokes. Thank you.

[23:40] Thank you very much, Dr. V, very entertaining. I'd like to welcome now Dr. Naveen Pameraju to the stage to discuss updates in myeloprolifioneoplasm. Dr. Pameraju, thank you. Thank you, Dr. Qadiya and to the organizers of.

[24:00] total health. Hello, Vale. Let's do this, okay? We're about to enter into a new golden era of the MPNs and you've been sleeping on it and that's why I was invited here to enlighten all of you. Myeloproliphim neoplasms, a chronic disease that becomes a very acute, life-threatening blood

[24:20] cancer in many of our patients. For many of you who are not seeing the NPNs, the reason why it's relevant to you is that this is a new golden era of drug development. I put a quick selection here for you, which is really to show you that some of these older diseases, polycythemia vera, is undergoing multiple drug therapy trials, which I'll show you and even

[24:40] essential thrombocytosis and the more rare mpns of systemic mastcytosis and the 8P11 syndrome. In myelofibrosis, which is the majority of my talk, there are some new drug combinations moving beyond JAK. We're focusing on the anemia of myelofibrosis and completely novel agents beyond JAK, including telomerase and other

[25:00] target. So let's take a survey of this. Polycythemia vera, an old disease, Osler's disease, all of you have known it since medical school and beyond, but what's important is in addition to teaching folks to rule out secondary polycythemia, so renal cell cancer, a rethocytosis from other origins, smoking, once you get to

[25:20] to PV, the standards, as you know, have been hydroxyurea and interferon. Those are okay, but we're trying to go for a new era of disease modification. And so there are new formulations of interferon, Ropeg interferon in particular, which are FDA approved here in the states. And then the recent approval of Ruxalitnib in the past several years has been added to

[25:40] the armamentarium. The other interesting thing is that there's new drug development. HDAC inhibitors and other drugs, hepsidomyetics, that have come into this field and were highlighted at the ASH meeting. So the ruxalitinib, which is FDA-approved initially for intermediate to high-risk malifibrosis, and also carries an approval for GVHD, is also now approved in polycythedronin.

[26:00] the case.

[26:20] NPNs can benefit. This is the magic study led by Claire Harrison in the UK, an ingenious study which actually is investigator initiated. All patients had had hydrea before, go on to ruxalitinib, and for the first time in our field, it showed that the JAK inhibitor was superior to best available therapy for not only CR and duration of CR.

[26:40] But for the very first time, EFS and OS, the patients who had maximum benefit actually had a leal burden reduction. We are nowhere near Dr. Cortez and CML on this, but we're getting there for the very first time. And the second exciting agent that I'm a part of the development is that of Russvatide or PTG 300, which is a hepside in my medicine.

[27:00] or modulator, which has opened up a new area of drug development and there's four or five drugs active in this space. This positive trial was known as the phase 2 revive study in which we took patients who were phlebotomy dependent. So you had to have three or more phlebotomies over the prior six months to get onto the study and there were patients who were allowed

[27:20] to stay on their active agent but still having a suboptimal response. Of course, the goal of therapy for PV is to make sure your hematocrit is below 45%. So in this phase 2 revived study, the primary endpoint was met, which was again to become phlebotomy-free as compared to the other study group here, as you can see.

[27:40] More importantly than the phlebotomy-free achievement, it's a weekly sub-Q injection, is that patients were able to stay on for quite some time, years now, and actually in terms of safety, outside of a mild skin reaction in some of the injections initially, overall well tolerated. These patients are expected to have thrombotic events, and so we did see some

[28:00] of those throughout the disease course. And so this is now with the phase 2 positive study. We've now moved into a randomized phase 3 control with this hepiomyetic, russfertide versus best available therapy. This is the phase 3 study which is ongoing, and I'm proud to share with you that the phase 2 was actually published in New England.

[28:20] journal recently, again, showing that for the first time in the field, you have something that can completely replace the phlebotomy. So we actively await the phase 3, hoping to go for approval. So now moving to myelofibrosis for the remainder of the talk, the main area of investigation in our field. To level set, there are four approved JAK inhibitors.

[28:40] as I mentioned to you was ruxalidnib led by our colleague Dr. Verstavsik in Harrison, approved now almost a decade and a half ago. Ruxalidnib first in class, Comfort I and II studies in New England Journal, and this has actually been really the longest running JAK inhibitor in the field. After that we had the approval of fudratnib, approved in August of 2016.

[29:00] of 2019, the second in class JAK inhibitor. Interestingly, all these JAK inhibitors have other targets. So this one has Flit3 and other activity bromodomain and MIC as well. This was also approved in intermediate to high risk. Then we had the third approval, PaCritNib, approved in February of 2020, and this drug was specifically approved for

[29:20] myelofibrosis with platelets less than 50, so representing the first time regulatory pharma partnership for a very specific niche area of unmet medical need. The fourth of these JAK inhibitors is Momalot NIB, which actually was a sea change approval just in 2023 September, which was for myelofibrosis with anemia.

[29:40] I mentioned earlier, that's an urgent unamet medical need in our field. So with that background in mind, this is the kind of comfort one for ruxalitnib kind of benchmarks that we use frontline untreated patients with myelofibrosis. Important to remember these numbers. So it was 42% what we call SVR-35. So spleen volume reduction, 35.

[30:00] 25% by imaging at 24 weeks. That became the gold standard in the field. And the second endpoint, which is usually carried as TSS total symptom score at week 24, usually we like to see a 50% reduction, and that was around 46% in rucks. These trials compared against placebo, as I'm showing you here, as well as best available therapy.

[30:20] disease. The reason why I wanted to make sure that you have that background is that although the JAK inhibitors led by Rux have been a revolutionary change in the field, the first targeted therapy-approved class, these drugs largely do not cure. This is a disease that the only curative modality remains allogeneic stem cell transplant. If you get into the

[30:40] collapse for a fracturey setting, let's suppose in the front line your survival was measured in decades, it can actually be two years or less. This was a paper by our colleague Dr. Palandri in Italy which showed kind of shockingly that at three years in a series of over 218 patients, almost half the patients are off their JAK inhibitor, almost always for bad reasons. Side effect.

[31:00] complications, infections, progression of disease, or spleen, only a few of those patients actually going to a transplant. In multivariable analysis, the only thing that factored into greater overall survival after this happened was getting onto a clinical trial or having an investigational agent. So with that in mind, we led a group to write a white paper on this.

[31:20] And the term is now called disease modification. Can we move beyond hydroxyurea? And just managing counts and blood transfusions to maybe put forward a three-pronged approach. Intervene earlier, potentially intervene with combination, so more than a monotherapy, and then intervene with drugs beyond the jackpot.

[31:40] stat pathway and I think that's why I mentioned that this is a golden era of drug development. These are just some of the main combination therapies. I led the study with my group for the BCL-XL-Navidoclax. Ultimately did not get FDA approved, but we were able to go to randomize phase 3, showing a two times improvement of the SVR-35, the main primary endpoint.

[32:00] But alas, the symptoms were not improved, so therefore not FDA-approved. The same fate with the palabrasive, bromodomain, or bed inhibitor, randomized phase III study, SVR significantly positive, but the symptoms did not quite hit. And so it raises the question, when you add a second drug, can you still improve the symptoms from JAK inhibitor monotherapy?

[32:20] And I think we're losing good drugs because we have not yet changed our endpoints. The two remaining in phase three are the ones at the bottom, MDM2 inhibitor with nav to Madeline. And kind of surprisingly, for many of you in lymphoma, myeloma, Dr. Yee is cell and XOR at a markedly lower dose than what you guys used, 40, 60 milligrams POE.

[32:40] weekly has now entered into randomized phase three studies. And again, this novel agent, this is from our group, this actually has to be wildly updated. We thought we included everything from there, but everything from CD123, CalR, mutated, so surface attack, immunotherapy for the first time in our field, intracellular targets, and of course, borrowing.

[33:00] from AML and MDS, which you'll hear more from Dr. Dauber. So a quick survey of some of these novel agents. This is work based on from Dr. Kadia from our group who led the first ever Treg cells to be given to patients with myelofibrosis. And this is now in a next phase trial led by my colleague, Dr. Moserova. In this ingenious

[33:20] study, you have regulatory T-cells, which we know can suppress inflammation, and therefore, given from an umbilical cord blood non-matched source, can it then restore hematopoiesis and even improve symptoms and reduce spleens. Early on, this is the first 10 patients that were shown as an ash-orbed presentation. Not only you had reduction in spleen and symptoms,

[33:40] but you also had correlation with TDF beta levels, which was part of the hypothesis for this new. So we've entered into immunotherapy for patients with MF. The second trial highlighted at ASH by our colleague, Dr. Moscaranus, is that of Nav2Madolin. I mentioned the MDM2 inhibitor. This is in the relapse refractory post-JAK inhibitor failure.

[34:00] One tip is that MDM2 overexpression prevents P53-driven apoptosis in these MF stem cells. What I think is amazing about this agent, this is oral, again, non-JAC, a new pathway. You have to be TP53 wild-type for these drugs. Large study, 183 patients, randomized either nav to madelyn to best available therapy.

[34:20] therapy. And again, although it's modest, this is relapse refractory setting, so not frontline. You do see in patients treated, especially here with the waterfall plot, SVR-35 and TSS-50 being achieved in this relapse refractory setting in which the overall survival is estimated usually at 2 years or less. Disease modification, our new mantra, we are seeing a reduction.

[34:40] infection in the VAF and bone marrow fibrosis, and this drug is now an active phase 3 trial in the frontline setting, suboptimal. Safety, this class of drugs, MDM2, has always been associated with GI side effects, so you do have to watch out for that, particularly given Celanex or this drug and others, all of which have pretty serious GI effects and a chronic disease.

[35:00] where you're giving double oral therapy. And this is the phase 3 that I mentioned. Very ambitious, very proud to see this trial, 600 patient trial planned, which is you're already on your JAK inhibitor, ruxalidinib, and you add in this new drug, the MDM2 inhibitor, for suboptimal responders. Another exciting drug presented by Claire Harrison is the L-Rittercept.

[35:20] Some of you may know this shrub from the MDS space. This is Care 050. The aim here is to improve especially the blood counts, the anemia, due to ineffective anaepoiesis through the TGF beta superfamily. So this is in the same class of drugs of other TGF beta before. What's amazing about that

[35:40] this trial, what we were all surprised and happy to see among the first 80 patients treated either as monotherapy or with the JAK inhibitor is in addition to anemia improvement and being a safe drug, we're also seeing improvements in spleen size. So this is already having early signs of disease modification. Let's see if this continues into the.

[36:00] later stage studies, but this is one to keep our eye on, helping all areas of myelofibrosis, anemia, spleen, and symptoms. Just a quick comment for the rare MPNs. That's where I spend a lot of my time. There is this rare entity, the 8P11 syndrome. Most of you haven't heard of it because we've been missing it. It's been hiding in plain sight. It's an FGFR overexpressing

[36:20] tumor. Can you believe already one FDA-approved drug for this, Pemicatinib, which is also co-approved for cholangiocarcinoma, same pathway, but it leads to deep cytogenetic and molecular response. It's actually an acute, deadly leukemia to have, either a single agent or in combination with other chemotherapy, and that's led to a second drug, Olverin-Batinib, which is a

[36:40] which is being tested in the late stages for CML, also being active in this drug. So this drug was updated at ASH. And again, for my pharma colleagues here, this is my usual plea. Don't forget about the rare diseases, because they're diseases to the patients and the families and the spouses who have them. And we've had quite a bit of success, actually, in drug development going all the way.

[37:00] say. For the looking forward to this year, what I'm most excited about is the targeted therapy era in MPNs has finally arrived. I mentioned the JAK inhibitors hit the wild-type pathway, so JAK-STAT pathway, but we've never had a mutant selective or specific approach. Two trials which have just opened the doors to phase 1.

[37:20] Enrollment is the AJAC study, which is a type 2 JAK inhibitor, kind of hitting the inactive conformation of the JAK. So that's just started. And then with insight, we have the mutant-specific JAK2V6.7F oral agent also, just going into phase one. Obviously this will be in the relapse refractory setting, and we're eager to see those results.

[37:40] And not to be left out is CalR, the second most common. So JAK2 is the most common, CalR is the second most common driver mutation, MIPL is the third. Because the mutant traffics from the nucleus to the surface, it's amenable to neoepitope presentation and immune attack. This has opened up a huge new area.

[38:00] area. Vaccines have already been tried and tested in phase one. Now we've moved on to monoclonal antibody, which is open and available through Insight, the mutant CalR by CD3 by specific, which I'm involved in at J&J. And then there's preclinical work for CAR-T, the first ever CAR-T in the NPN field directed against CalR from our European colleagues.

[38:20] colleagues. And so, ladies and gentlemen, I leave you with this chronic disease that many of you may have forgotten, but please don't because it's such an area, an active area of drug development. For the first time, drugs are being developed in our rare space and then going back into AML, MDS, and possibly even lymphoma and myeloma. I would end by

[38:40] saying that with this new era, we should also be engaging our FDA regulatory regulators together. Dr. Dauver, Dr. Kadiya, and my colleagues in AML have done this nicely. And maybe as Dr. Hagemeister pointed out in an earlier trial, maybe we should be making overall survival EFS-PFS as our endpoints. Rather than spleen and symptoms,

[39:00] which served their purpose in the JAK inhibitor monotherapy. But as you're seeing here now, we have non-JAK inhibitor drugs, we have people who are dying in two years, and we have to be able to capture the benefits of good drugs rather than killing them prematurely. Thank you very much.

[39:20] Thank you, Dr. Pomeraju, and I'd like to next welcome Dr. Dauver, who will be talking to us about AML. Please welcome him to the stage. All right, well, thank you very, very much.

[39:40] Dr. Pemaraju is a huge fan of Dr. Osler. In fact, yesterday he said his dream dinner would be to have Dr. Osler in attendance. I'm like, I don't know what kind of party that would be, but okay, that's your thing. I party differently, but go for it.

[40:00] has been a disease that has seen a lot of progress. We're catching up with myeloma and drug approvals, but not in survival yet, but I think that will come soon. And it's kind of difficult to give an overview of all of acute myeloid leukemia in one 10 to 15 minute presentation. So I'm going to focus really on targeted therapies.

[40:20] and unfortunately unlike lymphoma, myeloma, CLL, ALL, we have not had the plethora of immunotherapies. I don't think it doesn't mean that we will not have them. I think it's just going to take longer. And a lot of this is because the biology of AML is highly multiclonal, highly heterogeneous. It's really multiple cancers in one and you're just targeting that first clone that

[40:40] that is kind of the tip of the iceberg. So immunotherapies I think will have to be more evolved, more thought out than what we do currently with single antigen, car, or bi-specific. So we have found success in that angle with the targeted therapies, so FLT3 inhibitors, IDH inhibitors, Menin inhibitors, and I think this is going to continue with other targeted therapies.

[41:00] therapies, which will at least improve the duration of remissions, the event-free survival, the quality of life, transfusion improvements. We may not get curative outcomes, but if we can get like myeloma, median survival that's gone from three years in 2000 to 15 years in 2023, then I think that would be success in my mind. So talking about the target

[41:20] therapies, I think the Flit 3 inhibitors have really paved the way for this, not just in AML but across many heme malignancies. This is kind of a major targeted therapy group. Somebody asked me today morning when I was getting coffee, what happened to Flit 1 and Flit 2? That's a good question. So anybody can answer that will probably be a millionaire,

[41:40] No, combinations are absolutely required from the beginning to target the Flit-3, but also to suppress other clones that may actually be pre-existing clones such as NPM1, TET2, IDH, and others. And that's kind of how the field has evolved. So we saw limited success with single-agent Flit-3 inhibitors, especially the earlier ones like Midastor and Spry.

[42:00] often they've been moved very quickly to combination approaches in the front line setting. These are two randomized studies called the RATIFY study and the QANM first. Both of them looked at intensive chemo backbone, 7 plus 3 anthracitin-cytarrabine, which has been a standard for about three to four decades. And we added to that the FlIT3 inhibitor on one arm, the plesusae.

[42:20] on the other arm, and both these studies showed that the addition of Flit3 inhibitor in Flit3 mutated AML-improved survival to the backbone of intensive chemo. So the question now that is being asked a lot is, which of these should I choose? There's no randomized data head to head. The myeloma speaker said, you know, we shouldn't do cross-trial comparison, but I love to. I agree with him. We have to do cross-trial.

[42:40] master at comparisons because we have no choice. We're not going to have every trial for the 500 questions we have. And I think looking at the data with Kuzartnib as a single agent, which actually was led and championed by Dr. Cortez when he was with us at MD Anderson, looking at its efficacy pre-clinically, as well as its better tolerability, and now the frontline data suggesting, at least in ITD patients,

[43:00] giving us a better four year survival, we are using quizartinib and most centers in the US have moved to quizartinib in the frontline setting for the ITD. Now if you have a TKD, remember quizartinib will not work, midastorn is reasonable. Now what about those above 60? I don't think intensive chemo is the way to go there. We have moved heavily towards lower intents.

[43:20] intensity backbones such as HMA venetoclax, I'll talk about that a little bit, cladimin, lotus, and ersivin. And even this randomized study, which is a very recent study, it was actually done between 2017 and 2021, you can see that above 60, even adding a T-cat intensive chemo, median survival is 14 months with a lot of toxicity, early mortality. So I would say that's a great idea.

[43:40] say to Emory Anderson and I know many big centers. Above 65, we are really avoiding intensive chemo unless they have a core binding factor or something very, very sensitive to intensive chemo and I think that may even be above 60 now given some of this data. So one of the updates from ASHRAE was looking at the baseline molecular mutation profiles in the quantum FERS study, which is the quasar-

[44:00] randomized study of seven-placidicus art numbers or seven-placidicis placebo. This was presented by Mark Leves. And what they found was actually quite interesting, that there are certain co-mutations among the FlIT3ITD mutated, all of these are FlIT3ITD mutated to get on the study, that predicted for a better response, EFS, OS, these are NPM1, DNMT3, A4, and A4.

[44:20] and TET2. Now in most of the others as well, quasardnib seems to have some degree of benefit but not as striking as these three mutations. And they showed this for survival, that those who had an NPM1 or a DNMT3A among those Flit3ITD had quite a significant survival benefit with quasardnib in terms of overall survival.

[44:40] And in fact, the trifecta of these mutations, so if you have NPM1, DNMT3A, and FLT3 together, seems to really benefit from chrysarptenum. Now this is really interesting biologically because historically this trifecta was associated with very poor outcomes to OS. So if you had the triple mutation, you actually did worse than those who had FLT3 without NPM1.

[45:00] PM1D and MD3A. In this setting, it's actually not neutralizing it, it's actually showing a sensitization. So this group seems to really benefit a lot from quasartan-based therapy. As you can see, there's a 30 to 40% survival difference at three years, and for sure, we should be giving these people Flit3 inhibitors, we should be giving it to everybody with Flit3ITD.

[45:20] Now there's also data coming out about transplant and the role of transplant. I would say in AML today, for Flit3ITD mutated, we are still transplanting all our patients in the first remission. And I say today because there is data that has come out from UK, and we're looking at this in MD Anderson as well as in the US in a cooperative effort suggesting that MRD.

[45:40] Especially using NPM1 or FLT3 specific molecular NGSMRD may predict patients who may not go to transplant. But it's very early data and today we have not shifted our practice. We still go to transplant. This was the data from the quantum first showing that transplant still had a survival benefit even in the era of the addition of a targeted therapy.

[46:00] both independently give you a survival benefit. So one is not replacing the other. Now you got your patient into a remission. Let's say you gave him intensive chemo quasartanib. Things have gone well. They've got to transplant. Wonderful, Dr. Lucy's ready there. He'll transplant him right away after cycle two. Well done. Now you're here. Day 50 post-transplant patient looks good. In grafting.

[46:20] He's on some azoles, feels very well. What do you do? So maintenance now has become a critical part of the treatment armatarium in AML as it has been in ALL and myeloma. And for flithery, in fact, all of the drugs are recommended by NCCN. This is the NCCN guidelines that I've pasted here to be used as maintenance or often in midastorhone, guillotritinib, quizartinib.

[46:40] As data though, I would say post-transplant for maintenance. Randomized phase III, the only one that has done randomized study in the post-transplant setting is the Morfo study where they clearly showed giltritnib improved the EFS post-transplant compared to placebo in those who are Flik III molecular MRD-positive. Whenever I give this talk, people email me later.

[47:00] and say I have a patient, flow MRD negative, what should I do? None of this is based on flow MRD. I do not feel comfortable making any of these decisions on flow MRD. The molecular MRD that we use, this is called the Invivo scribe, there's other commercial labs that do it, can go down to 10 raised to minus six. So it's almost two to three logs below flow. So we're talking about a very ultra-sensitive.

[47:20] test if one is to make some decisions. Then what do you do if you cannot get this test? Today I would give them maintenance. If I do not know if I can get this test, I would err on the side of giving the maintenance which gave you a 80% for your EFS. But I think more and more we're getting access to this molecular MRD. So we're making a lot of progress in young patients with Flit3 just about

[47:40] About 15 years ago, the expected survival for this population was 25%. This was published by many groups, including ours. Today we publish our most recent update and it's about 65 to 70%. So quite a major improvement in the five year survival. There's also data now coming out that maybe we pigeonhole these drugs into Flit-3 targeted therapy.

[48:00] because that's how humans like to think. You have a target, you have a target of therapy. But there may be efficacy beyond them. So this study I find quite fascinating called the Kiwi study, this was done out of Spain, where they used quasartinib in combination-intensive chemo in the flitory, non-mutated patients. Again, actually something that Dr. Cortes had shown in JCO.

[48:20] almost 12 years ago as a single agent, that there are responses in wild type. They took it to a frontline randomized study. The updated data shows clearly improvement in OS and EFS. This is now led to a very large study called the Quantum Wild Study, 250 centers, 800 patient study that is going to see if quasart networks, not just in the flither mutated where we know it works and is a problem.

[48:40] approved, but also in the wild type. And there's also a signature that has been developed using RNA sequencing. So this may be very similar to the Philadelphia-like signature, there's a flit-free-like signature. So I'll wait to hear more about this in the near future. Now what about those people above 65? And I would say maybe even above 60, 65 where I'm nervous to give intensive chemo,

[49:00] maybe some frailty, maybe some comorbidities, maybe some cardiac liver issues. So HMA then is a poor standard in the Flit3 ITD, I would say. When you look at this lower right curve, that is the curve that was published by Marina Kona-Plava from the Viala-A, AZN outcomes with Flit3, and in fact, you can see the median survival.

[49:20] is actually quite low. In the flit 3 ITD it was even lower, it was 10 months. The aggregate was about 12 to 13 months. So we then said, well why should we only use Azavn? You have targeted therapies like guillotritinib, quasardinib. Can we find a way to safely add those and optimize the doses? This led to the Azavn-guillotritinib study that Nick Short and our group has been working on. This was the

[49:40] publication exactly a year ago last January in JCO showing high efficacy, 95% remission, majority of them full CR, which is very important to note, full count recovery with a deep molecular and martenian negativity, and an OS with about an 18-month follow-up that was not reached. Nick updated this data at ASH where we actually pooled our frontline

[50:00] triplets, A's event guild, and A's event quiz, and we're actually now starting to see that there is a median survival here, but it's actually quite good. 38 month median survival, and I put below in the box the numbers that were seen with VLAA. So the expected median OS from VLAA with A's event was 11.5 months. Here it is looking at 38 months, and if you look at the

[50:20] ITD alone, it was about 9.9 months. Here it is, 28 months. So I think this is probably the way to go, but it's still not curing patients. So we may still need to continue to evolve on this in the future. And here, just looking at the various regimens, this triplet is probably the one showing the best activity. I'm gonna move quickly here a little bit to the Menin inhibitor.

[50:40] So this is another area that has emerged much more recent than Flit 3 just in the last 3 to 4 years. I think many of you may know, but if you don't, KMT2A is a very very high risk subset. So after TP53 and MECOM, historically KMT2A rearranged AML has had the poor outcome. You can see here median survival less than 3 months in the salvage setting.

[51:00] almost no patients make it beyond a year. It's about 8 to 10% of relapse AML, more common in the younger population, so reasonable subset. Relapse NPM1, when we started doing this, the FDA said, well, relapse NPM1, the bar is higher, the outcome should be better, everybody says it's favorable. So we actually did this analysis, Dr. Issa, myself, and others, to look at

[51:20] outcomes in relapse NPM1 and MD Anderson, 200 patients with the mutation versus 1,500 without, and guess what? In relapse NPM1, there's nothing favorable. Relapse AML is not favorable in any setting. The median survival in relapse NPM1 is 5 to 6 months, the same as those without the mutation, and this should be considered a population of pretty much

[51:40] equal unmet need in my view as the KMT2A. So this has led to now a plethora of manin inhibitors. You know, the Flit3 took us 10 years to get three Flit3 inhibitors. Here within three years, we've already have four manin inhibitors, all of them actually showing efficacy. There are differences in them in terms of the pharmacology as well as the kinetics, the half-life, the bi-dilidosis.

[52:00] binding and the safety, especially differentiation syndrome, QTC are quite different among the different drugs. Efficacy, I'm not yet sure if we're going to see differences. They look similar in terms of CR, CRH. Revuminant is the only one that's approved. This was approved very recently, October of 2024. This was the update of the approval study, the augment study looking at relapse retractions.

[52:20] KMT2A. It's only approved right now for KMT2A. The relapse refractory NPM1 data was just released December and hopefully will also get to approval in relapse refractory NPM1 in a few months. CRCRH rate, about 25%. CRC rate, which to me is more important and to Dr. Lucey is more important, I've achieved a matter of remission with some count recovery.

[52:40] I can move to transplant was actually pretty good, 40, 45%. But we do see differentiation syndrome manageable with revumin. I say it's quite a manageable differentiation as compared to maybe Zifter or Blexy, but the QTC effect is specific to revumin. It has been something we have to take into account. We don't see this with other men and inhibitors. And if you're adding Azole, Quinolone, Zolent,

[53:00] So Fran, you have to be careful about the QTC with revulamin. But all in all, I think quite a good drug approved and will be used a lot in the salvage setting. Bleximinib is another menin inhibitor, came more recently. I'm not going to spend a huge amount of time. It's a little earlier. We don't have as much robust phase 2 data as the phase 2 actually has started. The big difference here is the differentiation.

[53:20] syndrome with Blexy is more powerful. There were fatalities, there was an FDA hold because of this. There is a more ramp up dosing, earlier use of steroids and prophylaxis. I think it's manageable, but that will be something to look out for once it, if it gets approved in the future and gets into the community. CR, CRH rate actually quite similar as you can see about 30% with a composition.

[53:40] as it's CR also very similar, 40 to 45%, does not have a QT effect, which is good. And the nearest player on the block is Enzomeniba Drug. We've been working on all of these, and MD Anderson, Enzomeniba is kind of the more recent one. And I have to say, the safety profile has been very, very encouraging. We've now treated 85 or so patients, no DLT. We have not seen any grade 4 DLT.

[54:00] as mortality discontinuation and the QTC does not seem to be in effect and it actually has a very short half-life which I think will become important as we move into the combinations and may help us titrate the doses more tightly. The efficacy many people at ASH get excited and had we've had hundreds of discussions on this is it better I don't know I think it's equal to

[54:20] slightly better, we have to get more numbers, but we are seeing close to 35, 40% CR-CRHs, but I think the data and the combination will be most important. All three of these are now in pivotal phase 2 studies. And lastly, I'll just mention, again, like the Flit 3 story and the IDH story, single agent is going to give you 30, 35, 40, whatever number you want.

[54:40] want to use, but it's not going to give you a 70, 80% response. Here, the combinations will come into play very much like what the myeloma ALL colleagues have done. Gasisa and our group have started building combinations. This is a safe study, oral, the site of being an HMAV, revuminib, and we're seeing now close to 80% remission rate, CRC rates of 60%.

[55:00] and we have to get more follow-up, but I think the survival will also look better than what we've seen with the single agents. And then lastly, I'll just mention IDH. There hasn't been as much, but the frontline data with the triplet, the Dr. Nardanar group has been working on A's of NIDH, very similar to the A's of N guilt that Nick, myself and others have worked on, is looking very, very good.

[55:20] especially in the newly diagnosed non-therapy related AML, the triple therapy is giving us now a three year survival of 90%. So this may be a way to go for IDH as well, the combinations and many of these have now gone into randomized studies in Europe and other areas. So I think in conclusion, we have definitely made progress. Flid 3 survival

[55:40] has improved. I think we'll see KMT2iIDH also improve dramatically. But there are many subsets like TP53MECOM for which we still have unmet need, a lot of efforts ongoing, some have failed, but we will keep trying and I think immunotherapies will eventually play a role in that. So hopefully we will talk more when we have the dinner with Dr. Olaf.

[56:00] in the few years. Thank you very much. Thank you very much, Dr. Dauber. Okay, folks, we have another break now for lunch. So go ahead to the room, grab some lunch, and work your way back over here. We're going to be getting ready for the Pfizer session, looking at outpatient care of patients with myeloma.

[56:20] Why don't we start that?