Jens Hillengass of Roswell Park leads a discussion, with Attaya Suvannasankha of the Indiana University School of Medicine and Mansi Shah from Rutgers Cancer Institute on the latest developments in management of new and relapsed and recurrent multiple myeloma and the role CAR T-cell therapy can play.
All right, um, next I'd like to kick us off for our multiple myeloma colleagues. Um, I think last year we were at the very end of the whole, um, conference, and, uh, this year we want to make you all a little bit earlier so people can kind of stick around and we do have the raffles, my shameless reminder again to grab those tickets, uh, that'll be at the very end as well to try to get people to stay for, for my talk at the end in the middle of a hockey game, but I'm just kidding, it's OK. Um, so it's my distinguished pleasure to introduce Doctor Otaya, uh, Tuvananaanka. If I'm mispronouncing your name, Doc, please, uh, feel free to correct me. Um, Doctor Z Tuvananaanka is a professor of medicine, clinical medicine, and Gladstein professor of cancer research in the division of Hematology oncology at Indiana, uh, University School of Medicine. Doc, um. Please come kick us off for multiple myeloma and uh initial management of um that disease. Thank you. Thank you so much. It is such a great pleasure to be back here after 20 years. I was actually a fellow at Russell Park, um, and this is still a place that I like to call home whenever I get to come back. All right. So, um, not only, uh, Sorry. He doesn't want to go for it. Yeah, OK, right. Well, so first of all, not only I'm thinking about Russell Park dearly, Arthur Park actually um put a major milestone in what we learn, how to, how we learn how to treat myeloma because actually there was something called RPMI media, which is the Russell Park kind of like homegrown media that's used to grow cancer cells. It used to be that you cannot grow lymphoid cells outside the human body. So if you cannot grow anything outside the human body, you cannot test anything. So the media was actually invented here in 1966 by Dr. Josh Moore and his group and continues to be called RPMI media until today. Also, the first cell line, the first myeloma cell line came out of the patient from right here. Um, same group actually used this RPMI-8226 cell line. We still use them today and, uh, really with the media with the cell line since then there's now been explosive number of cancer cell lines that's been generated since, um, and that leads to a whole lot of things that I'll be able to share with you today. All right, so I'm tasked with talking about newly diagnosed multiple myeloma, um, which I really think that it's a place where a lot of things are changing, but as a reminder, so we are no longer just diagnosing people based on whether their organs fail, we also now have an amendment to the diagnostic criteria so you don't have just the. criteria, which is, um, high calcium, renal failure, anemia, bone disease, but also the slim crab criteria that slim include high percent plasma cell, um, more than 60% in the bone marrow, or serum free light chain ratio more than 100, or in the case of lambda, you inverse the ratio, so it's less than 0.01. That high light chain burden also cla uh classify patients as having myeloma and also MRI study showing more than one focal lesion and uh Doctor Hillyas and his group here also has contributed significantly to the how we understand imaging and its impact in multiple myeloma. So now you know how to diagnose myeloma. I think first decision actually matter the most and you never get 2nd 1st line, right? So what we're doing is hopefully helping patients launch their whole journey of myeloma. And I think if we think that we're ever going to cure myeloma, it starts with the first line therapy, right? The chance of if you think about attacking anything that's evolving in time, your first bet is to actually do the thing right the first time around. So there are a lot of decisions that we're helping our patients make. Um, I'm hoping that by the end of my Summary, you'll get these 5 things. So first, we define high risk myeloma a little bit differently now, and I'll share with you what that is. And quadruplet regimen that has 4 classes of drugs together is now a new baseline in anybody who should be able to tolerate it. We are now talking about customization of treatments that's not based on just 3 versus 4, but rather using patient's own response to guide decision. MRD is a minimal residual disease, and it is a tool that's emerging. Um, not only to get FDA approval of new agents, but also as a way to help customize care. Maintenance therapy is also evolving. It used to be that you're maintaining what you got, that's the best you get, but that's no longer true. Maintenance is also the time to deepen remission and also think about modifying the immune repertoire in that case. And also we have a whole lot of immune therapies that are entering the front line. So I think that what I'm telling you today will be wrong in the very near future, and you'll just have to invite me back. So I can visit home here again. All right, so this is, this is, thank you. So this is a new high risk definition. It's getting more complex than ever. Well, the whole sleuth is we never really quite know when someone's gonna do poorly or not so, right? All of this is a look back, meaning that people are with myeloma, they're treated, and then we retrospectively, retrospectively ask ourselves, was there something about that patient that we could have segregated them aside to actually say that if you were to have these things, you're actually not going to do as well. Some of the things we already know to be true, um, those translocation 4 1414, 16, 1420, that's been diagnosed by fish, you and I have those tools, gain or amplification of one Q has sort of been hinted for a while now that it's actually potentially a poor risk, but it's now actually emerging, particularly if it coexists with other abnormalities, the monoanalytic loss of one P. So chromosome 1 is the biggest chromosome. There are a lot of madness that can that can actually happen in that chromosome. If you have gain of 1Q or if you have loss of 1 P, or if you have your two things together, not good. Now, we still cannot forget the tool that we all have had. Outside of the genetic thing, beta 2 micoglobulin and albumin and so on have been what we can actually test. It turned out beta microglobulin being elevated is a bad thing, but it tends to occur in a setting of kidney failure. If it happened when the kidney is normal, not good. There's actually something very aggressive about the tumor behavior. Now, one thing to keep in mind is we now have mutation of TPA 53 being also included in the high risk definition. So we're going to enter the era where a fish alone isn't actually adequately telling us um what our patient to risk group is because fish won't actually show the mutation analysis. So we're going to need next generation sequencing and so on. So that kind of test is hopefully becoming more available near you very soon. Um, the classic foundation one he doesn't quite give you that because it doesn't isolate out the plasma cells. So for the tests to look at TP53 specifically on the myeloma cells, we're going to need to sort out the myeloma cells first before the cells go through the next gen sequencing. So now, we're using biology to actually classify people, because we also learn why these abnormal chromosomes are driving the risk because there were certain gene changes that occur within those abnormalities. So, because you and I will not remember all of this, or I don't, um, there is that useful tool, myelomarisk.com. So, you know, quick and easy, um, in the clinic, right? Um, plug in the information and it actually spit out the risk um assessment and projected progression-free survival. All right. So, the thing is, I was telling you about what happened inside the tumor cells, but what we can never forget is, it's actually the patient's characteristics that you get to see that will also still play important role, right? So we know that disease that present with plasma cell leukemia, increased circulation. tumor cells, not good. Extramedullary involvement's not good. And of course, we look at our patients, um, host factor, the age from um comorbidities, frailty, barrier to healthcare. And then there's this new entity called functional high risk. It means that you look good in every way. But then down the road, we don't know why you just don't follow the rules, such as people who are refractory to their um upfront therapy or people who relapse quickly. Um, so retrospective analysis, uh, analysis suggests that 18 months or less of median progression fees survival post-transplant is actually a bad deal. But probably now in an era of quadruplet therapy with many patients extending their remission passing the 3, median remission passing 3 years, anything less than 30, um, 30 months is probably not good. All right. So, now, we're going to talk about depth of remission as a model, because of course, depth of remission translate already um to the knowledge of progression free survival and overall survival. So rather than waiting for the PFS or OS to um be the criteria for approval, which means that a lot of patients are going to miss the boat on getting new drugs, MRD, which is really allowing us to look down very, very deeply, um, in the bone marrow classical. To, um, down to 1 in a million cells have actually been our adopted tool, um, as a surrogate for a drug comparison, who's, who's driving good MRD but also for our own patients, right, it's telling us about their biology and their degree of response. So what do I mean by MRD in clinical trial? So this is really sort of different clinical trials over the years and you're looking more on the right side where MRD. Actually was also integrated as endpoints and you'll look at the dark blue bars comparing to the purple bars. So people who are MRD negative are actually um a far likely to do better than people who are not. Um, and this is why rather than PFS being the primary driver, you'll see more of MRD negativity being in goal for clinical trials. So I'm going to show you some of the quadruplet data that actually support um using quadruplet. In the Alron therapy and it is a lot um leaning on the MRD negativity. So this is the first quadruplet that's approved in the US called CaCOPA trial. It's adding daratumumab to the backbone of Velcade, thalidomide and dexamethasone. And you'll tell me that no one here use thalidomide. I hope we don't anymore. But that's still being used worldwide and CaCOP is actually a global trial, leaning hard on patients outside the US. So you'll see that there's MRD. Negativity rate that's actually improving over time. You already see some in the post-induction, better in the blue bars, which have patients getting quadruplet and consistently improving post consolidation with transplant. So goes to say responds better with time, with the different strategies we use in the quads are actually superior. Um, eventually, there was also progression fee survival that confirmed that early MRD negativity translate to that improvement in PFS. So quad approval in the US, no one use BTD. Um, backbone. So we move on to Percy's trial, which was Dara um being added to the RVD backbone, which is the most commonly used standard of care at the time. Um, um, Perseus has two parts to it. So you do the quads versus the triplet transplant, and then there's consolidation. Then there's maintenance. The maintenance part, though, people who got Dara continue to get Dara, people who didn't get Dara before continue to be on lenalidomide alone. So, what I'm going to show you is a PFS benefit of the quad on the blue line, you see that the PFS actually split pretty early. Um, even before that one year mark and continue to actually extend and spread out over time. Then on the right hand, you'll see the um MRD negative rate. Um, the FDA approved MRD negative rate is actually at the 10 to -5, which is in a way, a low bar, meaning that that's 1 in 100,000. We like to be able to go to 1 in a million. Um, but then the sensitivity in different labs are starting to actually get a little shaky at that point. However, of course, this is showing both MRD. Negative at 10 -5 and 10-6, you see the blue bar outperformed the red bar. So the blue bars were the quadruplet with the Dara RVD. But even more important, but kind of squeezed to the side is a sustained MRD negativity, right? We like to think that we achieved the first win, but that win has to sustained. It will do no, it will do no good to get the win and then the cancer re-emerge. So in this case, a quadruplet. So sustained that MRD negativity better over time as well. And this is uh the the data that I'm showing is being updated as we go, right, because this group of patients are still being followed, MRD conversion can still um occur down the road. And this is the median follow up duration of uh 47.5.5 months, but there's actually already updated data, which confirm um this early observation. So that is there to map. But we also have escetuximab, which is another CD38 antibody. While it belonged to the same class, biologically, it's a little bit different, made different as well. There's no great comparator between the great studies to compare the two. But this is actually show the cetuximab in the quadruplet regimen, the design is a little bit different. The GMMG HD 7. Um, is a classic kind of semi, similar to the Percy's trial I was referring to the quad versus the triplet transplant, and people who got ISA stay on ISA plus LE, people who didn't get ISA just got LEN alone. The GE The MMG concept is, I think, going to be a game changer because although it is a smaller trial, it's a non-randomized phase two trial, it's asking a question specifically in the high-risk myeloma population, which is a population that we continue to question. Whether we have served them well. This is using carfilzomib containing regimen as a quad. So not abortizomib, a newer, more potent protisome inhibitor. Patients are getting is a KRD transplant or if they're not transplant eligible, they were included in the trial too. They just skip transplant, they get that extra consolidation, and then um it's a very extended consolidation post. Transplant followed by maintenance therapy for two years. So we're actually really hitting this group of patients pretty hard with a lot of treatment, um, knowing that even if they achieve early remission, they don't tend to sustain in remission. This is what the data look like for the GMMG HD7, which is PFS and MRD negativity, showing separation already improvement of PFS with the quads is a Toximab RVD comparing to RVD. And again, you're seeing the MRD negativity that's better with the quad 66% versus just um 47.7%, which really was what we were happy about not so many years ago. So it goes to say that yet another one, right, antibody quadruplet regimen, um confirming what we have already seen as well from Perseus. How about GMMG concept? Which I was kind of excited about because I think high-risk myeloma needs to actually be considered separately, um, rather than being lumped in part of bigger study, and they're always small number. And really, we oftentimes struggle with trying to define what's the best thing to do for them. So in both transplant eligible and transplant ineligible, the quadrupledt regimen actually boost the MRD negativity, uh, with the additional of ISA2 already boosted triplet using carfilzomib based regimen. So in my mind, probably carfilzomib, quadruplet, including CD38 is going to be what we do across the board probably for younger patients who can tolerate it. This is another phase 3 trial, um, that's also using MRD negativity um after transplant as um Uh, a surrogate for success. This is called ISAKA trial. Um, again, looking at ISA KRD now comparing to KRD and you go through the transplant, there's also consolidation and there's the so-called light consolidation, which is not that light, really, but less intense carfilzomib, um, and um MRD is being studied serially to understand um the impact on the depth of The response. This is the only slide you need to remember from that is a KEA trial because I think it probably will continue to keep being reported at upcoming meetings. The super high risk population, people who have high risk cytogenetics, more than one, they're called a double hit. This group of people, they don't follow any rule at all. And um even if you get MRD negativity early, they tend to not stay in that MRD negative state. They like to keep coming back and they're resisting therapy. So the best data we have come from this ISAK trial with KRD Dara, um, and uh you start to see significant difference comparing to KRD in that super high risk group. Um, so, Because we're talking about quad, we're talking about MRD and the MRD percentage is going up and up. What about transplant, right? I hold it dear. Is it still adding any value or is it becoming redundant? So, this is an older trial determination that is already reported out. It's comparing RVD plus transplant versus RVD and delayed transplant. So, those patients could get transplant, they just didn't get it right away. It turned out though, when they progress, they didn't always come back to get it either. About 28% of patients who were randomized to the triplet without transplant ended up getting transplant. You see that PFS, um, so transplants seem to actually still be um prolonging the progression free survival. However, However, there's no overall survival benefit. And you remember that people actually opted to not get transplant. So if you were to look back and ask, so who didn't seem to be losing benefit? Who were the people who actually didn't get transplant, but their PFS were similar to people who got transplant. There were people who were already in CR after induction. So it begs the question whether a transplant is still necessary. Now, so that's Not going to be fully answered on this study, because that's a retrospective look back to understand the subgroup. But if we were to look at the cytogenetic risk, the high risk population, they don't do well no matter what, and it's even more important for them to get transplant. You see the big separation between if they were to get transplant versus not in the blue line above the orange line, um, In, in your, um, in your left hand panel, and the standard risk, there's benefit too. Whatever we do, it tends to actually help. If it helps the standard risks, it tend to also help the high risk patients, but in this case, it's dra dramatically improving the outcome of the high risk. All right, so I'm going to say transplant becomes so much more of a conversation. It used to be that if you're young, if you're fit, you're getting induction, you're coming to a transplant center, unless something happened, you're probably getting transplant. And I think that today, we're looking at things in a more thorough manner. We're looking at the depth of uh remission, the depth of response after induction. We're also seeing patients standard, well, patients risk disease, see also who they are. Because I think, you know, as we're, even if we're transplanting people who are 75 and above, and some of them do well, there's a concern about toxicity. And then, you know, maybe it maybe it's a conversation whether patients who are MRD negative must have transplant or not. Um, and for, for me, people who are high risk continue to proceed to transplant and they get very extended maintenance therapy. So when I may not transplant, I think standard risk with sustained MRD negativity, it's a conversation, it's a shared decision, um, patient's preference comes into play, and we typically will try to store the stem cells so that we're not closing the door on being able to use transplant down the road. So what do I tell patients, I tell patients that their own response is guiding. The approach that we will cook up together and patients who have high risk disease, they're bummed by it, right, because they cannot control what happened in their cancer cells, but it's telling us that we can't back off and perform under, um under treating them because they're going to do poorly down the road. Now, how about the transplant ineligible? I'm gonna glance through this mostly because I'm about to show you a few phase 3 studies that are more or less looking at patients who are transplant ineligible, and they do, again, show that the quadruplet outperformed the triplet. So, this is cephia trial, which is adding Dara to the backbone VRD in patients who are transplant ineligible or they didn't plan to proceed to transplant. So there's no transplant there. They just, after the induction for 8 cycles, they just go to the maintenance and they're either getting Dra plus um RD or RD backbone. So, this is MRD negativity, which is now a primary endpoint of the study. Um, so you see MRD negative rate is much, much higher with the Dara RVG. Again, sustained MRD negativity at 12 months is better. Um, and, um, this translates to a much better PFS as well. So now we see this looking like we did not leave the transplant ineligible people behind. They actually benefit from the quadruplet regimen as well. Um, well, because we talk about daratumumab, which is 1 CD30 antibody we have. CD 38 antibody escetuximab was also tested in the same way. This is a randomization specific to patients who are under 80 years old and transplant ineligible. They were randomized to cetuximab VRD versus VRD um followed by the continuous treatment for maintenance. Well, the graph split, number looked good, MRD negative rate confirmed. So now, Is aituximab, um, CD30 antibody to the backbone is very helpful as well. I want to remind everybody about the benefit trial because I think it's important to know that in the first trial that I mentioned, the IMROSs trial, uh, even though it actually enrolled patients up to 80 years of age, it was actually using ritizomib twice a week. Most of us actually don't use britizomib twice a week anymore, um, because of the toxicity. So if patients are a bit more frail, you don't think that they would be. Able to handle the vertizomib twice a week. There is already now data using vertizumib backbone of once a week, which I beg everyone to highly consider. Even in patients who don't have baseline neuropathy, it's very difficult to actually do vertizumib once, uh, twice a week. And once people have neuropathy, there's usually the point of no return. You don't always get their nerve back. This is a once a week, um, vertizomib, um, as a backbone together with Lindex and with cetuximab actually being tested. Um, In phase three manner. And um you are now seeing um ISA VRD versus ISARD actually having again the quadruplet showing significant benefit. So, I'm showing you the induction. I'm gonna glance through the maintenance because LEN has been the mainstay, but also in this past year, we actually had Dara LN being approved for MRD positive patients post-transplant, and I wanted to mention briefly about the high-risk population. So this is older data, but Actually generated and led by Doctor Phillip McCarthy, who's right here at Roswell, and he's just a dear mentor of mine, uh, when I, when I was really a youngster trying to learn how to treat blood cancer here. So this is Len, um, comparing to nothing post-transplant and you see Len being of benefit and it's been standard of care for many years now. Cassopia um was a post-transplant quadruplet versus uh triplet, but it was comparing Dara maintenance. versus nothing. And of course, being on something is better than being on nothing. So, this one proved that DA maintenance was helpful. So, if two things are helpful in different circumstances, we just combine them, right? So, AIA is a phase 3 study that actually took patients post-transplant, who actually were better than VGPR but they're not in MRD negative state, right? And we're saying MRD negativity is what we want. So, this is a group of patients who participated in the trial. They were actually Dara naive. So I'll just say right away that they're mostly not necessarily people who are treated in the US because we're incorporated data upfront already. So this is comparing Dara Len versus Len, and primary endpoint was MRD negativity, split quite early. This is a median follow-up data at 32.2 months, and you were seeing dramatically improvement in MRD negativity rate, um, MRD conversion from positive to negative with a doublet comparing to L LEN alone. All right. Um, how about the high-risk population? I was telling you already that we tend to just treat these people for a long time. There's actually reason um for that because this is looking at Kyprolislen versus Ln alone, um, according to risk status, and really, um, the standard risk patients, they benefit too, but the greatest benefit were actually people with high risk disease and people who are double hit. You will never be able to make them look like they were normal. But because without any help, their maintenance data really didn't look very good, the depth, the um improvement of adding Kyprolis actually seemed to be um most beneficial in people with the worst risk. And um so, just a reminder, MRD is, look, it's a rough look inside the bone marrow. It's not a whole body. So this is data from the Casipia trial incorporate PET scan. Um, to also look at Other areas that we might not always be getting to with the bone marrow and actually incorporate the PET to the bone marrow assessment, give you a much, much better tool to be sure that we're looking at a person as a whole, right? Because you cannot be sure that just one spot that we stick a needle to, to do a bone marrow is going to truly represent people as a whole. Um, so Doctor Helicas and um, And really the uh working group have already launched a guideline, which we all follow as far as um routine imaging. So the discordance is real and you don't want to miss the multifocal disease. Um, in reality, I think, um, 10 to -6 is probably the new bar, but the approved standard is 10-5. You want to look at sustained MRD negativity, not just a one time point. The timing of MRD testing is still a debate. Um, it's it's still um an issue of debate, but mostly, We like to at least be able to do it before transplant, or post transplant, just to mark a milestone before the maintenance therapy. How frequent to do it during the maintenance therapy is going to be a little bit up in the air. For people who are high risk, I tend to do it more frequently because I just think that if you want to do something, it's going to be in that group where MRD conversion allow an opportunity to escalate care. Now, how about people who are sustained MRD negative after multiple years, it might also be a data to actually have a shared decision um with a patient about whether they would want to de-escalate uh care and come off from maintenance therapy, for example. And we're still waiting for more clinical trial data to guide that. Um, this is Midas using MRD to actually um guide therapy. We're waiting for this trial, but it is, it's a KRD um and um randomized patients to different arm, uh, for consolidation and maintenance using MRD as not just a surrogate tool, but to use it as a tool to really direct therapy. Um, and just as a reminder, PRSI actually has a second part to it, which is using MRD status to de-escalate their, um, patient's maintenance regimen. So, in a few years, we all know that. Um, another trial just to remember the name is Dramatic, which is also an MRD guided maintenance therapy. I'm over time, so I'm gonna just go back to what I promised you that I'm hoping to review the high-risk definition to showcase of the quadruplet. To showcase why MRD will matter. And I'm hoping that we're thinking about obtaining such data, because even when the phase 3 study come down the road, you're going to be able to use the data you've already collected from your patients today to actually potentially impact the duration of therapy, be able to offer them a chance to come off therapy. Um, and maintenance is evolving. It's no longer lenalidomide. As a one tool, but maybe the doublet also so high-risk, think also about protisome inhibitor, particularly carfilzomib, but immune therapy is entering frontline and uh my colleague Dr. Shah is gonna talk to you also about by specific antibody CART and so on. But this is why we should be excited. It's really because this is introducing bi-specific antibody into upfront regimen. This is testing the litumab in different um schedule and combination um as an upfront induction. And uh 49 patients across three arms early report but it's a 100% response with at cycle six already 85.7% of patients achieving MRD negative rate and you remember I was showing that these were typically occurred. After patients are getting transplant and maintenance. So now, the, that milestone that typically happened at a year post-transplant, we're now already seeing it very early with the introduction of bio-specific antibody into earlier line. So, hopefully, things will keep changing. Um, as just a reminder, quadruplet, unless patients are too frail to get 4 drugs, those super frail people, triplet is still a good idea, or start 3 and then figure whether you can add the 4th. There's on clinical trial, you're either on 3 or 4. In real life, you can start 3, add 1, but the whole idea is to drive the depth of response, hopefully also providing reasonable. quality of life, high risk definition, um, think about classifying, know your problem before you jump in to start treatment, if you can transplant improve PFS, but it could potentially be deferred in selected cases and maintenance, um think about um using them, uh, monitor the MRD during the maintenance therapy, and I'm hoping that in the future, we're Going to maybe um using patient's biology to guide therapy and using tumor specific um novel immune therapy rather than highly toxic um alkyators like Melphan that we use for transplant. Thanks very much. Fantastic you see out here for like. That was a fantastic talk and uh a hard act to follow, but I think um Doctor Jens Hillenas from Roswell Park uh may be up to the task of of kind of cleaning up whatever mess uh was left over after the front line therapy uh uh so please, without further ado, uh Doctor Jens Zengas. Thank you so much. Um, I tell you, I was, I was really, uh, very happy to see what you presented because I would have said the same thing, so which honors me, right? It just shows, yeah, that's true. Aside from that, and I think it's mostly true, so we might be wrong on a few, uh, occasions, but in general I think this is the way to go. But as Matt said, and thank you so much for inviting me, Paco, for inviting me, I'm really honored to be here again. This is an amazing meeting and and I think super important to get these summaries because we cannot keep up with with everything that's happening at these conferences and I have the pleasure to talk about relapse refractory as you mentioned right we we might. Keep people in a very deep remission for a very long time and we might even start talking about a cure for myeloma but there's still the majority of patients the disease comes back we have to deal with relapse disease. Um, these are my disclosures. Nothing of this has any influence on what I'm going to say and just to kind of pick up what you, what you, uh, left off with is that MRD negativity is currently, I think, a very, very important tool. I don't think it's the only important tool but super important. And since I'm, I mean, obviously up front we really wanna bring our patients in MRD negativity because that is the closest to a cure that we can get right now or that we can measure and of course imaging, thanks for mentioning that I really appreciate that um if we do a biopsy at our pel at the pelvis of our patients we might miss something something somewhere else so imaging is still important and we have to get better at imaging as well with sensitivity because obviously a bone marrow biopsy is more sensitive but I think we are working on that and getting better with this as well. So MRD at frontline treatment is I think a given, but if you look at this retrospective analysis of really a large number of myeloma patients, you can see MRD negative patients even at relapse do so much better than MRD positive patients at relapse, and I will show you that we have the privilege now and the, the luxury to be able to look into achieving MRD negativity even at relapse of disease, which was unheard of maybe when, when we trained and I mean trained before you obviously but. Um, even then, uh, it was still really challenging. So just briefly to let you know how complicated, uh, relapsed refractory myeloma has become if you don't know that yet. Um, what I do think is nowadays with the availability of CAR T cells, and there will be a whole talk about this, uh, after I'm done. Um, so I will hurry up that you get to the, the important part, but, uh, the CAR T cells are kind of the benchmark that we have to compare everything else we do to right now. That's my feeling because CAR Ts have so many benefits and you will hear all about it, but CA CARTs have changed how we treat and how we see myeloma and one trigger. Um, was really the outcomes even at late lines of therapy and you can see here as I said, it becomes more and more complex we have the luxury of having so many drugs um that we can combine that we can sequence where there are a lot of factors and I will go into that a little bit that kind of guide our our decision together with the patient what next line of treatment we wanna. Do and please don't read through those because you can all look them up at the NCCN guidelines. I wanna give you an overview on how to manage this and how to navigate this, this abundance of um availabilities. Carfilzomib has been mentioned. I think it's a really excellent drug that we can use at relapse if you have not used it front line or if the patient is not refractory to the frontline treatment. And then um what we have to deal with now with the avail availability of maintenance treatment with daratumumab or escetuximab, so CD38 antibody um treatment and especially relevant for these high risk patients where we are more kind of inclined to do that, we will have more and more patients who are actually refractory to CD38 so we have to switch and my approach is usually to switch as much as possible, right? We have a quadruplet, we have a triplet, maybe we have a doublet as a maintenance. But I want to change as much as possible. If I have uh an imit backbone, I would rather switch to a protosome inhibitor. If I have a CD38 antibody, I might switch to a pro protosome inhibitor, another imit and so on, right? Not going just with the same thing, um, because I don't think the, the clonal tidy that we see in myeloma where certain subgroups of myeloma cells respond to one kind of treatment but don't to the other, um, allow us to just continue with the same thing or just go from. Lenalidomide to pomalidomide, which still can work and we have something at the horizon that I will also mention, um, that might overcome that as well, but still I think changing the mechanism of action is very helpful and then more than two prior lines of therapy then becomes even more complex. But to be fair with all the options we have, we also at one point do run out of options, right? And that's something that we also have to keep in mind. Um, I was, uh, in the beginning when we were. Started to have all these options I was kind of in the under this impression because I grew up in an era where we had melphalan, prednisone and thalidomide, right, and then we were done or maybe we had cyclophosphamide and vincristine and stuff like that that they barely use anymore but in my mind I always kind of wanted to keep something for later, but we have this abundance now, so we should really, as I completely agree with you, we should read, uh, we should try to cure frontline or at least bring in a very very long remission frontline. But that means also that we will run out of options eventually, right? So it's still important to have new drugs and here for lenalidomide refractory, I mean that's our standard maintenance so there are also options there and then again it becomes even more complex because you can you can mix and match, but a lot of these drop out because we have used them before and the patients are refractory. I don't say we cannot reuse some of them, but I do think just going on with the same thing is really helpful and we see it in our clinic practice, clinical practice. So what are the what what are the the things going through my mind when I sit in front of my patients with with relapse disease? Obviously patient preference, have they decided to get a transplant up front? have they still the option to get a transplant later? Have they, uh, do they have, um, toxicities from their treatments? How long have they been in remission? If they have been in remission for 10 years after an initial stem cell transplant, I would even consider another transplant, right? If they have been in remission on an imit forever. I know this disease is very susceptible to, to treatment with an imit or at least a similar treatment. All these things come into uh into play. Are they refractory to something already? Have they progressed through a certain treatment? And I would not use this treatment anymore and then persistent side effects you mentioned neuropathy with potezomib that's unfortunately still a problem we got, we got better, but we have to get even better and then comorbidities obviously those patients when they're diagnosed, they're maybe 69 is the median age of diagnosis and then they hopefully live a very long life, um, on an initial treatment, but then they relapse they have maybe acquired more comorbidities that we have to keep in mind. And then obviously performance status, uh, which is I think something that we now really have to consider in myeloma when myeloma patients live 2 to 3 years I didn't really have a choice to look into quality of life into performance status, into eco performance status, whatever we measure or or uh patient reported quality of life, um, but now we can do that we have the privilege to do that and should also do, um, that in our clinical practice. Briefly mentioning C CAR T cells for everyone who's not at Roswell and hears about CAR T every day before and after lunch, um, this is how it works. We take the T cells out, we put a gene in, and they develop a car, a chimeric antigen, chimeric antigen receptor, and then we give them back and they kill the cancer cells, which is amazing. We all know that, and you will hear more about it. But this is the outcome that we saw in heavily pre-treated patients, which is just for myeloma. This is amazing. This was would have been great front line back in the day when I was young, but now we have this in heavily pre-treated patients. I would not say there's a plateau. Some people wanna say there's a plateau. It made it to the New New York Times, so it must be great, um, so you can see this is really. This is something where people started to dare to to to use the word cure in myeloma just because even late in therapy where the disease is evolved where the disease is heterogeneous there's still um the the chance to bring them in a deep and and long lasting remission. But I want to talk about another option maybe after CAR T cells and we can talk about that in more detail as well, but I do think we can also use the bi-specific antibodies where we don't have to collect the T cells because some patients might not want to do that, some patients don't want the setting of it. They don't want some side effects that I'm sure you will hear about, um, so we can. Do something that's maybe a step before or after that we call the bi-specific antibody. Similar concept we bring the T cell to the car uh to the myeloma cell and kill the myeloma cell in in that way. And there have been really nice publications recently encouraging us to use these drugs even after CAR T or sometimes instead of CAR T. and this is one that kind of caused a really a lot of buzz at the AS meeting. Um, and I will show you why this was comparing, um, taclistumab and BCMA directed uh by specific antibody together with daratumumab versus standard of care treatment with daratumumab either with bortezomib or with pomalidomide, which is I think a really decent comparator arm. But this is what's happening um it looks very, very different and such curves we have really barely seen in the past, right? A combination of a monoclonal antibody and a bi-specific antibody with two different targets show in a survival in relapse refractory patients which is just mind blowing to me still. And uh again the comparator arm was not bad. This was nothing where I would say, OK, and those patients have not had datumor before, which is also a bit of a limitation obviously because if someone is refractory to the CD38 antibody there might be a little bit of a difference in outcomes, but we still think that. How the dra tumor mark makes the tickly stomach better, and I don't have time to go into mechanistic details, but it improves the immune system which then can be used or the T cells which then can be used by the specific antibody. I think there's still a value even in patients who've had a CD38 antibody before. And this was basically true for almost every group of patients and again we are of course interested in the high risk patients we are interested in patients who are refractory to lenalidomide it basically made everything it it made it better for for every patient um in this in this uh study. And again coming back to MRD negativity 10-5, I completely agree we should nowadays we have the privilege to aim for 10-6 or higher sensitivity, um, but you can see here 10-5 has been done in in most trials that are being published right now. And you can see the difference here. This is our goal. We want to bring patients in a deep and long, long lasting deep remission, which then translated also in a, it's I mean it's a short follow up, but still a pretty impressive overall survival benefit for these patients. Um, also mentioning other combinations, so BSpecific has been around for a while. They're approved for later lines of therapy, but now there are studies combining them either with the tumor map, as I showed or with other, uh, CD38 antibodies. But there are also trials from some people you might recognize the name on the uh right lower, uh, corner. Um, my, my, my dear colleague was published, uh, and presented where el ranatumab, another BCMA, uh, directed by specific antibody in combination, which I think is a very smart combination with a so-called C cell mod, a cereal modulating agent, um, which is kind of a successor like the, the rational development of cerelon targeting drug, um, after, uh, which I, uh, sorry. Which, which imids do as well, lenalidomide and pomalidomide, but ibertomide makes does it more and then there's missigdamite that is also in development which makes that even more, which blocks the cerebral pathway even more, um, and those make a lot of sense because A they're very effective by themselves, but B they also make the, uh, immune system stronger which then makes gives the bi-specific antibody more to work with. And this is just a quick summary just to mention these antibody uh by specific antibody combinations are coming and I think they're very promising and you can see here the the overall response rates which are just impressive, um, depending on the dose level really. Actually not so much depending on the dose level it was impressive in in every single dose level and you can see here this is something that I think will will really shape the future and as you said what we're talking about now might be completely outdated in maybe even 1 year. Which is a great problem to have. We can also combine two specific antibodies um as has been done here and this seems to be very effective, especially in patients with high risk disease in this case extremyy disease which we in my experience um see more now that we have better treatments. The patients who relapse on these better treatments, they oftentimes have really nasty disease and I literally tomorrow I will call a patient who has really now extremallar disease, um, relapse after CAR T cell therapy. Only 8 months after she is one of these high risk patients, she's very young, so I will definitely try to to get my hands on things like this where um Sa Usmani has published this showing that those patients with extre medaly disease respond very well to this combination of the two bit specific antibodies. I still have to find the insurance that pays for this, but this is something that we need. This is a small, still a small number of patients, a small percentage, but this is an approach that might be very helpful there. And this is how it has been done Talcatumab and tlistamab and CD BCM 8 directed by specific and the GPSC 5D by specific, uh, and those together, um, have just excellent outcomes in those patients who really usually almost don't respond to anything but the pace and even that not very long. So you can see here the duration of response was actually good for this very, very high risk patient group. And then coming to other combinations again mentioning the Selmots, a very nice paper from Ola Langren's group, um, where they had the rekindle study. I just like the uh the, the name that they found, right? It's a very good, um, it's, yeah, and it's, it says what it's, what they were trying to do. They use a quadruplet not only up front but also at relapse again, so they combine, um, the dratuma again with Kerfield Smith and with the vice uh sorry. I'm really too many options in my mind right now, um, a Selmod and then dexamethasone and as you can see here again high MRD negativity rates even at relapse that's what I showed with these curves initially we can aim for MRD negativity even at relapse with uh rational combinations because those drugs work very well together and actually I don't have time to show the toxicities but it is really manageable surprisingly right all these combination. Nations, but we have to be careful more and more now when we have experiences, especially this winter. I'm not sure how it was in Indianapolis, but in Buffalo we had so many upper respiratory tract infections. That's something that I want to talk about with the toxicity. We have to be very careful. Those patients get typical upper respiratory tract infections, pneumonias, and also very, very weird viral infections that we usually only see in the setting of allergenic transplant. So something to keep in mind um if the patient develops weird symptoms including sometimes prolonged fatigue sometimes um prolonged fevers those we have to be very careful and look for very uh very rare things as well in the side of of infections and I will also since I got the time here I will shamelessly promote some of our studies that we do. Uh, and mesigtomide, as I mentioned, is a spe uh, oh come on, not a bi-specific anti, but I sell mod, um, as I mentioned, ibertamite, mesictamomide, they are really coming, um, they're very promising. They're all treatments we can combine them with the, the treatments that we have already, and it has also been shown. To be effective in extremedullary disease, we are using this in patients even with non-secretory disease. So if you want to refer a patient who is not eligible for any other trial, we specifically designed this trial also to allow for non-secretory patients where we cannot measure light chains or M protein anymore. And then we do biopsies before and after 3 cycles and we have seen really tremendous uh outcomes for this already we have seen patients going into deep remission even though they had really soft tissue lesions everywhere which is very encouraging and another study we still. As I said at one point, we still run out of options, and this is a new drug that um in collaboration with Doctor Mohammad Pour from our uh cell stress department we have developed. We sent him the samples. He did analysis, single cell RNA analysis of the immune system. And we found that there are very mature neutrophils, especially in these soft tissue lesions and in these, these tumors we call them focal lesions in imaging, where we found that these mature neutrophils are immunosuppressive. They don't allow the T cells to do their job and kill kill the myeloma cells. And uh we have seen if we if we co-culture them, the T cells are just less effective in this combination. So we added this drug that is available to block CXCR2, which is a marker a marker pathway in these mature neutrophils, and we were able to combine this with standard of care treatment with datumumab and Kerfieldsmib and dexamethasone. And we have the 1st 6 patients enrolled. We have cleared dose level 1. We are aiming to enroll 1 patient this week for dose level 2, and this is really promising. It has barely any side effects because it's so specific in blocking these mature and actually useless neutrophils. We have not, uh not even seen neutropenia really because it's specifically killing this, this bad kind of immunosuppressive neutrophils, so showing there's more development to come, uh, and that gives us more options. So in summary, the goals of our treatment are deep remissions and sustained remissions even at relapse. We can't dare to to ask for that. CAR T cells are kind of the standard of care that we are comparing everything to, right? Is it better is it better than CAR T? Not much, but is it good after CAR T? Is it helpful before CAR T? Is it good around CAR T, like for example, the cell mods might be. And then by specific antibodies are something that can even be given in the community, which is a great combination with excellent outcomes you have seen these overall response rates. This is something we have not seen in the past and then as I mentioned, the Selmods and other classes of drugs are coming. Thank you so much for your attention. It's another fantastic talk by another fantastic doctor. Um, it's my distinguished pleasure to introduce our third speaker in our myeloma section. Um, Doctor Nancy Shaw is our associate professor of medicine in, in, uh, New Jersey. Uh, no, I'm just kidding, uh, clinical director of multiple myeloma. She's gonna talk about how to hopefully, uh, cure some more patients, uh, dare we say, in multiple myeloma, um, and if not, maybe why not. So Doctor Shah, please join us. Thank you so much for having me here today. I am so delighted to be here with my esteemed colleagues, um, everyone here, and I get to talk about new technology and I think of Methylin and prednisone like that desktop computer that you had and then you had to do dial up Internet and then you had to figure out and find a time to get online. And now we're talking about phones, uh, which have Internet you can watch movies you can get, you can do whatever you want on your phones, listen to music, um, and so that's what CART is in my mind and so we're gonna be talking about Ash updates and some of this was already, uh, alluded to, um, but the C word, uh, cure is being discussed, especially with cell to cell at 5 years. There are pipeline agents with, uh, improved. Uh, toxicity profiles while maintaining the efficacy and then we also know that patients relapse and so how do we overcome that relapse potentially overcoming antigen escape by dual targets and antigen switching and now in vivo CART and fast manufacturing programs, um, those are really changing how we think about manufacturing these CARTs and really improving access to care and we'll really round out by discussing sequencing and toxicity mitigation. So, just to anchor us, these were the landmark trials that allowed for approval for Iacel and Silta cell initially in the lateline setting, followed by Karma 3 and Cartitude 4 for, um, third line and beyond, excuse me, 2, 3rd line and beyond and then second line and beyond for sil to cell. So really these are the topics that we're gonna be talking about today and so I'm just gonna dive right into it with a long term follow up for Cartitude 15 year follow up we're using the C word um it was in the New York Times. I'm gonna show you that article next um, 33% of patients, uh, were. Myeloma free 5 years out after a single infusion, that was something that is remarkable and that's something that hasn't been seen before. Um, out of those patients, 12 out of 12 were MRD negative negative, um, including PEET, um, the whole, whole gamut of MRD negativity was found. And they also identified some predictors of long remission, you know, having a low tumor burden at baseline prior to T cell infusion, looking at the T cell health, um, and because of this we are using CART in earlier lines of treatment and so this is the New York Times article uh. Um, I had to bring it up, um, but really I just wanted to also, I inserted this graph where, uh, the previous cured fraction of patients, so we do not cure the majority of patients with multiple myeloma or historically we didn't. The observed sur uh survival or cured fraction was less than 15%, but I think we are on the verge of, of improving that number significantly in the near future. So I'm just going to move on. So because we can use CAT up front, now second line and beyond. And thinking about new targets like BCMA or GPRC 5D or FCHR 5, we are thinking about how can we combine these therapies, how can we move this up front to the right side of this panel, and there's a lot of data being generated and a lot of studies happening, um, that will, which will tell us what to do and really can we put our best foot forward up front and achieve the best longest remission. Um, so this is Cartitude 4, patient population, including high-risk cytogenetics like deletion 17P, translocation 14-16, 414, and gain and, uh, or amplification of 1Q were included. I really just wanted to kind of put this side by side. Cartitude 1, if you remember, was lateline. Um, 3 or more prior lines of treatment, uh, were included, and then carditude 4 was patients who had relapsed at least once, and you can see the differences in the PFS and OS curves already separating from the very beginning, um, and ongoing, achieving deeper and longer remissions. So there was a primary analysis and then an updated analysis and really just the takeaway is the overall survival benefit continues to improve, uh, the CR rates continue to deepen, the MRD negativity is similar, um, but a PFS is still not reached. This was, um, the benefit was shown across the board across high risk cytogenetics. Extramedullary disease still had meaningful progression free survival and improvement. Um, and really the takeaway is if the patient is less heavily pre-treated, those T cells are healthier. The immune system is able to really lean on those CAR T cells or use the CAR T cells to its benefit. And so let's get these patients in earlier, uh, for CART or BCMA targeted or GPRC targeted therapies, um, and across the board with early CART use, uh, there was benefit. And so can we move it up and can we knock out transplant? Can we get rid of that desktop computer that you have that's still there, a relic in your basement somewhere, um, so let's move it and, uh, let's look at CARDIitude 5 and 6 and so Cartitude 5 is looking at newly diagnosed patients, uh, transplant not planned, uh, followed by a VRD in. and a a single infusion of silta cell uh versus just maintenance, um, and then CI 26 is looking at quad induction. This is kind of what we do as as our new current standard of care followed by silta cell and it's looking at PFS sustained MRD negativity, and if positive, these will really change how we treat people with multiple myeloma. So can't forget about toxicities. These are really important and so acute toxicity cytokine release syndrome, pretty common, mostly grade 1, and we are getting better and better at mitigating these and, and responding to these earlier so these don't escalate to the next grade, uh, grade 3 or higher, and we've come a long way. We used to wait until someone was hypotensive on pressers, um, to, to really intervene. Um, and that was really, um, not something that I was comfortable with because I had to watch the patient, uh, before I was able to escalate the CRS grading. Um, with that being said, uh, we are doing much better intervening early. ICAS, um, that is not so common, um, but you can see, uh, about 17 to 21% across, across all trials, um, and the treatment for ICANNs are steroids early intervention. Tosi does not cross the blood-brain barrier, so it doesn't help with ICANNS, um, and then there is an HLH-like entity that's very, very rare, but something to be aware of that can happen relatively early and these are the. The things that we've learned how to manage now delayed toxicities is something that we are currently working on and and trying to think about how do we mitigate these risks. So MNTs, motor neuro uh cognitive toxicities, these can be potentially irreversible. You can see that it could be something, uh, like a facial nerve palsy, Parkinsonianism, uh, ataxia. It can be, uh, it can develop weeks to months after the CART infusion. And we haven't quite figured out how to treat it once it does happen. But, uh, just awareness is important and early intervention is important. We're going to look at how can we potentially reduce the risk of these side effects in the next few slides. Cytopenias are common, um, actually less common in the, in the less heavily pre-treated patient population than, than the heavily pre-treated patient population. We are looking at supportive care measures like growth factors, uh, ESAs, as well as TPO receptor agonist, um, and trying to predict some of the risks of cytopenias with this car hematotox score or other scores that are similar, um, and trying to see can we mitigate some of these cytopenias maybe with a stem cell boost, um, if we collect. Cells, but that's a whole other can of worms we're not gonna get into, um, in terms of insurance approval and and resource utilization. So infections, infections are a big deal even prior to these therapies, uh, patients with multiple myeloma have functional hypogamma globulin anemia, and they require anti-infective support or prophylaxis, um, and. So, in addition to bacterial, viral, and potentially even fungal prophylaxis, these patients need supplemental IVIG. Uh, there are some guidelines, but this IVIG, especially with CART, uh, should be continued for at least 6 months, um, in my opinion, and, uh, potentially beyond that because these patients remain hypogam for a pretty long period of time. OK, so, uh, this was, um, something, uh, from Serbian group and it really it was presented at Ash actually and, um, so we know the risk of this delayed neurotoxicity exists Parkinsonianism, cranial nerve palsies, um, and, and infections and how can we identify who's at risk for those side effects and how can we potentially stop it. So bridging therapy is extremely important, debulking that. Tumor burden, um, using what you have at your disposal and that's easier to do in the second line or beyond setting rather than in the fifth line which is when we were actually historically and historically is just 3 years ago when we were using CART uh that late, um. Relatively historically, uh, it's hard to keep up these slides are old already, so, um, anyway, so and then looking at some of the kinetics of the absolute lymphocyte, uh, count, and we know that if there's a rapid expansion again historically in quotations that was really. Exciting when patients had a rapid lymphocyte expansion you knew that patient responded and then now we know that those are the patients who are going to have a higher risk of neurotoxicity so optimize the bridging, think about steroids at that at that rapid CART expansion, um, see if that helps. Uh, we don't know yet, um. But it's a, it's a relatively simple intervention that can be used, um, and also think about uh infection risks and especially if you're using steroids, especially if you're using Tosi upfront. OK, so we talked about the side effects. They're scary. I hope I didn't, um, uh, scare you away, but there is a new drug on the line, or CAR T cell, Anitael, um, which is using a novel D domain binder. Essentially it's a wrap it on, wrap it off, so it has a good, um, efficacy signal while potentially mitigating the neurotoxicity that we are seeing with the earlier agents. OK. So this is the Imagine one data. Uh, you can see that the, uh, it was 3 or more prior lines of treatment, um, for patients who were included. Nearly 90% of patients were triple class refractory and 40% of patients had high risk cytogenetics and uh 18% had extramedullary disease. So pretty high risk patient population that was included and just on the right, I just wanted to include a snapshot comparison of Anita cell and Silta cell, um, and we're gonna just go into the results. So initially, uh, at 16 months follow up, you could see a 96% overall response rate with a very rapid. Uh, time to response about a month. deep responses 74%. De MRD negativity rates and um, at 24 months the progression free survival was 62%, which is pretty good and you can see that on the right bottom panel that um this was. Uh, the good responses were sustained across the high risk groups Penta refractory, which this is truly maybe historically I need to, um, uh, triage my historical, uh, references, but, um, but, but, um. Prior to BCME targeted therapies, the overall survival for those patients who are pentorefractory was thought to be less than 6 months. And so this, this is really a groundbreaking, um, where we are seeing patients responding so well, even with high risk, uh, features such as cytogenetics as an extramedullary disease. And this trial also included patients who had prior BCMA therapy. So we talked about the efficacy. Let's talk about the safety. So, uh, the CRS is pretty similar, um, a little bit higher again it's cross trials, but, um, it's pretty predictable. Median onset is about 4 days, which helps us with administrating these therapies potentially outpatient, potentially in a hybrid setting. Um, and you can see that most patients' CRS resolved within 10 days, so you have that 10 day window where the patients might need to be near your infusion center if you are doing this outpatient, um, or maybe you can use that predictability and admit the patient for the peak onset of the CRS and then see them outpatient so that it's not such a burden, um, to them and also the, the system, uh, to admit the patients for the duration of the potential. CRS and ICANNS. Now, on the right, yes, ICANNS occurs 8%, mostly grade, uh, two. There was 1% grade three. However, so far, we are not seeing delayed neurotoxicity and, um, uh, cranial nerve palsies. And so far we are not seeing the enterocolitis and so, um, but this is early so I have cautious optimism about what this looks like. So, uh, this is that next generation of CART, um, and I do think, um, this is going to be important, uh, in the real world how this pans out. So BCMA, um, people can become resistant to these therapies. People still relapse and while there is some sort of a plateau with the CART data, um, not everyone is part of that plateau, right? Only about 33% of those patients were, uh, myeloma-free 5 years out from the CARitude1 data. So, um, how do we figure out who will respond to the next line of therapy and what do we choose, so. We know that BCMA antigen escape drives about 30 to 40% of relapses after BCMA CAR T, and these are some of the predictor of relapses. And so looking at BCMA expression, looking at the T cell health, um, and, and trying to predict, OK, who, what do we use next. And so, well, we can use a different antigen. We can use GPRC 5D. We can combine the different, uh, antigens and see if we can get better responses. And so there's a lot of, uh, work being done, uh, using dual targeting CARTs or a newer, a different antigen, uh, for the CART. And so the furthest along is Arlo cell, which is the GPRC 5D targeted CART. Um, it is, so 5D for short, is mostly found on high, uh, malignant plasma cells, and its expression is independent of BCMA. So it's not really impacted by BCMA antigen loss or escape. And, but there is, um, limited expression of 5. On normal tissue cells like hard keratinized cells so you can see dry skin, um, dyscusia, uh, nails become brittle, and so those are some of the on target off tumor effects that we have to deal with, um, and are seeing with this, uh, target. So this is the the phase two data, 87% overall response rate, median PFS of 18 months, uh, deep MRD negativity rates, and even in those who are post BCMA failure. And so this is very exciting as the, the next line of treatment that you can use as a single infusion post BCMA CAR T. Toxicity profiles are pretty similar to the BCMA agents, um, in terms of CRS and ICAs and cytopenias are also pretty common, but, uh, importantly, skin and nail toxicities which are on target are present but relatively lower compared to, uh, the bis specific agents that's already approved for GPRC5D. And so in my mind, where does Arlosel fit, you know, potentially after 3 prior lines of treatment, mostly because of that skin and nail toxicity after BCMA cart, I think about it as how these drugs are approved and what kind of patients were included in those clinical trials that led to the approval. And we have to counsel our patients about the skin toxicities, but really it's, it's, um, present in the initial time period and it, it really decreases over time. By the 3rd month after the, the infusion, we're really not seeing those um on target, uh, on tumor, um. toxicities. On target off tumor toxicities. Excuse me, what a mouthful. Um, OK, so, well, now we have BCMA, now we have GPRC 5D and remember that computer and now you have your cell phone, but now you have AI on that cell phone, and this is what in vivo CT is in my mind. Um, you just inject that lentiv viral vector into the patient and the patient, it becomes your CART producer, um, and so you don't need to collect any cells, you don't need lympho depleting therapy, and the CRS rates are potentially lower. Um, this is incredible, um, honestly this is, um, this is great, so. Um, very small data so far. Um, 4 out of 4 patients achieved MRD negativity. Uh, the CART expansion peaked, uh, around day 15 in this, um, study. No lympho depletion required. They don't need to keep coming back and forth. It's one dose and it's become like a off the shelf. By specific antibody, um, which is really, really exciting to see. So more to come, and there are other, uh, phase one, studies that are ongoing with in vivo CAR T. So, despite having CAR T available, still about only 25 to 30% of patients who are eligible for CART get CAR T. So access is still an issue because not everyone can administer CART. So we need to figure out ways to improve access. So is in vivo C T one of the answers, or is this fast car CT, um. Or is aloe carte an answer, right? So this is another, uh, concept of CAR T cell therapy that was presented at Ash. Ash was really busy with myelomaCar T, um, so you can see pretty great responses, um, and aloar T, you know, specifically we think about GVHD. And we have ways to eliminate the potential for GBH GVHD using CRISPR technology, um, so it's pretty cool stuff and um more to come and then I just wanted to highlight the fast car technology, um, also, um, being studied in the newly diagnosed patient population but in the relapse, uh, refractory setting. The vein to vein time is about 2 weeks, which is very fast, and again, so that improves access because one of the. Um, issues with CAR T eligibility is you might be eligible, but disease kinetics or logistics might not allow that patient to get the CAR T right away. We can, we can apheres them, but somehow we can't get them, uh, reinfused with those T cells. And so if we can manufacture these cells faster, can we capture more patients? Um, so that's one of the concepts for this fast car. And again across the board you just it's really amazing to see everything just says above 80% overall response rate, um, and nearly 80% or higher MRD negativity, um, so this is just another concept that is being evaluated as well. This is a snapshot of all the Ash carts, um, um, that are being studied, um, and they're the closest ones to approval are the Anita cell and the RLO cell. So how do we figure out what to do? Um, there are so many options and um. The, the really the takeaway in my mind is, if someone is relapsing after quadruplet therapy and potentially doublet maintenance after transplant. That patient needs to get a CAR T and because in my mind that is the new functionally high risk patient, um, and it depends on how long they have been on that therapy, but these quads haven't been around for that long and so those are the patients that we need to get in early. Especially those patients who are high risk that we keep adding all these drugs and we are getting better responses but can we use one drug to overcome some of those high risk features or one therapy um I think that's the case and. Sort of, you know, we give, we think of, we have a pause when someone has CNS disease, but actually we have some small series that shows that CART works in patients who have CNS involvement, um, and actually the risk of uh CRS is not as high or ICANNS is not as high as we would have thought um, again it's a small series uh of patients but proof of concept at least in my mind. Um, and if someone's so heavily pre-treated, maybe CAR T, um, or, or their T cells are completely exhausted or depleted, maybe now is not the time for CART, but get them in earlier so we can always have CART in our back pocket, um, in terms of sequencing. Because of approvals, um, CART has been used prior to BCMA therapies, but that's changing, especially with Tecdera, right? Um, I think. The future is time limited and so if they have time limited exposure to BCMA or GPRC-5D targeted therapies, I don't think it's going to matter whether we use CART first or or by specifics first. However, if they've had ongoing assault on their BCMA or GPRC-5D, there's an increased risk of antigen escape or or T cell exhaustion, um, and in that case I would. I would urge people to think about using CAR T first, followed by a bi-specific, and we do have some data, it's early data that it will still work. The bi-specifics are still efficacious, while the other way around, they seem to, if you use a bi-specific first, it can also potentially impact the T cell yield, um, and the outcomes are not as good as what we're seeing with fresh CAR T cells. So this is the summary. Um, the C word is no longer just cancer, it's cure, and I think we are going to be, uh, curing more and more patients with, um, these newer technologies. Uh, Anitae is right on the horizon. Dual CAR T may be uh the way to go in terms of antigen escape and overcoming resistance and Arloce is another option for a GPRC 5D targeted CAR T. So another one-time infusion where patients. Not getting continuous therapy, uh, is, is really, really valuable in terms of time off treatment and time back into the world, uh, and in in vivo Carti is something that, as you can tell I'm very excited about and so we will see, uh, with that I thank you. It's great. Fantastic uh talks all along. We're exactly on time, um, so I used to give our speakers, uh, one more quick round of applause altogether and then we'll. Um, bombard them with questions, so we're gonna butt them up before we hopefully, uh, make their life difficult for 10 minutes. Hey, um, hi Sammy, I'm Sean from NYU. Um, I'm actually, uh, a, a lymphoma doctor by trade, um, but I actually have, I have two questions for you guys. One thing that came up yesterday in a lot of the lymphoma talks was that we actually have a lot to learn from the myeloma space, uh, in the immunotherapies in terms of particularly, uh, like infection management, especially post-scar, and there's data actually in both the lymphoma and the myeloma space like from Sadusmani's group that the bi-specifics actually may be worse. In terms of the, the infectious risk, so what are you guys doing? because in the lymphoma world there's zero consensus. We don't know what to do about IVIG. We don't know what to do about prophylaxis. So, so how do you guys think about that? And it's a little different because you're depleting, um, plasma cells rather than B cells, but it's the same idea. So I, I would love to learn from you guys about, about how you think about that and, and what your practices are with, uh, your, your BCMA directed, uh, immunotherapies. I'll take it away. Um, I'm very passionate about IVIG, so it's CAR T and IVIG and bi-specifics and IVIG. So yes, they're two drugs, but, um, primary prophylaxis is important, uh, whether they're on a bi-specific or a, uh, BCMA CAR T. So I started even before I, um, start a BCMA or GPRC 5D by specific. And that's because of the sequencing they're usually in my practice already exposed to a BCMA CART when they are relapsing, and we are seeing improved, uh, survival and PFS actually because you're able to get efficacious therapies to these patients for a longer period of time. And that's regardless of the IGG levels. Postcard T at least 6 months regardless of the IGG levels is my practice. Now getting that approved is a challenge, um, and so especially if they're less than their IGG is less than 400 in my practice 500. Richard, um, I will continue to appeal that IVIG denial, um, and using HSV prophylaxis indefinitely, so, um, I, I don't take my patients off of that even if they have been, um, vaccinated, especially after transplant because we are seeing. Shingles and it's terrible um and PJP prophylaxis for BCMA and so we did look into the CD-19 cars versus BCMA so the risk is not as high um and this is um because of the B cell maturation antigen um therapies but that's what we do when we don't stop uh and PJB prophylaxis is something that falls off all the time and the other thing is being vigilant about viral reactivation, um. Because it might not manifest as anything significant clinically, thankfully, but we are seeing cytopenias, which is the most sort of common manifestation of CMV viremia or reactivation, um, and then treating that early NCMV being the most common one, but we see the other viruses like EBV as well. Yeah I mean I, I, I think if we learn anything we learn that this treatment can work really well and therefore being able to hold back when people are sick and decrease frequency specifically for the right specific an entirety it's been helpful while we talk a lot about the IGG because it's what we can measure um CD4 count tend to be very low in this group of patients as well and that's why we're seeing this. Opportunistic infections, although I don't say that we should be checking CD4 in this group of patients, just also be thinking in mind that they really do function like HIV patients, for example, and, uh, that's why we're talking about CMV reactivation. I mean, JC, um, you know, uh, related PML have been reported, but also this is why if you're facing situation where people are having like fever of unknown origin. Really be thinking about rare things but also I think this is where collaboration with sites that have infectious disease um team with. Some expertise, um, dealing with the immunocompromised patients are gonna be helpful. Um, why by specific is worse than CAR T probably because of the time, um, dependent, um, ablation of the immune system, right, because we're talking about the T cells are gone, um, because they're overly used and the, um, plasma cells are gone, but the CAR T population will have. Re-emerging of their normal plasma cell clone down the road, the people who are owned by specific who keep getting their newly made plasma cells are gonna get cleared out. That's probably why there's more longer term concern. But as we're getting a little bit smarter to be also thinking about being able to stop therapy fixed duration that lymphoma field have actually set stage. It's hopefully what we myeloma people get to learn from you to sort of not continue good therapy forever because at some point it's a negative return of investment, um, so I'm, I'm hoping that now we're getting smarter we we should do better but for folks who are um facing insurance issue because I, I, I get it it's really taking so much time out of your day to day thing. Um, I usually have better success submitting your by specific prior authorization together with your IVIG. It becomes so apparent that, and it's clearly included already in the NCCN guideline, for example, that these two things are going to be necessary together. Um, people always look at the raw number of the IGG, but that's really not what functional IGG is. If your M protein, just because we have mostly the IgG monoclonal protein, um, that relates to the myeloma, you're gonna have to subtract that myeloma protein out of the total. So for example, if people have like M protein of 2 and your IgG is like 2200, I mean insurance could come back and sort of say wow, your IgG is really good. What are you talking about wanting IVIG for? But you have to. Be careful that 2000 mg of that's really not what you can count as functional IG and you're truly probably having 200 if that right but also I think vaccination becomes critical. Also barriers very important. I mean I'm, I'm with Jn entirely in that I mean people are sick and really the old school mask and gloves and you know barriers are still very helpful. Patients who are transplant eligible. who relapse after more than a year or so. Uh, what is your recommendations, you know, transplant versus specifics or CATs, or would you really say this patient is eligible and we should go for transplant? Yeah, that, that's a great question. I think with, with this abundance of new treatments we do see less usage of um relapse. Refract or relapse transplants, I think they really have to have had a long, long time after their initial transplant. The rule of thumb is a little bit that they get about half that they got the first time. So if they had 10 years before, they might get 5, which I think is reasonable. If it was 2 years, I tell the patient that's an option. I usually don't really support it. I rather say. I mean 2 years is nowadays as I think you said right this is functional high risk nowadays if someone relapses within 2 years even I'm I'm just writing a protocol for functional high risk and our discussion is is 3 years after transplant relapses that maybe even functional high risk right? We're so spoiled now in a in a good way um I am very I'm a transplant in my heart like my colleagues too and I have relied on transplant and brought so many patients through transplant. I do think that relapse it's not that important anymore and Cartitude 6 will show us how much relevance it has and then I sat next to Doctor Griffith, our uh leukemia doc and we discussed our patients who got transplant lenalidomide and then an ALL. Or an MDS, right? So as much as I love melphalan high dose, I'm very hesitant to do it to patients who might potentially be cured, uh, and then they get a second primary malignancy. So there are a lot of factors that I think we have to be careful with doing more transplant. I still offer, especially in the high risk patients transplant upfront at relapse really rarely nowadays just because we have much better than other options. I mean, the number of 2 like salvage autos going down so much across the US In fact, a lot of centers are now planning to not collect the second dose of the stem cells just to have because a good majority of people were never coming back to get that second bag luckily, if you think about who Jen's patients are gonna be who may be considering second transplant, so first they're probably reasonably young when they got their first transplant. That's why 10 years later they're still fit enough to even consider a second transplant. And those number of patients are gonna be relatively small being that if we're thinking about average time, um, average age at the onset of diagnosis is really about 65 to 68. 10 years later they're really kind of out of good window for transplant, um, and I think even people who are so-called transplant eligible today based on really good induction therapy, more of them are gonna be MRD negative and it becomes more debatable whether you have to do transplant then or do you collect the stem cells, think about it later. And when, if and when that they are losing their MRD negativity, do you actually do auto or do you actually have novel T cell engagers, whether it's CART or by specifics to actually salvage them? So it's entirely possible that we are actually moving away from aculators now. That is the privilege of being in the US, I think transplant is still a critical component of myeloma care all really all around the globe becomes actually a much cheaper tool to do comparing to any of these novel things that we do today. So even in the novel age of therapy now with immunotherapies across the board, we're not curing everybody and we're leaving many people with relative immunocompromise after all these therapies, especially as they're piled up on everybody. It may very well be time to throw out the old IBM PC, but there's another old computer in the basement that might need to be looked at again, which is allo transplant. So now from the older literature we know there was a good number of patients who were cured in the old age of therapy, and the correlation was if you get a deeper remission before allo transplant, you have a higher chance to actually be cured with a good functional immune system long term as well. So what do you all think about how we might choose patients in the modern age of therapy who get these deep remissions but aren't going to be cured for allo transplant? Thank you so much for leading us into this mining field. I appreciate it. We all look at each other and we go, oh no. We, we need, we need more of those questions, by the way, it's, it's a great question and actually literally this week I spoke with Dr. McCarthy who was mentioned earlier because I have the 53 year old patient who relapsed early after transplant, who relapsed early after CART, but I still have my specifics to bring her back in an MRD negativity where she was, and I will talk with her if we bring her back in remission about maybe even a haplo with the post-transplant site gives us options, right. This is not, um, I don't think this will be mainstream, but I think individual young high risk patients, and I, I come from a country where I have seen a lot of allo transplant in myeloma just because of the lack of other options. I think all those standard risk patients who live 10 years after the initial treatment, they are definitely out of that picture, but these few high risk, high, high risk patients. To be fair, in my experience as well, um, I have seen a few plasma cell leukemia patients surviving allergenic transplant really, really well, probably cured, to be fair, but these are individual decisions and it it has to be very, very selective because the data if you look back, I don't remember was it 6. 45 studies showing that allo was better, 54 showing that all was better, so the data doesn't give that, but I completely agree with you that we have to reconsider that because then also even if they relapse, we have a new immune system to work with and use all these fancy drugs that we use with a better immune system. So great question but very dangerous terrain. And given that Anito's cell doesn't seem to have the neuromuscular things which we worry about the most and the fact that it's probably gonna be approved later this year, what are you doing with your myeloma patients now? Are you kind of waiting until that gets approved? Are you still taking the risk with Silta cell and I'm a CT girl. I, I am already at iPhone. What are we at, 1617, whatever it is. I'm not going back to the mini, um, so with that being said. It's a small percentage and we have better ways to mitigate and I try and identify those toxicities when you see that in the second line setting, it does give you pause, but Anitoel will not be approved in the second line setting and so we won't have access yet to those therapies. I'll, I'll, I'll probably just take a stab on this. I actually find, I, I, I think though that when you're thinking about the fact that people can actually get other things to actually buy their time. Um, and you project that you present both options to patients. A lot of my patients are like, um, I understand it that if you're on by specific entirety so long and then you progress on it, your T cells are shot. You can't do, uh, you can't do CAR T and think that things are gonna go well, but we're not even doing that today. I mean, we're using by specifics if it's potentially as a bridge to CAR T, is it not at all possible to think about, you know, waiting out, seeing the response, um, doing fixed duration and. Then you know the car technology is gonna continue to evolve whether a better version or less side effects become apparent or if we can project better who are gonna get this rare side effects then we'll be in a much better shape. Um, I'm actually seeing that a lot of patients are like, you know what I'll do by specific even though it is true, right, that we, we have some data to show that people who fail by specific, they have harder time, um, giving us their good T cells for us to make CRT that was really historically. Like we're, we're, we're, we're not in that era anymore. Everyone is relatively fit coming in. Honestly, I, I think if I would have to go to Vegas and put money down, I think by specific in Taiwan it's gonna surpass, it's gonna surpass the CAR T because it's just faster to get to and um, we're just gonna have to keep improving the CAR T technology so that you can come back with it. Electively and then stop the ongoing by specific but I'm, I'm with you. I think that Anitael could potentially be an interesting choice in comparing and just one quick thing, what do you guys think of the controversy about the light chain ratio now? You know, the original trials thought it was, uh, 70% progression, but now the modern trials show it's only 20% progression. Some people say take it out now as a definition of myeloma. Where do you all sit on that? Um, good question, because the thing is this, I, I think if you were a call smoldering yesterday and today you're called myeloma, a lot of people are gonna be very, very worried. So I mean, in my mind I usually just sit down with patients and sort of say, you know, if you have actually been abnormal ratio, no bad things happened. It doesn't rise. You're just as good today as you were yesterday. You do not have to actually today get treatment when you didn't need to yesterday, right? Life is kinetic, but if we were having people who didn't meet criteria otherwise aside from the light chain ratio and you're just checking them every time the light chain keeps going up, you're not buying yourself much of anything by not treating them. What I don't like to do though is to actually. Lump them together with a high risk motoring which as you know is also a very much evolving um concept because there are now early treatment that have actually shown survival benefit and in fact it's actually been approved. The last thing we would want right is to undertreat smoldering but I I'm, I'm with you. I think that biomarker alone doesn't always put together the kinetic and I, I, I think that it's individual decision. It's not wrong to treat, but I don't feel that I need to rush to start either. Do you feel that way. That's why we're good friends. I think we've time for one more question, OK, very quickly, very brief, yeah, very, very quickly. So, um, actually to the point of the, of the motor neuron toxicities, um, so you know, Doctor Chai, as you mentioned, right, there's data that shows that the, the kinetics do correlate, and, but we all have kind of just decided to do it and actually. I, I literally reference like Rahul Banerjee tweeted a slide from a conference and that's what I use like on rounds I pull up my bookmark tweet to decide when I'm gonna give my steroids for, for an extended ALC. What are you guys actually doing in practice? Are you, are you doing steroids anecdotally? Is it helping or are we just treating ourselves? Oh, good question. I can't answer the second part because I think I'm treating myself, um, with the steroids, but I am doing it. As soon as the ALC goes above 2000, I'm starting steroids. Uh, I use DX 10 BID times 3 days. Um, but if I am seeing actual neurotoxicity early, and sometimes we are seeing this, um, sort of musculoskeletal pain or sometimes. patients are having some kind of cranial nerve or nerve palsies, um, and that helps, but I am escalating faster. I'm checking the CSF. I'm actually thinking about IT chemotherapy and sometimes have used Cytoxan to, uh, just nip this in the bud. Sort of like it's, it's crazy right that we are seeing this robust expansion but then too much of good things not good and the concern is going to be now that we're going to have many more patients who are eligible to get CAR T when their T cells are probably quite fit. The question's going to be, are we going to see much more expansion and, uh, we're just crude right at measuring absolute lymphocyte counts, but we're not really looking at some type of a lymphocytes that are causing problem. It is projected that a good number of those are CAR T cells, but they're just more recent data to say that it's not, that actually that's part of the problem, but really the non-specific expansion of your good normal lymphocytes were also the contributor, and, uh, that's why we're so non-specific in how we're killing off these cells. We're just going old school hydro steroid, cyto cytoxins, and so on. Fantastic. I've I've one extremely brief question, I hope, but with all these new drugs on the on the block and coming, thinking about how bispecifics are generally to be avoided, especially within along with high intensity chemotherapy immediately before leukapheresis for CAR T. But are there any of these new drugs that excite you as far as you know the optimal bridging therapy, say pre-leukapheresis? There's really good data with telcatum maps or by specifics just because they were quick and they work well, right? That's one thing what I'm excited about we, we're working on a study with, with the, um, cell moths, the mesecttomide and ibertamide, and I think there's a, a lymphoma one. As well, and I forgot the name. Yeah, thanks. Um, I think those are very exciting because they make mechanistically sense to improve the T cell and reduce the exhaustion, make them better for the CAR T and for the bios specifics. I think as you've shown in your phase 1 B. Hopefully phase 1, so small number, but, but, but, but truth, right? So sort of when we're thinking about, well, if we're not doing the CRT are we hurting somebody? So the key thing is gonna be if you can actually prevent the T cell exhaustion and use less of the of the T cell engagers, and maybe you're still going to have all of those available choices later and this is why that study was really done with far far less intense, um, Loratomab scheduling and also in combination with ibotamine. Because it's every other week or anotherab and then it goes down to every month, um, and the issue is gonna be do we actually stop it just like what our lymphoma people have actually done and shown that you didn't hurt people by stopping it when people are already in sustained remission after 2 years and so so I think the myeloma field is gonna follow that. I just wanna add that you know the tau bridging is also it almost gives that dual target approach uh because you're getting the GPRC 5D impact on those plasma cells and chasing it with the BCMA and so you get that time limited limited. dual approach and I think that's the way to go. Exactly. It's actually just short enough before people are having all of this like loss of taste and skin toxicity and all that because you already stopped it by the time that you get your BCMA card so I've actually tried to use that as well. OK, so I did have one question, and this is extremely naive. So I, I'm a leukemia doctor, just full disclosure, um, could you ever use the stored CAR T cell, the stored autologous product to generate any of these, um, novel cellular therapeutics as an alternative use of this thing because I, it sounds like there are quite a few patients who have these things in the freezer. We do use them in vivo kind of right? We have had patients who are in like cytopenic for a while and we have not dared to send them to you yet, so we think this is just toxic, uh, especially after long emit exposure and and things like that. So we have done a just a stem cell boost to then collect oftentimes what we do not to waste the good stem cells, we give still some kind of treatment like 100 mg instead of 200 of melphalan. Then give the stem cells, then let them recover and then collect the CAR T cells. It's not my first choice, but in in some patients, especially these young high risk patients, we oftentimes have no other choice, and we have been successful with that. Can you in vitro use that product directly? I, I know that you asked that. I try to avoid you asking that. I don't know. I have to admit I don't know. There's sort of been some study trying to go back to use the T cells that are in the CD34 back. It's just not, um, as robust, mostly also because of the quantity there, um, but I think in the future hopefully we'll be having capacity to be able to collect the CD34 and the and the T cells right in the same setting, right, because you already have the line in, so you just collect the T cells and do GCSF and collect CD 34. So now you have. You know, a bag of each for a rainy day, um, but that, that's, that's going to be a cost driven, um, problem more than whether it's technically feasible and I think to that same token, um, with the CD 34 collected back it's, it's more going to be is there going to be enough, um, drive. From the marketing and strategic side to actually go back to those bags, um, it feels that the field is moving so fast but I think that's a valid question. Thank you so much. I think it's all the time we have. We're gonna take a break, about 10 minutes. Uh, please feel free to grab your, uh, raffle tickets while you're up there, a little bit of coffee or tea, a little snack, and then we'll come back. Uh, please, one more, uh, hearty round of applause for our fantastic myeloma panel.
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