Hamza Hasan from Roswell Park is joined by Jack Khouri from the Clevland Clinic to discuss new developments for treating multiple myeloma and plasma cell disorders.
It's my pleasure to introduce a friend and colleague, Dr. Hamza Hassan. He's an assistant professor of oncology in our multiple myeloma and plasma cell neoplasm division. Um, Doctor Hassan is an expert in amyloidosis and also multiple myeloma and our plasma cell neoplasms, as is Doctor Corey, our distinguished last speaker who has to catch a flight. So we'll try to stay on time. Uh, Doctor Hassan, please, uh, come join me on stage. floor is yours, sir. So. Thank you, everyone who has stayed here till the very end. I'm gonna make it a little bit interesting, um. Very interesting. I know, um, so I'll, um, the mainly the topic that, um. I guess, uh, in the agenda which was included was, uh, to talk about the initial diagnosis, and I think the most important trial in the myeloma space, um, is not in the initial diagnosis of multiple myeloma, it's probably in the smoldering multiple myeloma, so I, I, I have maximum number of slides on that study because that's probably practice changing. So we'll go into the smoldering before we go into the initial multiple myeloma, but I just wanted to put this out there. The first randomized trial in multiple myeloma was Coca-Cola versus placebo, and that was 1966, and we have come a long way and now we are talking about prevention of myeloma progression from smoldering to actual myeloma. Um, so this was published in Blood Journal, and soon I think the whole aim of all this research is actually um from cola to cure, um, and there were about 1200 abstracts that were just on myeloma out of uh the, the, the, the 20,000. So I think there is so much going on. So to jump right into it, let's talk about smoldering myeloma first. So this was the Aquila study. It is a large randomized phase 3 clinical trial of active monitoring as compared to high risk smoldering myeloma, and it was presented by Dr. Demopoulos as well as many of the US sites were included, including Mayo Clinic, and the design of the study included, uh, mainly, uh, Dara monotherapy as compared. Uh, as, as, uh, for, for 39 cycles, basically for 36 months, uh, as compared to active monitoring. Uh, I think the most important piece, uh, in, in, in this is, uh, to know what they included and The high risk definition has kept changing over time, and when this study was designed, the Mayo 2022 criteria was not out there and what was actually out there was this uh previous version where patients with clonal plasma cells, more than 50%, less than 60%. Uh, along with an M protein either more than 3, an IGS mooring myeloma, presence of immunopresis with two uninvolved immunoglobin light chains, or a serum free light chain ratio of more than 8 and less than 100, um, around this time, the 2014 update of slim crab was already in place. So, so slim basically out of the slim crab, uh, were not included in this. And the way they did active monitoring was, was follow up with blood work every 3 months. Imaging was performed at a range of 6 to 12 months. So that's what I do in my clinic, and that's very important to know what you actually define as active monitoring, because someone can say active monitoring is once a year or every 6 months, but it's not only the biomarkers, the blood work, it's also the imaging which is very important. The actual paper was right next the same day published in NEGM and they didn't specify how many patients got 6 months imaging and how many of your patients got 12 months imaging, but at least like it was, it is mentioned at least 6 to 12 months um uh imaging was done. So, um, the primary endpoint was progression free survival and, um, what's mainly very why what makes this, uh, uh, this clinical trial of most important a it has a good competitor arm, which is the current presumed. Standard of care what we say is active monitoring because there are many other studies and smoldering out there with their single arm and they don't have a competitor and they show, uh, you know, prolonged progression pre survival, uh, that, that kind of like, uh, doesn't answer the question. There's a uh early treatment kind of changes something. So, so these are the pluses. I think it's important to keep in mind and uh The results actually showed uh the, the, the baseline demographics for more or so were pretty much matched patients. Um, um, they did retrospectively divided patients in based on the 20, thank you so much, 2018, uh, high risk, uh um um male classification. 40% of patients. Were uh high risk by the 2022 criteria. So, um, with that in mind, uh, basically 65% of patients were able to complete the therapy. There were some side effects that were noted um uh to happen as a result of therapy. Um, this study was enrolled before COVID, so COVID was not actually uh one of the worst events, but progression events did happen, uh, in, in, in, um, in, in a higher proportion of patients in the active monitoring. What's important to note is progression was not really like an end organ damage, so fractures didn't happen. Dialysis didn't happen. What happened was biochemical progression or maybe appearance of a lytic lesion. But it's important to note that even with active monitoring, patients did not develop a major debability, um, kind of like needing dialysis or or or um or, or develop CKD or, or kind of a fracture. So, um, so that is an argument in favor of still kind of thinking, can we do active monitoring and I'll leave the, you know. To conclude this moldering session actually with some questions to think of because the, is it really questioning the current standard of care of active monitoring based on this graph, it shows there is a very clear difference in the progression free survival which was expected because if you give Darzelex to anybody who has smoldering plasma cells, it will kind of increase their time. It will kind of. The progression to act in myeloma, but it did not lead to kind of creation of a super myeloma when the patients actually develop myeloma, which is the PFS2. So, um, because there's always this counterargument should treating early and exposing them to data kind of makes or gives birth to a very resistant myeloma clone that's not going to respond to therapy. So that was not the case. And overall survival benefit noted with a good comparator arm in a study which, you know, used monthly Darselex after, after 4 cycles. So, so it does bring into question is this practice changing. Um there were some adverse effects as they were expected, so obviously, To think of these are asymptomatic patients who, who were per definition smoldering myeloma, and if they are getting infections, is it worth it that goes against, but if there are several, I will benefit. I think Jansen has already submitted for FDA approval, so the author's conclusion for this was actually there was the greatest PFS benefit noted in the high risk smoldering myeloma group retrospectively identified by the Mayo 2018 as well as in other groups, but mainly in the high risk population, and there was an overall survival benefit. So I mentioned I put these two studies which were single arm or they were also presented at this AS meeting that included Darselex with bortizomiblanalidomide dexamethasone in the high risk, as well as the car prism, which is silta cell in smoldering in high risk smoldering myeloma from the Dana-Farber group. So with this, is this time limited sub QDX 439 cycles, or 36 months applicable to clinic tomorrow just to think it out loud and we'll have these questions in our discussion session. Uh, this is defined as a new standard of care. Um, I, I do also want to point out in the actual manuscript they mentioned that um patients. An average a median time to initiation of data on this trial was actually 8 months, and the range was 0 to 60 months. What that actually says is, let's say we see a patient in the clinic who is smoldering myeloma, we don't, or high risk smoldering myeloma in a class example. There's no rush to go ahead and start treatment right away because what if in 3 months. Their spike is doubling, and this is an actual indeed myeloma that we should be treating with 4 medicines in just 3 months later as compared to now treating with one drug and then then they're getting debility and then we are kind of always behind the wheel in that situation so. Time to initiation ranged from 0 to 60 months, but the median and the most common was 8 months. So it's OK to kind of do some 23 time points before these high-risk patients are put into therapy to make sure these are really, really just high-risk mooring myeloma patients and not actually actual myeloma, which will subject them to Darselex RVD. So, um, how we treat high risk molar myeloma at Roswell Park, this is an SOP that Dr. Hillengas and I developed in collaboration after this data came out and we updated annually. We have a clinical trial that actually looks into lifestyle modifications. Dr. Hillengas is a PI for that with that has diet as well as physical activity. The arms, so we can always try to offer that because, you know, that's also an unmet need. Is there any risk of the host factors within the person itself that's putting them or increasing them at risk for progression? And if they are eligible for clinical trial, we think if they are interested in parental treatment, and I underline this is mainly for the high risk at this time. And if they want to, I think it's very important to have an open conversation about data monotherapy for 3 months, and then sagoonal's data actually for lenalidomide for 2 years is the other thing. I still prefer and have been leaning towards opting to observe if the patient wants to do that, but I would at least do the same kind of monitoring that was done in the clinical trial because obviously no patients ended up on dialysis and no patients end up developing fracture. Um, um, it does also bring up, um, um, uh, the patients who ultimately did become myeloma. Only 18 person in the active monitoring arm got Darselex is their first line therapy. Which in other words based on KCOPI and all the griffin data, we know that giving quadruple, giving DTCD 38 monoclonal antibody increases BFS and this is very important. So is it just like some patients got data up front and then just got VRD and there are some patients who just got active monitoring and only 18% got database induction. Is it the, is the OS benefit overall that we are seeing because of that. I think that is uh also an ongoing question. But this was a perfectly done study, the, the, it has shown us how to actually answer these questions on the highest multiple myeloma. Um, and if planning to treat, um, um, confirm no rapid progression on every 3 months lab along with imaging based on symptoms, which may upstage the patients to a myeloma-like regimen if myeloma defining event is clinically evident or apparently imminent. So, um, um, this was last year when Dr. Cortis and Dr. Hernandez set up our and then invited us all for this AS review. This is where we had left, um, is, is really perse as the game changing is ICA data and which quadruplet to use and what to do in transplanting eligibility. Patients. So I think we do have some answers from the CIA and the MROS data. One of the most interesting study for the newly diagnosed transplant eligible population was from the German group, the GMMGHD 7. They actually compared isattuximab and other anti-mono anti-CD30 and monoclone antibody in combination with RVD as compared to just RVD. And what's very unique in this trial and only the part one results were presented, what's very unique in this study is there is a second randomization that happens for part two that will answer whether data has a role or, or I should say NTCD38 antibody has a role in the maintenance therapy, um, uh, which, which we are eagerly waiting. So, um, MRD negativity was the primary endpoint and consistently it showed that patients achieved a higher MRD negative rates using 4 drug regimens. Secondary endpoint included PFS from first randomization and the benefit was noted pre-transplant. It was noted post-transplant, and this is an exploration data without the effect and, and, and neutralizing the effect of the second randomization. And at the medium of 48 months, um, 18 weeks of IRBD induction without consolidation resulted in 30% reduction in the risk of progression and death compared to non-IA based uh uh regimen. So, uh, at, um, at the end of induction, there was a benefit at the end on the left curve and at the end of, uh, uh, at the end of uh um transplant as well as post-consolidation, there was benefit patients. who achieved MRD negative, which is the green curve, but we can see, you know, whether they were treated with I when they were treated with ISA RVD versus RVD. They still had some benefit. Even when they achieved MRD negative. So that kind of brings up the question, what's the effect of the, uh, what's the effect of uh monoclonal antibody in the immune microenvironment, because I think there is something that it does that we just don't know beyond MRD negativity, um. Uh, and, uh, and the same was noted since the start of maintenance. So overall, um, uh, all subgroups had showed benefit uh for that uh towards the right side that favored using ISA RVD that included non-statistically significant in the high risk group, but in the standard risk all of the patients have, have benefit but We eagerly wait for the results of the phase two because that will answer the role of maintenance, uh, um, and, and, uh, the, the other in the main study for the newly diagnosed, I think, mainly was first presented in the International Myomma Society meeting, um, in, in Brazil, but, uh, an updated analysis presented, um, given this is in our annual review, I wanted to put it out there for all the oncologists uh um treating myeloma in our buffalo City, um. It it this was a CIS trial which included Darxelex or Daumab with VRD for transplant ineligible patients. And at this time, the current standard what we give is data RVD in transplant ineligible. So what this study is basically questioning is should we giving quadruplets or quads to everybody irrespective of what their transplant plan is. And um Da ZLX was given per package uh label primary endpoint was uh overall MRD negative rate as well as CR rate. Um, there was no age limit, but faility score was supposed to be 0 to 1. And most of these patients, as you can see, um, the median age was 70 years in the data RVD and in the VRD it was 70 years. The oldest patient in the quadruplet arm was 79 years old, and about a third of patients had had ISS stage 3 and high risk disease. So apart. population that really, you know, we know would progress soon as well as still sort of um transparent and eligible, but there were some younger populations that we see in the parenthesis, there was someone who was 42 year old who was deemed to be non-transplanted eligible either by their choice or because of their comorbidity, those patients also were included. There was a clear MRD benefit by using 4 drugs. Patients have a deeper remission, which has been shown in the PerseS trial as well, which is in transplant eligible population. Mainly what we in the myeloma field wanted to know is what's the adverse effect profile, and it did not show very significantly more grade 4 or grade 5 infection related side effects, which was. Reassuring. So more or so we have been thinking, I think it does change the practice in a sense that if if we should start thinking, is this somebody who can tolerate quadruplet regimen as compared to just these transparent eligible patients. And even if someone is quadrupled ineligible in the beginning, what if the fraility gets treated with 3 drugs, and then we can add the 4 agent for the short period of time and then we can take it off? I think it does give them a benefit of a deeper MRD negative. So that's what I have started to incorporate in my practice. So mainly conclusion was improved MRD negative rate, leading to improved PFS as being the actual reflection of better MRD. And MRD threshold was 10 minus 6, which was very good in this study. The other important study in the newly diagnosed setting was for the transplant ineligible patients, which is a DEX-free regimen. This was the second time the study was presented by by Solomon Maner, and this is a phase 3 study that actually compared Darzolex plus lenalidomide as compared to lenalidomide versus dexamethasone plus dexamethasone. Basically, patients do not have steroids in the data RD or the green arm, which is the current standard of care. Patients did get steroids during the first two cycles because of the concern of, um, uh, you know, injection related infusion reactions. But after 2 cycles, these patients did not get, uh, the dexamethasone, uh, and it did show better PFS, so Dara are without steroid versus Revlimid dexamethasone did better. Just a critique on the study, basically what it is doing is, is data a better drug as the be to dexamethasone? And I think at the end of the day we feel the RLX would be stronger and it did not lead to a higher side effect profile. Quality of life metric was shown as well, and that actually showed much more better safety profile. It doesn't answer the question Is data RBD versus data RD better or data RD versus RD better? Um, we, we do know data RD versus RD would be better, but data RVD versus data RD is something that has not been compared. Um, so it's quadruplets for all, I think, uh, we have, we touched upon that and I more or so we should start thinking at these patients, someone who would be a quadruplet eligible. Um, whether with ISA-based regimen or with the RA-based regimen at this time, um, ISAR RBD is something which is FDA approved that is very easily accessible and able to give to the patients, but it is an IV formulation and with the IFM data, I think it does always bring up this notion. Can we go down with DEXx or can we kind of actually customize the dose of the dexamethasone for a lot of our patients. So, um, with that, um, I will move to maintenance therapy, and in maintenance therapy, there were two more two important studies, and, and to touch on them briefly, um, Origa study actually included patients who did not include drilexs in the upfront setting. They were randomized to either. Get Datumumab or Revlimi or Revlimid alone. It did show that patients who did not get dzelex in the beginning actually had an improved 45, 47% PFS benefit. Um, it does bring up that same conversation of smoldering, giving data to a data patient does help at some point in their stage. A MRD negativity. The patients who were not MRD negative at the end of transplant were more proportion were able to become MRD by addition of Darzalex to Revlimied, and at Ash they actually presented the high risk cytogenetic and the outcomes in the high risk cytogenetic population in the blue box, and the results actually showed in most of these patients it was the same. Another interesting study that was presented to it is not practice changing yet, and I just have one slide on that is telisamab being one of the bis specific antibodies is now making. It's its way into maintenance therapy. Those patients who were not MRD negative, they were randomized to either one of these three arms, but more to come on this in the next few years. And BMTCTN was is a study for patients who did not achieve CR post transplant. This was presented at tandem. But to bring it up for this discussion, I think it's, it's mainly transplant followed by PCMART. So it's, it's not really maintenance therapy, but it's kind of more consolidation. But I think it is very important because some of these high risk patients who actually just achieve a PR, even post transplant. IDA cell is the only data which is kind of at this time available. The transplant followed by, it is a single arm study, but the safety is actually out there. So I have some plasma cell leukemia patients who, who we have successfully done this based on some of this data, because some of these patients, we know they are just going to progress and if they have still having an extra medical disease that's pet avid. Can we just go directly to maintenance if they are all legal security. So I think there is some safety data which is available that makes it reassuring. Um, there was deepening of response. 87% of patients had an upgrade of response. I would say that most of these patients were already near already VGPR, so it just made BGPR to a CR or maybe uh CR with MRD positive status to an MRD negative. So, um, so that's for most part, um, for BMTCTN um uh 1902, um, and uh. So I think we will in the sense of time we'll discuss this during our panel discussion. Um, um, I'll, I'll skip over the AL amyloid doses, um, uh, because we, we, we more or so have now set down the stage that AL amyloid doses should be treated with our RVD, and this is what we do at Roswell. There's been a lot of talk about those patients who are transplant ineligible or those who are still having an MSPY. Uh, should we be giving them by specific antibodies. There were some trial data that is presented at this ash and more to come on that. And with that, um, I'll thank everyone who has been a part of Roswell Park Care Network and help us take care of these patients in a multidisciplinary fashion. Um, and, um, thank you for your attention and, uh, please reach out to anyone of us here at Rosb for any of your easy or complex, uh, myeloma or amyloidosis cases. Um, I'll invite Doctor Hoy, um, uh, our, um, to come and, um, um, talk about the relapse refractory disease. Thank you very much, Doctor Hassan. It's my privilege to introduce Doctor Jack Corey, um, his friend and colleague, we used to call him Uncle Jack and fellowship, even though he's only a couple of years ahead of me, um, fantastic teacher, teacher of the Teacher of the Year award, uh, several times, I believe, for our fellowship program. Uh, Doctor Corey is an expert in amyloidosis and multiple myeloma at Cleveland Clinic. Thank you. Let's see, how do you To just press the green, the green button or something, oh, there it is, OK. Hi, everyone, thanks for sticking around, uh, in sunny Buffalo. It's, it's kind of the same in Cleveland, so no, no major change for me. But, uh, these are my disclosures. Um, I will be talking about Relapse refractory myeloma. These are the objectives. This is a very complex topic, so I tried to make it as, you know, simple as I could, but this is basically what I tell my patients in clinic when I see them. I tell them that, you know, myeloma is a chronic disease. Uh, we go through peaks and valleys, and I always draw this curve to them. What I show them, you know, if they're in a smoldering phase, I tell them you're still in the smoldering phase, which is what you can see initially in the, um, the blue line. And then, you know, you reach the peak when myeloma is active and we have to treat it as Hamza was saying, we do induction therapy with currently with the quadruplet of daratumumab, with lanalidomide, bortazum, and dexamethasone that can be followed with consolidation with the uh with an autologous stem cell transplant patients who can tolerate it, and then we go on maintenance therapy. This is where you get to that green plateau, um, you know, as you can see there, which is the valley, and then this is supposed to go on for several years and potentially many years. We think that patients who get the quadruplet and then stem cell transplant and then maintenance, you know, they're supposed to be in remission for like 56, potentially 7 years before they have to. go through another peak and then you have to treat them again and they go into remission again. And as you can see in the, you know, on the graph and, you know, the blue frame, those um remissions that you get, you know, the valleys get shorter and shorter as time goes on, meaning that our progression free survival, the longer we treat myeloma will shorten over time, which is why. A well-known phenomenon in myeloma is attrition. You have to give your best treatment frontline. This is a must in myeloma. So if people tell you, oh, do not give triplet, you know, a trip, well, actually give a triplet for this patient, don't give them the quad, there's no overall survival benefit yet. You have to give a quadruplet because we know that our patients do the best when you treat them initially with your best treatment. And as time goes on, you lose your patience. You lose a lot of your patients, as you can see in the study from Rafael Fonseca from from Mayo Clinic, where actually if you look at your patient's duration of remission. As time goes on, it shortens and you actually, you lose your patience for a variety of reasons as you wait, you know, as time goes on. And, you know, less and less of them, they actually do get, you know, subsequent lines of therapy. So give them the best shot initially. So quadruple it for everyone, like Hamza was saying. Now, OK, when the patient relapses, what do I look for to basically pick my treatment? I look at 4 things overall, what the patient wants, their lifestyle, you know, are they willing to drive for, you know, to the infusion center for, for treatment? Um, are they, you know, better served with a pill potentially at home? You know, how frail are they? Can they tolerate car T cell therapy, which is something that we're doing in the first relapse setting. Um, do they have bone disease that I have to fix with, you know, talk to orthopedics? Do they have renal impairment where they have to, you know, to get dialysis or potentially plasma exchange? Um, the most important one though is what drugs have they received in the past? Drug refractoriness is really probably the most important factor when I think about relapse, you know, myeloma and what drugs to give, because if someone is not refractory to a certain drug, I can definitely use it, and if they are, I cannot use it. Um, so you have to think about, you know, drug refractoriness, um, making it safe, whatever combination of therapy you want to use and maintaining quality of life. There's a lot of category one, you know, options for our patients with relaps relapsed disease and the 1 to 3, um, you know, prime lines of therapy. That's the NCCI guidelines, um, from a year ago. There's been an update and patients are segregated based on whether they're refractory to lanolinomide because everyone gets Len. You know, for maintenance and or bortazumab. And now they've added another category of theatumumab refractory patients because as Hamza showed, there's a lot of work going on on, you know, giving theiratumumab with lanrolunomide in the um in maintenance. So many of the patients, when they get to the 1st 3 labs, they'll be actually refractory todera, and then that's a different cat. of patients. The most important thing, as you can see, if you look at the bottom, is the approval of CART in the earlier lines of therapy setting. So this was a big deal a year ago in April when CART was approved with um Silta cell being approved for the first relapse and beyond and I cell being approved for the second relapse and beyond, uh, which was a major milestone in myeloma. So this is how I think about relapse myeloma. So you have, you know, you give your patient a quad, you take them to BMT or not, and then you do some kind of maintenance should be le based, right? Either Lle alone or with datumumab, and then you get diverse relapse. So the way I think about it now that we're giving more and more DEA with Len um and maintenance, you know, it, I think about whether the patient is refractory to len only or refractory to Daatumumab and Len together. And then if someone is, you know, only refractory to lend, I, you know, I give an anti CD3 antibody in combination with potentially a protosome inhibitor, mostly carfilzumab based on certain data, which I'll show in a second, or in combination with omeletamide. So if someone is not, there are refractory at the first relapse, there are or um isottuximab is a must. So someone who has not, is not refractory on their uh or is uh um the refractory to land the first relapse, you have to give an anti CD38 monoclonal antibody. Um, silta cell is approved for the 1st 3 labs, so it's fair game for some patients, not everybody, and we'll talk about which patients actually do need early, um, siltace. Now, if someone is, um, you know, datumumab and land refractory because they got both for maintenance, then you have to think about prodsome inhibitors, you know, mostly carfilzomi in combination with palmelinamide. KPD is something that I give a lot in this setting. Um, I do give a fair number of cyclophosphamide with carfilzomib. I do see great responses, although I'm kind of trying to stay away from that, um, lately because we're, you know, we're taking people to early CART and cyclophosphamide can impair your, your T cell fitness. I do use a lot of Celenex or with carfilzomib, we do have some data that Sully. Actually prime your T cells before you collect them for silta cell. XPO1 inhibition can actually help with reducing the expression of inhibitory markers on your T cells, your PD1, your like 3. So you can actually enrich your factor T cells before you collect them by using selenaor. And then after that, you know, the second relapse, further You can actually do ISL um if, you know, if CART is something that you want to consider, again, clinical trials, and then when you get to your 43 laps and beyond, this is when by specifics actually come into play. And these are your by specifics that target BCMA, Eatamab and taclistaab and your GPRC 5D by specific talquaab. OK, so let's say somebody is len refractory, they're not on theatumumab at the first relapse. Uh, anti CD38 antibodies are a must in these patients. So either Dera with carfilzomib dexamethasone, based on the Kor study, as you can see, the PFS is about 28 months, OK? Or istuximab, which is another anti CD38 antibody in combination with carfildex based on the IEA study. Look at the BFS there, 28 months to 35 months. These are the best BFSs that we've seen with triplets in myeloma, and you know, one of these, um, you know, triplets is a, you know, is a fair game. Now, also, there are with Palm Deck or ISA with PalmDX, also, um, they're good combination of combinations, although the BFS is a little bit shorter, but overall, my preferred um go tos are there are with Carfil or ESA with carfil. OK, now, OK, who gets early CARI and this is what I'm gonna spend some time on, you know, taking, talking about. So the Cartitude 4 study is the study that looked at um the Johnson and Johnson product um Silta cell, which was approved for late relapse. Um, this study looked at early relapse. Loma. So as early as the first relapse after patients are refractory to lanalidomide, and they randomized them to uh their Tumabalex or pomelitamide Brtezex which are commonly used, uh, you know, combinations in the early relapse, versus CART. So standard of care versus CART and two different center of care, um, combinations were allowed here. Um, as you can see in the table, um, where with the, um, red frame, all of the patients were land refractory. So these are patients on maintenance, stopped responding to land and now they're relapsing, this is when we did CART for these people or standard of care um triplets. This is the long term follow up after about 2.5 years of follow up. Look at the response rates. I mean, they're really fantastic, 84%, and the response is actually deepened over time where your CRs actually got better as time went on, uh, versus the standard of care. And if you look at MRD, you know, with the red, um, bars, obviously red is way higher than black here, so MRD rates are definitely better and as time goes on, MRD rates did deepen uh over time. When you look at PFS, uh, this is after about 2.5 to 3 years of follow-up. The red curve is CAT, and, you know, 60% versus 25%. So almost, you know, more than doubling of the PFS as time goes on, and then if you actually break the patients down based. On their prior lines of therapy, so patients who actually had one prior line of therapy did better with early CART than patients who had 2 or 3. So actually the earlier the better, you know, even, you know, your patients who actually are relapsing the second time or the 3rd time, they don't do as well with early CART as compared to your um patients who only received one prior line of therapy. So again, you know, another um argument that the earlier the better for CART. Um, and this is across all the subgroups in myeloma, as you can see in this forest plot, everybody benefits from early CARI, and there are no subgroups that actually did not benefit from CARI. Now looking at overall survival, that was a big deal when this was presented at the International Myeloma Society meeting last year in Brazil where There was actually overall survival benefit to early CART after about 2.5 years of follow up where 76% of the patients were still alive with CART versus 63, and there was a whopping hazard ratio of 0.5, which was a big deal for an early relapse myeloma study. Now looking at toxicity, OK, if we, now we know that doing CART early is better efficacy wise. Is it safer, right? So we know that CART can cause problems, you know, in the late relapse setting, and, and as Dr. Malik alluded to earlier today, uh, Parkinson's disease is a big deal with silta cell and Bell's palsy. We, we do see a lot of Bell's palsy. They do get better, but the You know, they, they do cause a lot of quality of life issues and a lot of fear amongst the patients. So when we looked at um early CART and toxicity, we did see a little bit less CRS, OK, and way less ICANs. So, ICANS was actually about 18% in the late relapse trial and here it went down to about 4%, so less ICANs. What was really awesome was that if you look at the And T1s or the movement disorder um side effects, 0.6% as opposed to about 5%, OK, for late relapse myeloma. Kalsies were still common, 9%, and neuropathy was about 3%, but the, I think the main thing is that delayed neurological toxicities with movement disorders like Parkinson's were way less when we did CART early. Uh, if you look at deaths on study, uh, what was kind of interesting was that we did see more deaths in the silta cell, um, arm that were not, uh, that were actually related to treatment. And that was mostly driven by COVID-19 related deaths. This study accrued, you know, a lot of patients during COVID, and, you know, 4% of the deaths were actually due to COVID, um, yeah, about 4% in the CART arm. So what I tell patients is that the 1st 3 months after CARIA are really critical to try to avoid infections because this is when the risk is high, especially viral infections like COVID. OK, something that's really important, myeloma, now that we're really trying to figure out, OK, who do we give early CART to? And a subgroup of patients that's really emerged as a subgroup that actually benefits a lot from early CART is this what we call functional high risk group of myeloma patients. These are the patients that relapse early, OK? Within 18 months from their diagnosis and starting therapy or even 18 months from transplant. And there was a lot of interest in studying their outcomes in the cartitude 4 study. And if you look at the curves here, so on the left, your, um, you know, your patients who are not functionally high risk and the ones who are, and if you look actually at the outcomes with silta cell, they're the same, whether you're functionally high risk or you're not, which was a big deal at the time when this came out, where the response rates were similar, 88 and 90%, and the PFS and MRD negative rates were similar. OK, so early silta cell offers better PFS, potentially overall survival benefit, less toxicity, including less Parkinson's, which is a big deal for our patients, and potentially better T cell fitness because your patients have not really seen, you know, all the alkyating agents and all, you know, um, you know, all the other, you know, medications that we can give that could alter our T cell fitness, but There are issues with giving um early silta cell. There's geography issues where if you look at this map, this is a great map, um, a great study that was published in JAMA, um, where if you look at the map of the US you see a lot of gray, and the gray means parts of the US that do not have CART, parts that cannot offer CART, and the colored ones are actually the parts that can offer CART. This is lymphoma and myeloma. You get, you see, obviously a lot of gray, way more gray than than colors, which is concerning, you know, um, probably 30% of our patients actually live in areas that are 2 hours or more, you know, or um farther out from CARI centers. So a lot of patients cannot really get to, to, you know, CARI, and this is an issue. So we have to figure out ways and drug companies are doing a better job at, you know, getting more centers certified to administer CARI. So this hopefully will be solved at some point in the future. Slot availability, we're getting more slots now. We used to actually scramble a lot back in the day when CARI first came out. We used to call all the time like we need slots and we used to, you know, um, you used to be concerned about that, but now I think we have more availability, which is not a major issue. Delay neurotoxicity, although it's less common, it still happens. And we need to, to get our CAT, um, you know, to be safer. So that's something that we still have to work on. We don't want Parkinson's disease. It's, it's a big deal. Second primary malignancy is somebody else touched on it today. The data are still kind of controversial. Um, there may be a signal that there is, um, increased risk of secondary malignancies, but, you know, that's something that we're still working on. Slow manufacturing is still a big deal. It's still taking 4 to 6 weeks to get to sell to our patients. So can we do better? Yes, absolutely, with BCMART. Um, so I don't really give it to everybody, um, right now in 2025, except for the functionally high risk patients or patients who are, you know, kind of triple class refractory at the first relapse. Um, otherwise, if someone is only on LE, they're refractory now, they're relapsing on LE, I'm OK with doing an anti-CD 38, um, antibody combination. And then waiting for CAT at the 2nd relapse. So do DRRKD and then, you know, that will give the patient potentially 2 to 3 years of permission and then. You know, when they relapse after that, we may have actually a CAT that's safer. I don't know, but um I'm OK with waiting for some of those patients. OK, this is something that Hassan Malik touched on earlier today. How can we improve on our BCMAATs, right? So if you look at the binding domain, as you can see, starting with the left one, this was the first CARI that was approved, and then the second one Silta cell. As you can see, the binding domain is way larger, right? The second time, I look at the 3rd 1, it's very tiny. Why is that important? Because you can actually have more car, you know, density on the surface of the. Cell if it's smaller. You have less hydrophobic kind of like interactions and less, you know, kind of pulling apart and more kind of, you know, concentration on the surface of the um of the, of the cell. Why is that important? Because when you have more car density, you have better binding and you actually may not need as big of a dose for the cells and potentially less inflammation and less toxicity. If you have more cars, more binding, maybe a lower dose, less toxicity. So this um A needle cell product was studied in the Imagine one study in um relapse patients, you know, more than 3 lines or beyond, um. And the data was presented at AshS last year, um, you know, triple clusterrefractory patients, 87, 86%. Um, all of the, almost all of the patients had um BMT. So looking at the efficacy of this product, the response rates were 98%, 97%, which is similar to what we saw with siltace actually in the late relapse setting. So great efficacy, and if you look at the median time, the first response very fast, so one month. Very promising. Looking at PFS still early data, but when you look at 1 year, 78% of the patients were actually still in remission, which is really great remissions, although, you know, short follow up. Overall survival rate was closely at 100%. If you look at toxicity. CRS was still, you know, happening mostly mild grades, so grade one for most of the patients, but look at ICANNs, way less, way less. So we're looking at, you know, basically 4%, OK, of grade 1 and grade 2. Now what was really cool about this product was that there was no Parkinson's scene. And there was no Bell's palsy, so nothing really in terms of delayed, um, toxicities no Guillain-Barre, which is something that we also see, um, you know, with CAT. So way less, not really, I mean no delayed toxicity, which, which is a big deal. Now this product is being studied now in the early relapse setting in the Imagine 3. Studies, so 1 to 3 relapse, and the standard of care arm actually is a little bit larger than what we saw with Cartitude 4 with silta cell. Here they did include theirumumabyrolus Dax, which was not included in the other studies. So this study is going to be really important on when we can actually get this product to the bedside. Now by specifics, as many of you know, are really important in myeloma. Uh, we currently have 3 by specifics that are approved. They're all approved for the late relapse setting, so 4th line and beyond. Uh, two products, um, block BCMA, so stemabinatimab, and one product called Telquenimab blocks GPRC 5D. There's uh three other products that I listed here that, that do not have an asterisk near them. Sevastimab targets FCHR FCRH5. Lymvo targets BCMA it will likely be approved later this year. And at the um 3A3 also targets BCMA It's in clinical trials. But if you look at, you know, the response rates with BCMA and GPRC 5D by specifics, they range in the 60 to 70% um range, and the median PFS is about 1 year to 1.5 years. So they're pretty similar in terms of how much mileage we can get from, uh from them. As Hamza said, a lot of these are moving to the frontline setting. Um, especially the losinab with, um, you know, frontline and then maintenance treatment and hopefully, you know, a lot of these will move to the frontline and it will get better PFS and better responses with these drugs. Looking at safety here, what we expect with CART, we see here, you know, cytokine release syndrome, um, eye cancer is not really common, so it's mostly cytokine release. Um, and infection is a big deal, especially with BCMA targeted by specifics. So that's the lisimab or rananumab, especially grade 3 and grade 4 infections. Um, and as time goes on, the risk of infection actually increases with these products, which is why a lot of the efforts in the field now are basically going to understand whether we can actually Not dose the patient's frequently and actually drop the frequency of the, you know, of the medications and that's been that's been shown actually to help with mitigating the risk of infection. IVIG is a must for everyone on by specifics. Everybody on by specifics um is really hypogamma globu anemic, and I always start IVIG from the get-go. I don't wait. I just give IVIG initially when we start the medication. Something interesting about alcoimab is um the brand new kind of set of toxicities that it's brought with it. And these are oral toxicities and skin toxicities, which was we're not really used to them in myeloma. They're kind of similar to what we see in colon cancer with, um, you know, 5FU and so forth, but patients can get really bad dyscosia. They can't taste food. They, you know, food tastes bad and that's a pretty common complaint. And so we're still trying to figure out how to treat this and there's actually a clinical trial that's looking at supportive care with this medication that's ongoing. OK, how do we sequence all these therapies? We talked about the first relapse, you know, anti CD38 antibody if the patient is not refractory to them in combination and then potentially early silta cell for patients who are higher risk. But then, OK, after the first relapse, what do we do, especially when we have by specifics. So what about, or do we do CART first or by specifics first, OK, or vice versa. You know, there was a small study that looked at, you know, doing um silta cell after by specifics. So patients who got by specifics or even uh antibody drug conjugate bentumab and so forth, so BCMA directed therapies that are non-CART or even CART on clinical trial and then they gave them silta cell. They looked at the outcomes of those patients and if you look, the overall response rate was 60%. Which was way lower than what we'd expect of, you know, the 90% that we would see with patients who got CART, you know, um, kind of, and no prior BCMA therapies. So yes, actually, if you do CART after by specifics or prior BCMA targeted therapies, the response rates are not as good and it's definitely better to do CART first and then move on to buy specifics. This is the, the opposite, so. Patients who got, um, you know, different BCMA target therapies and then by specifics that target BCMA. If you look at the, for example, for tlistimab, the white bar is patients who did not receive prior BCMA therapy before tlisimab, and the red ones are people who actually got BCMA therapies before tclusimab. There's really no major difference if you look at the response rates. You're looking at 60%. So it didn't seem, you know, it didn't seem to matter whether you gave toclisttaab first or another BCMA directed therapy first. So that's, you know, you did see similar outcomes for ranatumab, um, we did see something similar, although we did see lower responses actually of the patients, slightly lower responses if the patients received prior BCMA therapy. So what does this mean? There's really no perfect sequence, but I prefer to do CAT first. So CART, BCMA CART first, preferablyil to cell, and then move on to buy specifics. Uh, this is not really an issue right now because by specifics are still, you know, approved in the late relapse and we're doing CART early, so it's a no-brainer that CART is going to come first and then by specifics. But if someone is thinking CAT by specifics, CAT first and then move on to buy specifics. Um, you can actually do, um, By specifics after CARD, we did see similar results overall, although not, maybe slightly um lower response rate with Erananumab, but with tlistumab it looked like. It was the same. Now, a drug that's making a comeback in clinic is another BCMA agent, which is balentam mephedonin, which is an antibody drug conjugate that um has actually cytotoxic microtubule agent that actually gets internalized what the drug binds the BCMA and that can cause microtubule toxicity and cell death. The drug was pulled from the market in 2022. It's a GSK product because the phase 3 study at the time failed to meet its end point. But then, Phase 3 studies were presented at um at meetings last year, and both of them were in the early relapse setting. The first one is Dream 7. It looked at the first relapse, where it randomized patients to drug with Brtezex or their atumumab with Bortezd, which is the Castro regimen, um, and they looked at BFS as the primary endpoint. The the PFS blue curve is uh balentamab uh versus theatumumab and with uh Bortezex in both arms. Blue curve is better than red curve. I mean it's clear that the drug is better than uh DVD. And if, and then if you look at the overall survival, there was actually overall survival advantage to giving bentumab, um, where, you know, the, um, the median was still not reached at the time, but the projected median OS was about 84 months versus 51 months. So like almost 30 months of overall survival benefit with this drug. Another study that looked at early relapse and bent mephedoin was dream 8, so dream 7 and then dream 8. The combination here is different. So they looked at Palmex actually. With the drug versus the optimism regimen, which is Portes, Palmex, same thing, primary endpoint PFS PFS was better with Bentamab. So it will come back. The drug will come back. It will probably be approved later this year in the early relapse setting. Um, the main issue that used to drive people nuts with this drug, especially on clinical trials, and for the time that we had it approved by the FDA that we used it commercially, was the eye-related toxicities. People lost their vision. People could not see blurry vision was an issue. People could not drive, so it was a big quality of life issue. But what we did see from clinical trials was that dose modification and modified dosing frequency really help. So almost all of the patients recovered their vision um when we did modify the dose of the drug or we spaced it out, um, and only 9% of the patients actually on trials needed to actually stop treatment completely because of ocular events. So 90% of the patients did, or even more recovered their vision, uh, but you know, it's kind of hard to see patients go through it and it may take actually several months for patients to get better, but constant reassurance is um really important for these patients. OK, so as I said, um, like Hamza was saying, the quad should be, you know, uh, the center of care for everybody, especially transplant eligible patients. Uh, projected PFS is about 67 years for these patients. And then after that first relapse, if there's no refractorine is the anti C3 antibodies, do that, preferably with carfilzomib dex. Um, if someone is functionally high risk or early relapse, go toilta cell at the first relapse, um, otherwise, um, you know, you can delay it. By specifics like Hamza was was showing are going to be incorporated in the frontline setting and even CART is being studied like Doctor Mali. in the cartitude 6 study, um, comparing it to transplant. So a lot of changes will come, but for now, this is what we should do. And once CART and by specifics will move to the frontline setting, it will be a different paradigm which is what happens every year in myeloma. There's always, you know, different um thought processes that we have to, to come up with. But this is all I got. Thanks for listening. Fantastic talk. Um, I'd like to open up the floor to questions. I do have 2 online, but if someone's here in person, I'll give them the first shot. All right, well I'm gonna fire away, um, I think for both of y'all, but um, can you please comment on the value of uh Dara, lanolidomide, and dexamethasone versus the 4 drug regimen in non-transplant eligible cases. It comes So, so there's, there's not a head to head comparison, at least with Arzalex, and I think that remains an unanswered like Dadraumabrelami dexamethasone being the Maya trial regiment was not the control arm in the Sopheus, at least. Um, with, uh, with IAtuximab, there is some data on, on similar ground, the benefit, uh, in the first trial. Um, but IMROS is kind of exactly the replica of what the CIA is, um, but I think when it comes to, um, um, both of them, there, there is an MRD negative benefit and there is a PFS benefit, um, by you for using the 4 drugs, um. It, it, it does come down to, are they eligible in is the fraility in the beginning is the ineligibility to, to get transplant or for drugs is because myeloma related and if it gets better, can be for short term add a PI um or like a pro proteosome inhibitor and then maybe de-escalate. I think it's in, in embros it was also like. Uh, patients got, uh, 35 day cycles, um, of 4 drug regimen, 4 of them, um, and then they ultimately went to 3 drug, um, till progression, um, so it's not that these patients remain on PI for long. So I do find benefit of 4 medicine 4 drug combination even in transfer for those who can actually tolerate the 4 quadruplets. The DRD is perfectly fine for transplant eligible patients. I mean, the data from MA was really fantastic with, you know, where the median PFS was 5 to 6 years. So if someone is 80 and a lot of these studies that looked at the quad versus triplets and the ineligible patients, the. Age cutoff was 80, right? So all the patients who are in their 80s, they were not really included. Those are the patients that I always give triplets to. So the Maya regimen of there uh with uh Lendex. Even if someone is ineligible and they're younger than 80, I still think that DRD is fair game. Like Hamza was saying, we don't really have the data for there. We do have data for ISA and not everybody has ISA, uh, but DRD is really good and it's, you know, I don't think there are VRD is really, um. You know, preferable in general, so it's totally OK to do that. Hey, um, oh, perfect. So, uh, great presentation, guys. Um, I have a couple of questions for both of y'all, you know, take it however you want to, um, so as we kind of advanced in our clinical trials of B cell malignancies got better at kind of. Identifying managing toxicities and sometimes the toxicity rates and lower trial later trials started to lower so I'm really kind of interested in in INTs within the myeloma space and I'm wondering Anita cell Arlo cells are some of these are some of these toxicities going down lower because. The design incorporates for like earlier intervention with increasing ALCs or is there some change to those designs that are preventing them versus the the target not being um uh capable of meeting an INT so that's one and the second is about the infections. Do you all vaccinate on bites, um, if you're worried about infections? Thanks. You talking about tendencies. Yeah, so, yeah, great. Yeah. So with, if you look at a cell, if you look at the D domain, it's way smaller. So potentially you don't really need a bigger, like, you know, a really high cell dose to really get the efficacy that you want, which will potentially lead to less inflammation, and we, we do think that M&T is with, uh, with car T cell therapy, so movement disorders and all of that and cranial nerve. Falsies and all of that, they're really related to the massive inflammation that happens with T cells. So the infiltration of the T cells, now whether they're targeting BCMA or not could be, but not everybody potentially has BCMA and still gets, you know, those delayed toxicities. So there's this massive inflammation, it's like an autoimmune reaction basically that targets certain areas versus others. So by really, you know, needing a lower cell dose with some of these new constructs, you can potentially lessen the the, you know, the inflammatory reaction. And you know, you have less as we did see less ICANs actually with that trial too. And so that's one of the mechanisms that, you know, people think that could potentially lead to less toxic toxicities. The other one is disease burden, and we know that doing CART early is definitely better in terms of toxicities because our patients are not really as refractory, their clones are not as aggressive and Uh, what I'm trying to do right now in clinic, if I can actually reduce the patients before CART, I do that because we do see that patients actually do better. They have way, you know, less high grade CRS, uh, when they have low disease going into it. We've seen some cases of MNT even with low disease burden, but if I have the luxury to decide to reduce my patients before CART, I do it. Now for vaccines for bites, we don't really that was the question, right? Yeah, we do vaccinate our patients who are getting CAT but not bites right now. Yeah, I, I, I think I would echo more more so, uh, on the same ground, um, the PFS. In early lines or late line, at least with silho cell was the same, and it is not to do cross trial comparisons, but they were the same, um, but, but the fact that it was a randomized, uh, trial and it kind of, uh, did out show those triplet and, and candor data was not out there at that time. So Da KD, which is the other most common regimen to go after for second line patients. Uh, was not in the competitor, but the PFS was the same. I, I, I do feel like toxicities are more servicing from the real world data. And, and we do see even um with, with the earlier line use, um, the real world data is still showing um pretty much same amount of motor neuron disorders, much more higher than what the clinical trials have reported, um, 6% is from, from, from the cartitude cohorts, uh, as compared to real life up to 15%. So, uh, even in earlier lines. And there is a consensus consensus statement on by specific antibodies on on whether to vaccinate or not vaccinate. So every center is, is pretty much different, but good to know how it's been done at Cleveland. Thank you very much. I've another question in the chat, um, so just back to our, our prior discussion about triplets, let's say for the 80 plus year olds, uh, you know, DRD in this example, um, when do you consider adding on a, a PI, for example, to that back bonus, and I think that invokes MRD and slow sterologic, um, you know, loss of response, things like that, I would imagine. Yeah, so we are still, I mean, I do follow MRD, but in certain settings as in CLL we'll still, you know, trying to gather data, but if someone is relapsing on DRD, I do go to zone inhibitor, but I don't follow MRD for that patient population in, in this, you know, scenario, uh, but yeah, I go to potentially, you can do, you can use porttazumab or even low dose carfilzo and, you know, in older patients, uh, palmelitamide usually with either one of them, correct, or VPD. Uh, if, if one way of that question, maybe the way I interpreted is like if someone becomes MRD positive will we had a PI if that's how I interpret it. I think it's MRD progression or MRDP is a new term out there at this time there's no data to say let's escalate if someone was MRD negative and becomes positive and or on data RD and should we add a PI to then that's how I understood that question and then I think. Uh just MRD progression is, uh, is, is, is doesn't justify adding another drug, and maybe if it becomes biochemical progression, um, because that's where the most evidence is out there just to follow evidence. I'll ask another question, um, and then I think we'll probably end the session here, uh, spare you guys any more, uh, delays in your lives, but fantastic talk. Um, I was gonna just ask a quick question about BCMA. So like why with Belama, for example, do you get oculotoxicities with cart cell therapy and the by specific antibodies you do not is it related to the payload, different epitope binding. Combination thereof, just curious if you can elaborate on why we see certain patterns of toxicity, the payload, yeah, I mean neuropathy is something else that you guys see in lymphoma, right? So there and there's new ADCs right now that are actually changing the payload to make it more tolerable, so that's in clinical trials in early phase, yeah, it is the payload, yeah. But I think there is still a role for it and despite with the lower doses and all that because at the end of the day there is actually an upfront trial of Bantamab in combination um with uh versus 4 drug versus 3 drug and this was presented at Ash and. The question was actually asked why would somebody go with it instead of other things, um, use it front line. I, I think it all depends on access. If you don't have Darselex and if this is what you have available, there is better MRD negativity. So we just have to think outside the US as well what in terms of access is available. Um, so, so the goal to have as many options that all patients can have globally have as much better. Uh, MRD negative longer PFS, um, so access doesn't become a problem. I would have a question for you. Um, have you incorporated drzalex in, uh, smoldering myeloma in in your practice? This is a very timely question because I have not, and this is mostly because of the, um, the placebo arm, the treatments that they got you did show that about 30% of the patients only when they, you know, had active disease they went on to get there, right? So not many patients in that placebo arm went on to get Dera, so it's really hard to really know whether there's really overall survival advantage to do in Dera. So I'm not doing it, OK? But for example, I just had a patient maybe a couple of weeks ago soldering myeloma high risk, OK? And he has neuropathy, small fiber neuropathy, and we sent them to neurology because as you know, it's always a contentious, you know, um, topic when there is neuropathy, is it related to the myeloma or not, right? We sent them to neurology and they ran all kinds of testing and they said, well, we don't really see anything else that could be causing it. And the patient's neuropathy is really debilitating, OK? So I told him, you know what, we have this study right now that could actually justify treating you with Darsolex, which I don't normally like to do lanollunomide. I do think it has side effects and he's, you know, um, high functioning, you know, he's, you know, he has a job that demands a lot of, you know, brain fog is not something that he really. likes to have and we see that with lanolinomide so I told him we have this injection. It's the only drawback is that it's an injection so you have to go for your treatment to the infusion center and he agreed to do it, OK? So I, I don't think I'm gonna use it for everybody. Uh, it's always good to talk to the patient that at least you know I have some data, and if the patients want to try something and they're really anxious about it, I'm OK with it, but I'm not recommending it across the board. If if it was in the cell data, I know it was a huge drop you talk about relapsed refractory. Was there concern for second primary malignancies or lymphomas with interce as well, because I think that's really a hot topic withalen Bema. I can't remember what the percentage was, but they did report on certain um myeloid malignancies that happened. Now that's again, as you know, more follow up will be needed, but so far with, you know, um, systematic ana analysis and meta-analysis. Um, you know, especially the ones that looked at. You know, incidents in, um, patients who got CAT versus standard of care and those studies that actually were randomized, there was really no difference. You probably know that, um, the analysis that were done from Sloan Kettering and so forth. So so far it's really still we still don't really know, but you know we don't really think in randomized studies that the risk was higher with CAT, but obviously we need longer follow up. Fantastic, if there are no other questions. Going once, going twice. I wish I had a gavel up here to bang it, but uh thank you all so much for your attention. Please give um our last but certainly not least, uh, myeloma team a party round of applause.
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