- Welcome to this IMF program. It's an absolute delight to have you join us for the IMWG Conference Series, "Making Sense of Treatment." We have just come from an incredible conference, the American Society of Hematology meeting, which was held in Orlando, and we'll talk a little bit more about the details of that meeting shortly. But we have the privilege now of sharing with you some of the amazing work that came out of that meeting and what it means for patients with multiple myeloma and their partners, what it means for the whole of the myeloma community. Before I go any further, I'll just quickly introduce myself. For those who don't know me, my name is Joseph Mikhael, just call me Dr. Joe to keep it simple. I am the Chief Medical Officer of the International Myeloma Foundation, and with me are three incredible people who are not only amazing in the myeloma world, they're also dear friends of mine. The first is Donna Catamero. She is part of our Nurse Leadership Board, and she works at the Mount Sinai Health System in New York City. Thirdly, we have Dr. Sagar Lonial, who also actually serves on the IMF Board of Directors, and he's at the Winship Cancer Institute at Emory University in Atlanta, Georgia. And last but not least, Tom Martin. Dr. Tom Martin is at the University of California in San Francisco, at the Helen Diller Family Comprehensive Cancer Center. And we're very delighted to have all three of you here. So Donna, Sagar, Tom, I am thrilled to have the three of you. It's a privilege to sit with the three of you, and I look forward to a very packed 90 minutes together. So to give you a little sense of what the plan is here, first of all, we at the IMF really want to ensure that everybody can hear everything we say, can recognize what we say in their own language or in English. Of course, as we're currently speaking in English, and through this Zoom platform, you can choose closed captioning, which I don't know about the rest of our speakers, but I find myself doing that when I watch Netflix now, because I seem to miss a lot of words. But you can use closed captioning as directed here so that you have that opportunity to do so. And there is the capacity within Zoom to actually make it in your own language or in a different language. Also, we want to have your questions answered. So I'm going to present some of the data, and then Tom, Donna, and Sagar are going to be commenting on it as we go through. But we definitely want to take your questions. We're going to do a bit of a Q&A after each of the three major sections that I'll describe in a moment. So you see that there's a Q&A tab there, so please make use of it. I already see questions starting to come in. Hopefully there won't be any technical issues, but if there are, you can see that there's a support opportunity there, or you can just email directly to [email protected] (mailto:[email protected]) or some of our meetings team here. Shout out to Megan and all her work in preparation for this meeting. Thanks, Mo. They're there to help you if you have any technical issues. Lastly, I'd like to thank our sponsors, AbbVie, GSK, Johnson and Johnson, and Sanofi, for their help and support in making these seminars happen. We do also want to have your feedback at the end of the webinar. You'll have an opportunity to do so. You'll see how this will come up onto your screen, and really it'll be extremely helpful to us to get feedback from you. We do have this program really designed for patients who are already familiar with multiple myeloma and even health care providers. And we'll have yet another one in January focused primarily for patients. So we will always appreciate your feedback. This program, of course, is being recorded, so you'll be able to find it along with the huge panoply of choices that we have in our videos at the IMF. We really believe in using videos. It's a marvelous way to educate. And so if you go to the website myeloma.org and look under IMF videos, there'll be several ones there. And if you see in that list, there's the second one on the list called. "IMWG Conference Series," of course the International Myeloma Working Group Conference Series. Before we go any further, I just want to spend a quick moment recognizing the founder, one of the co-founders of the IMF, Dr. Brian Durie. Dr. Durie was a remarkable individual, had a prolific impact in the whole of the myeloma community, and of course in founding the International Myeloma Foundation. And in fact, he was always the host of this series. And so it's a tremendous privilege for me to sit in his chair, as it were. In fact, one of the reasons why I joined the IMF was that I used to be one of the panelists that he would frequently invite me to, and I really genuinely enjoyed this series. And so we want to take note of Dr. Durie's passing just a few months ago. We miss him deeply, and we're very thankful for all that he has provided to us. And I know the mentorship that he has provided specifically to me. At the same time, we also have new leadership at the IMF. And so I wanted to share that Heather Cooper Ortner has, as it were, come back to the IMF as our President and CEO. She had worked here at the IMF and had been in multiple roles at the IMF, including being the head of our development team. And now thankfully she's come back as our President and CEO. I just had a one on one call with her. I'm just delighted that she is leading our team now. And many of you on this call have either met her already or will absolutely meet her through many of the programs that we have at the IMF. So welcome, Heather. All right, let's get into the meat of it. So here we go. We have the Orlando meeting that just happened last week. ASH, of course, stands for the American Society of Hematology. Very quickly, I'll just tell you that we had 9,000 abstracts submitted to ASH this year, which is a thousand more than we've ever had. And interestingly, and very importantly to our conversation today, over 1,500 of them are related to myeloma. And depending on how you count it, when you include some of the abstracts that also include leukemia and lymphoma, we had almost 2,000 abstracts dedicated to myeloma. This is becoming a myeloma meeting, and it's remarkable. We are the fastest growing abstract category because there's such great work going on. Included in that are 100 oral abstracts that were presented, and two that were presented at what we call a late breaking session, where it was really hot off the press kind of clinical trials. And we will actually speak of those two late breakers. In addition, it was a big meeting. We had 27,500 people there, and we had another 3,500 virtually attending. So what's our agenda now for the next 85 minutes or so, now that we've gone through our introductions. Again, I want to welcome everybody for joining us. We know that about 1,200 of you have registered for this program, and several hundred are with us already. We're going to divide it into three parts today. First of all, we'll talk about what abstracts we saw in frontline therapy, and then what we sometimes call early relapse, which means when someone has had one to three prior lines of therapy, and then late relapse, everything that comes thereafter. This will be a natural break for us to spend about 30 minutes on each of these sections. And what I'll do for each of these is quickly highlight five abstracts and then move to our experts here to obtain their opinion about what these mean and what impact they will have on the myeloma community. So starting with frontline therapy, we're going to look at these five abstracts. The AQUILA study in smoldering myeloma, the BENEFIT trial upfront, and then some interesting novel approaches with teclistamab and daratumumab in frontline, a new CAR T, and using a bispecific antibody after induction therapy with linvoseltamab. So the first of which is the AQUILA study, which was big news last year, and we talked a lot about it over this past year. It led to an FDA approval of using daratumumab monotherapy for smoldering multiple myeloma. This is a particular area of work and interest of Dr. Lonial, because he had led one of the largest trials ever done in smoldering multiple myeloma. And I included this because there was an interesting analysis now looking at the so called 2/20/20 criteria, which is to say, what happens when we know that a patient can have one, two, or three of the risk factors of 20 percent or more plasma cells, an M spike of two or greater, or a free light chain ratio involved over uninvolved of 20 or greater. And this puts people into a category of low, intermediate, or high risk. And they looked at the AQUILA study based on this, because AQUILA included different risk stratification strategies. And the bottom line here was that we see really impressive differences in outcomes based on that risk stratification, where whether someone was low, intermediate, or high had a big impact on how they did on the AQUILA trial. And secondly, look at the difference between the two columns of daratumumab versus active monitoring, most pronounced in that high risk group, where at five years, 60 percent of people on daratumumab monotherapy still didn't progress, whereas only 23 percent in the active monitoring group. So I think it helps us appreciate the fact that that scoring strategy, the 20-2-20, can be used in smoldering myeloma, but we'll see what our panel thinks. Secondly, I included the BENEFIT study. This is a study also that we had seen before, but we had an update from it. And it was an important study looking at frontline therapy in patients who were not eligible for transplant but were given a quadruplet, a group that historically received a triplet. And it was interesting for two reasons, or many reasons, but two in particular. One, that it compared adding bortezomib as the fourth drug versus the triplet of isatuximab-Rd. But also that it planned to give the bortezomib only once weekly, as opposed to the earlier trial, the IMROZ trial, where it was given twice weekly. And interesting this study had as its primary endpoint the MRD negativity, but what we saw was a deepening of response. And here at this ASH we got a further update about how these patients did after two years. And it's really quite remarkable when you think of the fact that those people in the quadruplet arm after two years, that over 70% of them had achieved complete remission. And that really is, if you will, unprecedented as it were. And this, of course, was not surprisingly carried similarly along with MRD negativity, where we saw patients now staying in that deepest response of minimal residual disease. And you can see there, whether it was measured at 10 to the minus five or 10 to the minus six, that there was a considerable difference between the patients who were given the quadruplet versus the the triplet, which I think is now emphasizing again the value of quadruplets in the frontline setting. So now we will move thirdly to a combination that was discussed a lot at ASH, and we're gonna see this combination again shortly in the relapse setting. But in the frontline setting, there was a third abstract from our French colleagues looking at teclistamab in combination with daratumumab. This was part of two cohorts they looked at. We initially saw a little bit about cohort B when we add teclistamab to lenalidomide, but here they're adding teclistamab to daratumumab, and really quite impressive. Obviously, there were some initial challenges with infections, and we'll talk more about infections in the relapse setting, but look at this best overall response rate of 100%, granted only 37 patients, and we need more time for follow up. But initially, to see that depth of response and furthermore to see it sustained in the 10 months or so that they had followed up, obviously not very long, but long enough to at least get through that, most of the first year, we see that there actually have been no progression or death events. We never get to see flat lines, like at least the flat lines that we like to see, the flat lines in myeloma. And this was really quite impressive to see that. And then we had sort of a unique approach of a new CAR T cell therapy that we've heard a little bit about before, sometimes called the FasTCAR And what was different about this CAR T, the AstraZeneca product, is that it is dual targeting. So it targets not only BCMA, but also CD19. And why I included this in our list was that this is the first time we saw this drug and this approach of CAR T used in frontline therapy. So you can see that patients had their initial triplet and then followed that by a CAR T cell therapy. And thankfully, it was quite well tolerated. There were episodes of what we expect with CAR T, cytokine release syndrome, and the like, but they were mostly lower grade. They did not have, at least thus far, any short or long term neurotoxicities experienced by these patients. And again, the numbers are small with 30 patients, but we see here that the response rate was nearly 100% in all patients based on transplant eligibility or ineligibility. And at least for the limited follow up we have, we have these rather, again, impressive curves where out at the three year mark, progression free survival is 89% in those patients treated with this combination. And then I'm gonna close off our first section here by thinking a little bit about the IMMUNOPLANT study. And to be honest, I'm a little less excited about the results of this study, but more interested in the design of the study of this concept. And I thought earlier that Dr. Durie would have been happy with this concept and all the work that he did in MRD negativity. And the idea here was people get what they would typically get for their induction therapy in myeloma, they're quadruplet typically, but then what they would do is they would take those patients that did not achieve MRD negativity and give them a limited duration of a bispecific antibody. In this case, it was linvoseltamab for up to six cycles as you see here. So again, the data needs to be matured, and we need more information with time, but I just thought it was fascinating to say let's get people to MRD negativity, and then those who do not, maybe we can do so by changing the whole mechanism of treatment, by giving them something that targets BCMA and by using it in the form of a bispecific antibody. So in quick summary, I think single agent daratumumab we saw is validated with the 20-2-20 model. We saw the ongoing use of quadruplets. We saw that we can give teclistamab in the frontline setting in combination with dara. We have a new CAR T with dual targeting that's showing some pretty impressive early results, and that we have new ways of incorporating MRD negativity into the way we treat. But that's only Dr. Joe's view. I would much rather hear what our colleagues, what my colleagues here think. And so maybe, Sagar, why don't I start with you, because of course you've done so much work in smoldering, but you can comment on any of them. But in particular, did you find anything newsworthy, as it were, out of that AQUILA study?

- Yeah, thanks Joe. You know, I think this was an update of a paper published in the New England Journal pretty recently and mimics in many ways the data that we had when we went back with the ECOG trial and looked at benefit in terms of preventing myeloma by 20-2-20 risk criteria. So I think from my perspective, a take home message is, if you have low risk or intermediate risk by 20-2-20, there isn't necessarily benefit for early intervention. Now I'll say that, saying that we have a trial in intermediate risk with single agent iberdomide, really looking at immunologic mechanisms to prevent the development of myeloma. But in general, you know, the prevention strategy really should be reserved for patients with high risk myeloma. I think this data is very profound, and what I find quite interesting is when you sit in a room of a hundred myeloma experts, you get very few people saying that they're convinced by three trials, randomized phase three trials that have demonstrated benefit for early intervention. When you sit in a room of a hundred docs who live and breathe outside of academia, 99% say they love this data and they want to do something about it. So I think, you know, it's very uncomfortable for patients to have high risk smoldering myeloma and be told, "Well, we're just gonna wait for the train to go off the cliff." And I think for people in that mindset, these data really strongly support the use of early intervention as a way to delay the development of multiple myeloma.

- So well said, Sagar. And you've been saying this for a while. You know, we had two randomized trials and you're like, "People, you're not listening." And then now this is like literally icing on the cake. There was already a cake, you had baked part of it, and now there's clearly icing, and you know, I have to say I've had the same experience. I have a lot of community oncologists sending me patients now saying, "Shouldn't we be treating this person with daratumumab monotherapy?" Tom, maybe can I ask you. I mean, are you now routinely, obviously you gotta know Sagar's listening, no, but are you routinely offering daratumumab monotherapy in that high risk smoldering setting?

- Yeah, so thanks Joe, and very nice description of, you know, some of the results at ASH. And Sagar and I have been in many meetings together, and you know, some parts we take the same side, sometimes we take different sides, and that's what myeloma is all about. We all say, you know, go to eight docs, get 10 opinions. I think still the issue is some of us are worried about either undertreating or overtreating people, right? So if it's somebody that has MGUS and it truly isn't smoldering myeloma, but it is MGUS, then you're overtreating, because they won't need treatment, you know, for quite some time. And if it's somebody that has higher risk disease, like active smoldering myeloma, do they really have myeloma, and are we giving them some inferior combination than what we, you know, what you talked in some of the other abstracts, like a quad-based therapy. So that's a little bit of a quagmire. I think we need better ways to allocate patients to who needs therapy and who doesn't need therapy. That's the most important thing. That said, daratumumab is a great drug, and it's very well tolerated. And if you take a smoldering myeloma population who have no symptoms, right, and you're gonna say you're going to give them a therapy, Dara is actually a nice therapy in that they don't get a lot of symptoms specifically from daratumumab. And there's not a lot of, we say treatment related morbidity or mortality, not treatment related, you know, means that causes them to have symptoms or unfortunately die from something else like infection, you know, that they wouldn't otherwise have done. So I'm not going to answer your question, Joe, other than to say that I do think there's more reason, based on all the studies so far, to keep going and try to find truly the most active and the best therapy and the least toxic therapy for this high risk population.

- I hear what you're saying. If we were in the studio today, I'd make sure that like you and Sagar were not sitting next to each other right now. I understand between two of you. No, I mean, I think you make a very good point, and Donna, maybe I can bring you into this conversation, because I would argue that Sagar noted there are patients who become very uncomfortable with knowing that they are, if you will, sitting on this. I like your analogy, Sagar, I often use it. I think of smoldering myeloma, sort of, you're heading towards a cliff. Like I don't want to wait until you've fallen off the cliff. I mean we changed the criteria over 10 years ago to, if you will, catch people before the cliff. But sometimes people may be moving very slowly, other people may be moving very quickly, and sometimes these measures don't always capture it. I like to at least have two or three measures to get a sense. I had a discussion with a patient yesterday in clinic about the same thing. I said, "Well you know, you technically meet high risk by 20-2-20, but we only have one measure. Let's do one more to sort of see what may be happening." Because if their disease is going very quickly, I may, as Tom said, give them full treatment. And Donna, I know you have been like one of the world experts in the whole concept of shared decision making, and in making sure that we don't just tell patients, "Hey, you'll do it, you'll like it." Do you think the model of engaging the patient and their preference and their risk tolerance is important when we talk about smoldering myeloma?

- Right. Absolutely. And I have to say I do agree with Dr. Martin. I always worry about that undertreatment or overtreatment. So if I have someone who's high risk, I don't want to undertreat them, but I can absolutely understand the anxiety a patient has if they're given that diagnosis of high risk smoldering. And again, you're waiting, instead of the train going off the cliff, I say you're waiting for the shoe to drop. And you don't just want to sit there, you want to do something. So I think this offers patients a good option of delaying, you know, time to active disease. So shared decision making, really getting feedback from the patient on what their comfort level is on, you know, how they should move forward with their treatment.

- [Dr. Mikhael.] Excellent. Yeah, I agree.

- [Dr. Lonial] And Joe, I'm just gonna have one moment to rebut Dr. Martin, and Donna.

- Please.

- And that is, if under or overtreating was a clinically significant issue, then you would have expected the survival to be worse, and the survival was in fact not worse. And in fact, if you look at the curve, the survival is actually better. So the fact that you're not losing people as a consequence to this, and this over undertreatment argument, you could make the same thing for triplets versus quads. There is a large fraction of people that go into MRD negativity with a triplet, and yet we've accepted the notion that we're gonna overtreat some patients with a quad in order to benefit more patients who wouldn't necessarily get that same depth of response. So while I certainly appreciate that argument, I'm not sure that it bears out in terms of survival difference or PFS difference, both of which favor early dara.

- Do you think, sorry, do you think we're at the optimal treatment at the current time, or do you think we need to get to the next thing?

- No, but remember we're coming from 25, 30 years of doing nothing. So you get that crawl before you can walk, and the first step is to get a drug approved. Do I think we have the right answer? I'm not sure we do. Do I think we have the right risk stratification? Probably not, but you know, we're letting the perfect be the enemy of good, right? I think we gotta start somewhere.

- And I would completely agree with Sagar in that there are patients, and you, Joe, with you also, and I'm sure Donna at Sinai. There's a patient that comes in and they have smoldering myeloma, and you're like, "Okay, I'm gonna start you on therapy tomorrow." And the best therapy I think for you is daratumumab, and there's others that we might say, "Oh that guy, I want to wait, I want to wait, I want to see you again in three months, maybe six months." So I think we all really, we're more aligned than we ever have been on this scenario.

- Yeah, and I think you've all three of you have captured it so well, we'll move on to our next topic in just a moment. But I said it this way to the medical student in our clinic yesterday, when we were having the discussion about smoldering, I said, "You gotta remember myeloma probably has the widest confidence interval of almost any disease we treat." Meaning the biology is very different. You know, it's interesting, we have two questions in the chat that relate to this. Someone says, "You know, I appreciate Dr. Martin's comments about over undertreatment, you know, can you speak to Dr. Moor's research on genetic testing to identify this?" I mean, one of the things we're coming to learn is that myeloma is not fully captured just in the 20%, you know, two M spike of two and 20 free light chain. For example, we have patients with light chain only disease. They can't be put into that category. There are biological things that Dr. Moor and others are studying, trying to understand, you know, can we, as Tom asked, can we have a better risk scoring system? 20-2-20 is just so easy to remember and do, but doesn't always reflect the biology of the disease. A second person asked, "What if a person was diagnosed with high risk smoldering almost 10 years ago?" Well now all of a sudden that's a bit of a different scenario. If you follow Dr. Lonial's analogy, some people I think of them as cliff runners. Kinda like me, I run the hills of Arizona here, and I like running alongside of the cliff, and there's some people that are like that. It doesn't look like they're gonna go over the cliff. If I have a patient that I see freshly tomorrow, and I've been told they've had high risk smoldering myeloma for the last 10 years, I may not be urgently treating them, because if they've already shown their biology is almost MGUS like, as Dr. Martin said, we may want to just continue that. But while we're on the subject of frontline therapy, Tom, really quickly, you know, you led a lot of the early studies, you and I had the privilege together of working in the isatuximab era. Do you think the results of the BENEFIT study that we just saw, the four drug combination, solidifies that you're gonna give this quadruplet to patients who are ineligible for transplant?

- So, the study did involve patients that are, you know, less than 80 years of age, right? So in that patient population that do not move forward with autologous transplant, I do think, for me, that is the schema that I follow. I do use weekly bortezomib, because I think the neuropathy signal is a little lower. And whether, you know, we do a year's worth, 12 months, and then switch it to every other week and go to 18 months, if I can benefit, or whether stop early, really depends on the symptoms that people have. But I do think the MRD data is compelling enough, and the toxicity data, that it's generally tolerable to add on a CD38 to, you know, VRd, that is my go to in that patient population. Yes.

- Excellent. And Donna, in your practice at Sinai, are you using 80 as an absolute cutoff, or are you trying to sort of do more of a frailty assessment to determine if someone may be eligible for a triplet or a quadruplet?

- Yeah, so age is just a number. It's really, we should become standard of practice that we use frailty scores instead of age. I have 80 year olds who do much better than I do. They're running marathons. So we really need to look at frailty. And this study shows that really quads are standard regardless of transplant eligibility, and that we just have to titrate how we are giving the drugs. So bortezomib weekly, less dex, less lenalidomide, that we can give quads that are tolerable, even our frail patients can tolerate quads if we dose them correctly.

- Excellent. Tom, you saw the results of that frontline study with teclistamab and daratumumab in the French trial. You know, you've pioneered a lot of the work that we're doing in immunotherapy. Do you think this is the way that we're going, do you think that maybe, in particular, still speaking about that transplant ineligible population, which I know is, may not always be the best term to use. But nonetheless, do you think we're gonna go to a direction where we're starting to use bispecifics in that frontline therapy?

- I believe it's most likely that we're gonna be going that way. The two things that I worry about, one is infection. You know, is the infection signal going to be, can we mitigate that so that we're not having anybody not survive because of an infection? Most of these frontline studies, you know, the survival, the mortality in these frontline studies is quite low, and we want to make sure in the frontline setting it remains very low, because these patients have a very long, you know, now overall survival as frontline therapy with the drugs that we have. So that's one thing that we do need to do. The second is, can we do it safely in the community? Because the majority of these patients are gonna be treated in the community? We gotta make sure it's safe in the community and that the community can take this on. The academic centers, we can't take on all of these patients and start their therapy with us and then send off. It would be very difficult for us to do that. You know, the majority of patients are treated out in the community. So those are the two things. That said, those curves that you saw, the ones that are at 100%. You know, it's only 18 months, but still, those 100%, those are hard to look away from and say, "Wow, the hope is there." I have kept saying that. Now, we have always worried about attrition that from line one to line two to line three, patients unfortunately can't get to the next therapy because they have a toxicity or they have, you know, some morbidity that prevents them from going on. I like that we're gonna hopefully have reverse attrition. And the reverse attrition is that the treatment's gonna be so good that they're not gonna need another therapy after frontline therapy. So I think the race is to the golden space of frontline therapy with all these really important, you know, novel drugs, because I think it is going to be reverse attrition. Patients are going to get on their therapy, get a deep remission, and not need anything, maybe hopefully, for quote unquote, you know, five to 10 years, maybe longer, and that would be awesome. Reverse attrition would be just awesome.

- Well, you heard it here first, everyone, reverse attrition by Dr. Tom Martin, who I think is one of the most optimistic but yet realistic myeloma doctors that we have. So I think, Tom, that was actually beautifully said. Sagar, if I can turn to you for a moment for that CAR T trial. Granted, we know smaller numbers, but a kind of a similar question to Tom. I mean, do you think that CAR T is making its way to the frontline setting? I know we have some large trials that we are waiting on, but do you like this model of, you know, a few cycles of induction therapy followed by a CAR T, and part two of the question is, do you think this dual targeting notion is really going to be an advanced form of CAR T-cell therapy?

- Yeah, I mean, I think the idea of switched targets over time, limited duration sort of cassettes, that's how we call it at our center. We have a cassette for induction, we have a cassette for consolidation, we have a cassette for maintenance. How do we get the active targets in within short bursts of therapy? I think that makes a lot of sense. So you give a quad as induction for two to three cycles, and you come in with something that targets BCMA, and then you think about a different target in the maintenance setting. I think that makes a lot of sense. And so, to that extent, this idea of BCMA-directed consolidation, like an IMMUNOPLANT, or BCMA-directed consolidation like in the FasTCAR, I think those are all really great ideas. I think, to me, the tyranny of small numbers is always a problem. And while I hope that our French colleagues are being predictive of where we are going to be in the future, it was a very small trial, and I am sure they were hypervigilant for any risk of infections, CMV, EBV, all those other things that can complicate bispecific therapy, particularly in a newly diagnosed patient, to not allow that to impact their PFS or OS curve. And so I think we need to see, while I am encouraged by it, I think we need a larger data set to be able to answer that. I do want to, Joe, if I have a moment, go back to the triplet versus quad question, because that trial, along with other trials that looked at three versus four drugs, did so in a patient population that I know at Tom and Donna's institution would likely be transplanted. And the PFS for those patients is likely double. And so I think we have to be a little careful about saying quads for everybody who is transplant-ineligible, because yes, there is the 80-year-old who can get a quad and does fine, but the average 80-year-old probably can't get a quad. And so is DRd really the best way to go? And these trials don't answer that question. So I think we just have to be a little careful about who we recommend drugs for, because it may not necessarily be the patient that walks into a routine community oncology practice. And I have certainly seen people that I have had to pull back drugs on because they have had so many side effects from that kind of aggressive approach.

- And I think you captured that so well. I think a very important phenomenon is, if I can put it this way, a quad is not a quad, which is not a quad. Meaning, depending on how it is given and how it is pulled back or dose-adjusted, all those things can actually make a very big difference in cytopenias and neuropathies and the like. I included the BENEFIT study because they went down to once-weekly bortezomib. I know that is a whole other discussion, but I strongly agree with you that I think the definition of transplant ineligibility would be very different in many of our centers.

- And then case in point, why frailty is more important than age.

- Absolutely. Absolutely. Thank you, Donna, for emphasizing that. Well, Sagar, you were a little bit concerned about the number of the size of the trials. Let me tell you that there are more people on this webinar now than just about any trial I am going to present. Just to encourage us, we are well over 500 people live right now, for which I am very grateful. And let me speak to all 500 of you. Thank you for, at least it seems about 20 who have sent questions in. I will try to answer them as we go through and insert them, and we will have some time at the very end. But please feel free to submit more questions. But let us now move into-

- Joe, you are halfway to RVD 1000.

- I was waiting for that. I was waiting. If people aren't familiar with RVD 1000, it is a thousand patients treated at Emory with that triplet combination. When everybody else was saying, "Oh, we are not sure we need a triplet, we are not sure if we will get past CyBorD." Sagar was saying RVD is the way to go. So you are a trailblazer, Sagar, we appreciate you, man. Let's now turn our attention to early relapse. And I am going to first start with arguably the most discussed abstract at ASH. There's probably two, that were the top two, the two late breakers. We will come to the other late breaker in section three, but we will look at teclistamab and dara. We will look at some data around cilta-cel. An interesting combination using iberdomide that Dr. Lonial made brief mention of. And then we will come to this interesting work that Dr. Costa presented about whether or not we should be changing how we define so-called functional high-risk disease. So starting with this abstract, which was a late-breaking abstract, and as I noted, arguably one of the most talked about abstracts, two of our abstracts today were published in the New England Journal on the day that they were presented at ASH. This is one of them. It was the combination of teclistamab and daratumumab. So the same combination that we saw a few minutes ago in frontline therapy, but now given in one to three prior lines of therapy, compared to being given to the pretty typical triplets that we give in that context. Obviously now sometimes we do CAR T, but let us keep it to the triplets. When the study was designed, DPD or DVD, so dara-pom-dex or dara-velcade bortezomib-dex. And importantly and interestingly, the teclistamab was given following the typical daratumumab pattern, so weekly for eight weeks, every other week for six weeks, then once every four weeks. So a sort of built-in tapering of the teclistamab to match the daratumumab. If I could only show one slide tonight, it would probably, honestly, this slide. This was quite remarkable to us. I want you to notice two things about the slide. Number one, there is a bit of a dip early on, and we will come back to some of that dip in a moment. But at three years, you have 83 percent of patients still in remission, and this is relapsed myeloma. That is really genuinely remarkable. Not only is it remarkable, look at the difference between the curves. I mean, I don't know Sagar, you've been in the myeloma community for a little while, Tom and Donna, we all have. I don't often see a trial that has a hazard ratio of 0.17. I mean, that was genuinely remarkable. Furthermore, we saw an overall survival difference, which was quite impressive as well, also with a hazard ratio of under 0.5 at the three-year mark, as you see here. I give the caveat that there was an important infectious signal seen. Sadly, 13 patients in the study died before they implemented more rigorous infection reduction. And Tom, you mentioned already the importance of watching for that infection signal. Sagar mentioned that, you know, in these trials they would have been hypervigilant, but here it was not routine that everyone received IVIG, and there weren't protocols built in. Thankfully, when those got added into the trial, there was tragically still one, but only one infectious death thereafter. So that, of course, colors the results a little bit, but also just reminds us of the importance of infection in this group. And I'll be interested in a few minutes to hear the thoughts of our group. The second study that I included was looking at longer-term follow-up of patients treated with cilta-cel who were standard risk. We had seen a couple analyses of high risk, and sometimes we think of taking people to CAR T early on when they are high risk or functionally high risk. But they wanted to look at patients who were standard risk, both in CARTITUDE-4 and CARTITUDE-1. CARTITUDE-4, of course, is where patients were given this as a single infusion of cilta-cel versus a typical triplet in one to three prior lines. And the CARTITUDE-1 trial is when we gave CAR T in very late line therapy, on average six prior lines of therapy. And what they demonstrated was just to see the absolute benefit in that standard-risk group. First of all, you notice in PFS, that whether standard or high risk, the cilta-cel arms did better than the standard treatment arms. And we see that for both PFS and OS. To give a little bit of specifics in number, we can compare overall the standard risk in those who got it earlier line versus later line in CARTITUDE-4 versus CARTITUDE-1, where we see the 30-month PFS higher, 70 percent versus 60 percent, and OS of 86 versus 70 percent. So it is not just that you get a certain benefit from CAR T. Obviously, using things earlier tends to bring a better outcome, and that's not a surprise. To summarize this in the numbers here, you can look at the 30-month PFS and OS difference, whether cilta-cel was given in an earlier line or later line. You can see that in standard-risk patients, I can have a conversation now with a patient with standard risk and say that, on average, at 30 months, 80 percent of patients are still going to be in remission, and 87 percent are going to be alive. And in later-line therapy, 60 percent would still be in remission, and 70 percent still alive. Thirdly, I wanted to include this trial because I think it is giving us insight to one of the greatest hesitations we have in using cilta-cel. Which is delayed neurotoxicity and so-called non-relapse mortality, or when someone unfortunately dies, and it is not because their myeloma has become active again, but because they have had an infection or some other kind of toxicity. And it was an interesting study because they really wanted to evaluate these particular delayed toxicities that we know can lead to very challenging situations, like Parkinson's and the like. And Dr. Sidana led this from Stanford, where they reviewed 760 patients from multiple centers. And I won't go through all of the detail, but I'll just give the slide here as the key slide. That I would argue they had two major lessons that they learned that could have implications. And Tom, be ready, I am going to come and ask you about this in a few minutes, because I know this is an area of your interest and work. Lesson number one was, if bridging therapy was not effective, people had a much higher rate of developing those late toxicities like Parkinson's. And for definition for the crowd, when I say bridging therapy, that is explicitly the treatment that is given after CAR T cells are collected, but before they are reinfused in the patient. We are learning more and more the importance of that bridging. Lesson number two is that there is something to be learned about this absolute lymphocyte count rise, that somehow that more rapid expansion leads to a greater risk of Parkinson's and other challenges. And although we do not know, frankly, what to do yet, if only, Tom, we had an immunotherapy registry to answer this question, which of course Tom is helping to build, we might be able to have a more clear answer as to what to do. But when we see that rise of the absolute lymphocyte count, it should cause us to pause and wonder. The fourth abstract I wanted to include was an interesting combination, because it is not very often that we get to see a bispecific antibody with another new novel therapy. And this is iberdomide, which is part of a class of CELMoDs that Dr. Lonial has had the opportunity to lead many studies in. And I include it really more for the design and for the interest of the study, which is trying to say, can we better the effect of bispecific antibodies in combination with others? We have already seen a bispecific antibody with a monoclonal antibody, but now what about a CELMoD, which is a pill, very easy to take, generally speaking very well tolerated. And again, as Sagar warned us, let's not get too excited about small numbers. These are even smaller numbers, but in the numbers that we see, we see a response rate here over 95, if not close to 100% at the target dose. So very interesting to see that combination together. And then lastly, the final abstract in this area of early relapse was some interesting work presented by Dr. Costa to help us think about so-called functional high risk. I see some questions in the chat around defining high risk, and we just have a new IMWG-IMS classification of risk in myeloma, where we look primarily at genetic features that influence risk. But there is also this notion of functional high risk, that if high risk is like being the Porsche, which you expect has high horsepower and is going to be driving fast and the disease is going to come back sooner, what we think of low-risk disease is just the Prius, not moving very quickly. But sometimes the Prius is moving quickly. Sometimes people, even though we do not anticipate that they are going to relapse quickly, they relapse very quickly. And historically, we have said that functional high risk is maybe within a year of transplant, or maybe two years of transplant. But what Dr. Costa demonstrated is there's a much smaller fraction of patients now who are relapsing within the first two years because of the better treatments that we have, that even if we go out to three years, when we have 16 percent, maybe that is the more adequate definition of functional high risk, calling it FHR36, as he describes it. That is a group of patients that we really have to be better at treating, because their outcomes unfortunately are so poor. So in early relapse, we saw the tec-dara combination, remarkable, but obviously we have to mitigate infections. Standard-risk patients do particularly well with cilta-cel in early or late relapse. We have to learn better to mitigate the toxicities that we have from cilta-cel. And we have interesting combinations coming, like elranatamab and iberdomide, and maybe we should be redefining high risk, or functional high risk rather, at 36 months, based on what we have seen. So maybe I will kick it off with you, Tom, because I know, again, you have been very interested in the work that is being done in teclistamab in combinations. What is your feeling about that MajesTEC-3 study?

- I think the MajesTEC-3study does a couple things. One, it certainly builds on our optimism in momentum that taking the immunotherapies from later line when potentially their immune system may be a little challenged, it may not have as good we say T-cell health and moving them into earlier lines of therapy that they would have, you know, some more potency. So with any of the bispecific T-cell engagers, when you start 'em off as a single agent, there's 30 or so percent of patients that are primary refractory. You didn't see this at all at all. You didn't really see a primary refractory group. It was less obviously less than 10%. And here at 36 months of follow up, you know, over 80% of the people remain in remission. That's, you know, five times better than the triplet that a lot of us use right now. Dara-Pd, that's amazing. You know, to have a hazard ratio of 0.17, it's hitting it out of the park. If you do the math that has a PFS that's way too way too high to even say but more than six or seven years of PFS in one to three prior lines of therapy. That's unheard of. And it is gonna be, it's rapidly gonna come to fruition that we're gonna be using that in that line of therapy.

- [Dr. Mikhael.] Understood. Yeah no, I agree with you. Donna, from your perspective, you know that infection risk was kind of concerning, wasn't it? And yet it seems like when there was a pivot, it got a a little bit better. How are you and your clinic making sure that these patients on bispecific antibodies are, you know, have a less risk of infection? Interestingly, one of the questions that came in the chat, I'll add to, someone asked, "Can IVIG be given more than once monthly?"

- Well, I think first of all with the infections and with bispecifics immunotherapy, that's the main concern and we need to mitigate this. And we see that once we do mitigate, you know, that line became flat. So with the start of especially anything that targets BCMA, so with our bispecifics, our CAR T, we have to be, you know, we have to prophylax. So patients should immediately start on IVIG with that bispecific therapy, PJP prophylaxis. So pneumonia prophylaxis, patients need to make sure that they're up to date on their vaccinations, seasonal vaccines. And we see that once we put these in place and have proper monitoring, we can manage infections. And so you had asked, you know, in the previous section about these drugs going into the community and I think, you know, this is more feasible to do in the community. We're good at managing infections, we just need to prevent them. So adding in the prophylaxis at the initiation of treatment is key to have a successful, you know, to be successful in managing patients with infection.

- Excellent. Sagar, two questions have come in that I'd be interested in your response to is, do you think MajesTEC-3 was so remarkable because the two treatments are synergistic? Like do you think it's just, or is it like kind of what you described before, putting two cassettes together, I had this picture of you having a ghetto blaster in the workroom with your little old audio. But secondly, you know, there was a lot of discussion about CAR T and bispecifics. Does this help us understand a bit about the sequencing question?

- Yeah, I think there certainly are theoretical mechanisms of synergy between an anti-CD38 and BCMA bispecifics. So I think certainly it does support that idea that it's not one plus one equals two, it's one plus one equals three. And clearly the PFS, the hazard ratio, all of that data really does support it. I think to me the question is what is the better partner for BCMA bispecific? Is it gonna be an anti-CD38 antibody? We clearly have randomized phase three data that says that or is it something like an IMiD or a cell mod? And that's what the LRAI data really spoke to because the upside you get with the cell mod is that you are waking up T cells and we know that one of the mechanisms that happens with continuous dosing of bispecifics is you get a higher fraction of exhausted, less functional T cells. So using medications that can wake up the immune system along with having direct anti-myeloma activity might be a way to avoid some of that and get that synergy together. When we're talking about sequencing, it really is a difficult challenge to understand because as they are currently given, when you continuously give BCMA bispecific, a common mechanism of resistance is mutation or abnormalities in the receptor itself. That makes it more difficult to come back and treat again with BCMA-directed antibody. Whereas with CARs, the CAR duration is relatively short and so that loss or mutation in the receptor is a much lower frequency event allowing you to come with a bispecific potentially on the back end. But if we get to where I'm sure Tom and Donna want to go, which is limited duration therapy, that you're not treating high intensity for two, three, four or five years, you may eliminate that mechanism of resistance of mutations or abnormalities in BCMA that may allow you to revisit it. So I think there are multiple reasons to think about how do we optimally give these drugs, but one of them is how long do we need to give them and can we do things to give both the immune system and the patient a break and allow for recovery of normal immune protection.

- Wonderful. I mean we're seeing about... I mean it goes beyond our scope tonight, but we're seeing a lot about the biology of myeloma tonight, aren't we? About the importance of T-cell and of giving them rest or as I think you said to me once at a meeting Sagar, you know, giving a cappuccino to your T-cell in the form of of iberdomide but also, you know, the importance of ensuring that the target itself is changed. And this is one of the things I think is exciting. I was at a patient meeting this morning and we were discussing this notion that, you know, how did we overcome HIV? Not that that's the same disease, but there's some similarities. It wasn't 'cause we found one kind of magic drug as it were. It was that right combination of drugs together. 'cause it it is sort of a multi-target or a multi-complicated disease. Tom-

- And Joe to that analogy I'll say, 'cause our ID folks say that all the time, I'll say we did it first in Hodgkin's disease and non-Hodgkin's lymphoma and testicular. So we taught them the idea of combination therapy. We just need to learn it again.

- Correct.

- Although the old... Sorry, go ahead Tom.

- No, but to that measure, we can combine the three drugs too actually. We can combine a BCMA with a CD38, with a cell mod, and maybe be able to do it in a short burst of therapy and get a really big a big response, which would be awesome. I think that's what the future's gonna, you know, entail in us investigating those types of combinations.

- I love how the future of myeloma always gets peppered into these conversations. We wanna see, you know, in my country's homeland, my homeland country thinking of where the puck is going, not where the puck is, right? So this is, I think, you know, a really good sign of what's to come. Tom, can I ask you, 'cause I told you I was gonna ask you about it. But you know, the really nice abstract that Serbia presented about delayed neurotoxicities and effective bridging therapy and so on. I wanna wanna get your take on that because I know that this is a real challenge in the treatment of cilta-cel and we wanna reduce that toxicity as much as possible.

- So, as part of the IMWG-IMF database project, we've looked at characteristics for neurologic toxicity also. And I think the strongest predictor is the ALC rise after CAR T-cell therapy actually. And in our data here just at UCSF, you know, we looked at our last 200 patients and in fact, you know, the patients who develop late neurologic toxicity, 80% of those patients had a high ALC. That typical ALC is between day 12 and day 15 after CAR T-cell therapy. So 80% developed of the people developing neurotoxicity had that high ALC. Now the high ALC doesn't mean you're gonna get it. So actually those people have a high ALC. It's actually a smaller percentage. It's like 20% of the whole people who have a high ALC actually get delayed neurotoxicity. But, so we need more markers, we need biologic markers from T-cell health, we need the ALC markers, we need, you know, data like the clinical data like did they respond to bridging therapy to be able to predict that with confidence and more than 50% or 60% of patients that you have a higher risk of this. Let's treat you now before you develop that abnormality. Let's get you better before you can actually get neurologic toxicity. I think we will get there. We have a project that we're pushing forward through with the IMWG and with IMF and I think we'll get there. We'll be able to predict this, you know, during the CAR T-cell therapy and hopefully be able to prevent this type of toxicity.

- Excellent. I know Sagar, we only have a few more minutes of your time, so I wonder if I can ask you two quick questions and then I'll come to you Donna. One does the long-term follow up of the cilta-cel data that we looked at, that Dr. Costa presented, does that change in any way you're thinking about offering CAR T at first relapse in the standard risk patient? And then my second quick question was, do you believe that functional high risk should now essentially be defined at 36 months?

- Yeah, I mean I think, you know, we have typically said if you are a functional high risk patient, CAR is where you need to go in first relapse. And I think clearly the data supports that idea. I think we've all been a little more hesitant to do that with the standard risk data. But boy, it's hard to argue with some of that data there. And again, the upside is if your myeloma comes back, you could potentially get tec-dara if you got a CAR upfront. So, you know, I think it doesn't necessarily close doors to getting both of these as potential treatment options in that context. In terms of functional high risk, I'll say we published data almost, or presented data almost four years ago on our pom-dara-dex data in first relapse. And if you had 36 months between time of diagnosis and time of relapse, the response to PFS for pom-dara-dex was only nine months. Whereas if you were more than 36 months, the PFS for pom-dara-dex was 44 months. So we've been saying all along that three years is functional high risk. We're glad it's been replicated at a couple of other centers, but that number is what we have used for functional high risk at our program for a while now.

- That's the gentlest way I've ever heard someone say I told you.

- That was really well done. Thank you. And particular thanks to Sagar, we know how busy you are and how much is going on in your life right now. We just appreciate you so much joining us 'cause we know you have to slip away shortly. So thank you again for your contribution and all that you do for the myeloma community. You really are... We're blessed to have you.

- Thank you. I'm gonna take off.

- So Donna, I wanna come back to this before we move on to our final session, our final section. I wanna come back to this notion of introducing CAR T at first relapse. 'cause you know, you are at an extraordinary center at Sinai where there's been, you know, great work done both on the CAR T side and the bispecific side. And so, you know, in that realm, you just heard Dr. Lonial say, oh it's kind of hard to argue with this CAR T in standard risk patients. What is kind of your approach now at first relapse? How are you thinking about who you take to CAR T or who you may say no, let's use CAR T at a later relapse.

- So I think for the high-risk patients, CAR T is really one of the better options in that first relapse. We have long-term data from the CARTITUDE-1 trial, which is more heavily pretreated patient population. But we saw that after five years, a third of patients did not relapse. So, you know, begs to question what is cure? Are we curing a a percentage of patients with CAR T? So we don't have the long-term data yet, but with CARTITUDE-4 we see that there is a benefit in using CAR T earlier on. So yes, that is a viable option. I think we do offer it to our functional high risk, our high risk cytogenetic patients. But the, you know, it's also where the shared decision making comes in. You know, we're anticipating, you know, bispecifics to move up in that second line. You know, do you wanna one and done treatment? It's hard to look at MajesTEC-3 with that hazard ratio and that curve being so flat at three years, you know, we have two good options for patients.

- [Dr. Mikhael] Yeah, that's so well said. And I think what helps me too is what Tom shared, you know, around this notion that if we can really reduce that toxicity, what frightens me, or no, I shouldn't say frightens. But what concerns me the most potentially is someone developing something like Parkinson's. So if we can reduce that, that would be important. I saw that a few questions came in the bar in the chat. Again, defining functional high risk. I'm sorry if I didn't define it clearly enough. Functional high risk is different than cytogenetic high risk. Cytogenetic high risk. I can define at diagnosis or at any relapse. I do the testing, we see that you're P53 deleted, we see that you have these cytogenetics. That's what puts people into a biological high risk. That's what I kind of said was like, you are driving a sports car, we know your car is likely gonna drive quickly. Functional high risk just means that someone relapses sooner than expected. Whether it's 12 months, 24 months, or 36 months. Often we think of the functional high risk people as the people that didn't have high risk to begin with, but somehow they're behaving like they're high risk as it were. So that's why I use the example of the Prius. Like I look at the Prius, I'm like, and I go to San Francisco and visit my friend Tom and take my daughter there who almost went to the university down the street from his house and she's like, "Dad, there are Priuses everywhere here." I'm like, "Yeah, welcome to San Francisco, honey." And you don't think the Prius is gonna go very quickly, but it does in functional high risk. That was the definition. And the other question that came up that Donna and I didn't fully answer was typically we do not give IVIG more than once monthly, by the way, because we know the half life of the drug is such that it really covers, as it were, a patient for that whole 28 days.

- [Dr. Martin] Oh Joe, can I make just a couple comments on what you guys are talking.

- Oh please.

- So you know, the functional high risk, we've looked at that in the CARTITUDE-4 study. So for the early relapse CAR T-cell study, and you know, the functional high risk people actually do quite well with a CAR T-cell therapy, much better than if they were randomized to the non, you know, the non immunotherapy based triplet therapy. So going forward we're gonna... There's some questions here about, well, what do you think TEC-3 versus CARTITUDE-4, that's gonna be fodder for our debates at least the next year until we get a lot of follow up. That's gonna be a big debatable thing for all of us. But so what we're gonna-

- [Dr. Mikhael] Godzilla, right?

- Correct. So, but what we're gonna look at in each of these is, you know, how does the tec-dara perform in those that have cytogenetic high risk, how does it perform in functional high risk, how does it, you know, perform in those people that are this age or that age or this beta-2 microglobulin or have stage three disease, et cetera. And we're gonna look at all those even though we don't do direct trial to trial comparisons. It might be that one is better than the other in some of these subtypes. We'll just have to see. We probably will not see a randomized trial between the two of these. Our practice in general at UCSF has been to take patients who have early relapse, especially those that have Len-refractory, that's on the label for cilta-cel, is to try to do CAR T-cell therapy. Mostly because it's one and done even though you do have to get IVIG afterwards, but then they're off therapy. And really a year or two years when you're off therapy, the quality of life is different. Patients feel very well when they're off therapy for, you know, one or two years. And Donna told you they have patients at Sinai and we have some at UCSF that have been off therapy, have the original CARTITUDE-1 study five years, five years down the road. Those people don't remember what it was like when they had myeloma in the past. And that's what we would like to make it for everybody. Just, you know, again, wouldn't that be great? So, my personal opinion is CAR first, bispecific second, but it is a close race. It is a very close race and it really depends on what the patient wants.

- I completely agree. You captured so many things in that Tom, perfectly said. I would add two final comments before we move to our next section. One comment and then one question for you Tom. The comment being that the one area that we don't fully know is in the MajesTEC-3 study, only 4 percent of those patients had seen daratumumab before. So if I have someone who's relapsing, let's say on daratumumab and lenalidomide together, obviously we wouldn't, I mean it's still not FDA approved yet, but that would be someone obviously I wouldn't think immediately about that tec-dara combination 'cause we haven't been able to demonstrate that. So I just wanna make sure that's added here 'cause I know that's come up a couple of times in questions. The last question I'll give to you Tom for the one minute we have in this section before we move on is, someone's asking, "Can you further explain the ALC thing?" You know, it's something that is challenging for people to wrap their mind around and maybe you can just explain it one more time.

- Yes, absolutely. So in CAR T-cell therapy as part of lymphodepletion chemotherapy, the patient receives fludarabine and cyclophosphamide. The goal of that fludarabine and cyclophosphamide is to basically kill off a lot of the lymphocytes that are currently in the patient's body so that we quote unquote make space, but also don't have these immunosuppressive lymphocytes around so that when you enter in the CAR therapy, they have a warm bed to welcome them and they will sit there in the bone marrow and start to grow and not be suppressed by any other cells. So the absolute lymphocyte count, typically in the first week after CAR T-cell therapy goes pretty close to zero. So that's part of your white blood cell count. The lymphocytes are part of the white blood cell count. Often on Epic, if you can see your results on Epic. On Epic you'll get an absolute lymphocyte count, what the number is, it usually gets close, it might be 0.1 or 0.3, it sometimes goes to zero. But then over time it starts to climb up and typically starts to climb around day seven or eight after CAR T and it goes up to 0.5 and 0.7, then one, then two. Then if it gets greater than three, that is considered our normal range up to three. If it gets over three that's called a high ALC, that's considered a rise. That rising ALC, that rising lymphocyte count is CAR T cells growing. They're proliferating, they're growing in the bone marrow, they're spilling out into the blood and you see that rise in the blood. We've had somebody's white blood cell count rise as high as 20 or 30,000 and those are all CAR T cells in the peripheral blood. It's really amazing actually. And back in CARTITUDE-1, Donna probably did the same thing. We used to go in and high five them in the room and say, "You got 20,000 CAR T cells in your blood, this is awesome." But we don't high five them. We tell them you got a lot of CAR T cells, we might need to mitigate those. We might need to try to knock them down a little bit and we try to do that maybe with some dexamethasone.

- Well said. Thank you for that explanation Tom. Because I think what we think is maybe going on is that some of those CAR Ts, when there are so many of them, start to traffic in other places where maybe they're not really supposed to be like the brain.

- Yes.

- And that it may cause some of these side effects. Alright, well let's move to section three. We have about 25 minutes left and I want to come to the other abstract that was probably incredibly exciting for people is this notion, I've seen a couple of questions already come in about in vivo CAR T. So I'll talk about in vivo CAR T. A few other new CAR T products. One of them we talked a little bit earlier about and then some interesting combinations that use bispecific antibodies including the tec-tal combination. So to me this was sort of from a myeloma nerd standpoint, but this was arguably the most exciting data that we saw even though it really is only giving us information on three patients. But what our friends in Australia did is they really presented the first in vivo CAR T. Now, for those who aren't familiar with the term, let me quickly explain. As we've explained a few times tonight, and Tom beautifully just described, when do we do CAR T-cell therapy right now, the classic so-called ex vivo CAR T, we take T cells out of a patient, we manufacture them in such a way that those T cells will now express a receptor on the outside of them. That's why it's called CAR, chimeric antigen receptor. And those receptors are gonna be specific when they get back into the patient to go after that patient's myeloma like BCMA. And so right now that takes time. We have to collect the T cells, we have to go through the manufacturing, which is four to eight weeks long. We give the patient, as Tom just said, the chemotherapy to reduce their own lymphocytes. Then we give them their T cells back, then those T cells expand and they go and destroy the multiple myeloma. In vivo CAR T tries to skip most of those steps and says, what if I just give a drug directly to a patient that goes into their system, finds their own T cells, and basically converts them into CAR Ts by having those cells express that receptor on the outside to go after their myeloma. So theoretically, I mean it sounds like I'm describing a science fiction movie, but theoretically it's a brilliant concept. And pragmatically they showed that it happened. In their first three patients, who, by the way, were all high risk, were all heavily pretreated. All three of them were MRD negative within the first month, which was dramatic. You can see how their levels of their disease dropped here. But what was even perhaps further exciting to me, and I'm getting interested to see Donna and Tom's take on this in a couple of minutes, was in some ways not surprising. Not only was it quicker to deliver, it seemed to be safer to deliver. There was less CRS, there was less neurotoxicity, and in fact there was no delayed neurotoxicity. But there was even less low blood counts, maybe partly because they didn't have to give that lymphodepleting chemotherapy. So I don't wanna change the world based on three patients, I understand that, but what a dramatic difference to see that in these three patients. And so it'll be interesting to see what the team thinks about this in a minute. On the subject of novel CAR Ts, we saw an update from a study that got a lot of press last year, the Anito-cel study, Anitocabtagene autoleucel that was presented by Dr. Krina Patel at MD Anderson. And what was different about this one is this is a CAR T that has a different binding mechanism to the myeloma cell, what we call the D-domain binder here. That at least theoretically is going to be able to adhere more tightly and more carefully to the myeloma cell and not other targets. And be able to be more, if you will, specific to the multiple myeloma. And the update from this study remained impressive. In over a hundred patients, we still saw a response rate of 96%. We saw that at six... Remember these are heavily pretreated patients. At one year, 82% of patients were still in remission and 62% were still in remission at two years. So it tells us that the progression-free survival is gonna be, you know, definitely above two years and 83% of those patients were still alive. Arguably the most remarkable outcome though was that they had no delayed neurotoxicities. So there were no cases, granted only 117 patients, but still that's, if we think of the incidence of that being in that one to two percent range, they haven't seen any and they didn't see any of the cranial nerve palsies as well. So that may speak to the safety of this drug. We also saw the same drug we talked about earlier, the same CAR T we talked about earlier, that dual targeting CAR T that targets BCMA and CD19 at the same time, the AZD0120 study. We saw an update from them in their relapse study. And again, just to show that this is that dual targeting, that it has full CD19 and BCMA. And again, interestingly, they did not see as much toxicity as we typically see, no delayed toxicities. Granted the numbers here aren't massive yet, so we need time. But the preliminary results were quite impressive, especially because we also saw a 96% response rate in those patients who were treated. And interestingly they even had a few patients that had previously had BCMA CAR T. Thirdly, I want to talk about the Tal-tec study. So I know we've talked a lot about teclistamab tonight, but it definitely was the bell of the ball at ASH this year. But this was an interesting combination for a few reasons. One, it was using tec and tal together. So now we're using talquetamab, which is a bispecific antibody that targets the GPRC5D target on the surface of a myeloma cell. But they wanted to see if, can we give these two combinations in arguably the hardest type of myeloma to treat, which is patients with extramedullary disease, or EMD for short as we call it. And interestingly, Dr. Usmani presented this work, and it was also published in the New England Journal right after the presentation. And so here they gave patients every other week talquetamab and teclistamab at these doses. And for patients with extramedullary disease, I would argue this is probably the best result we've ever seen, where almost 80 percent of patients had a response. Over half of them achieved complete remission. And it was a durable response that we saw, that at a year, 57 percent of them were still in response and 75 percent still alive. Have to remember with true extramedullary disease as defined in this trial, typically this is a very aggressive course for patients. And then lastly, I thought it was interesting to bring in yet another bispecific antibody that's being developed, and Peter Voorhees beautifully presented the etentamig plus pomalidomide study. We talked earlier again about the feasibility and the importance of combining different mechanisms together. I'm always a bit fascinated by etentamig, because it's a bispecific antibody that right from the start is given once weekly that seems to be able to be administered more safely and possibly even always as an outpatient, which will make it easier for the community. Both Donna and Tom noted the importance of giving treatment in the community and not just in the large academic center. And so here is etentamig, and because of its binding mechanism that they think is what's partly related to the reduced cytokine release syndrome. And again, early on, not massive numbers of patients, but still overall in 82 patients we see an 82 percent response rate, which again is in late stage disease. So quite impressive to see the combination of those two together. So in summary, from our late relapse, this in vivo CAR T is I think quite exciting and interesting. I always talk about the I in IMF being international. Is this a way that we're going to be able to deliver CAR T more feasibly in centers without having to do the apheresis, without having to do all of the things that we do now with CAR T? I was fascinated by both anito-cel and AZD0120, and how we have, if you will, almost like a next generation of CAR Ts that have different binding ways and different ways of adhering to the myeloma cell. That combination of tec-tal seems to be quite potent in extramedullary disease. And among all the other drugs that we know are coming, it was fascinating to see that etentamig was a novel bispecific. I was tempted to add a bonus abstract. I didn't put it in, Tom and Donna, because I know we're running out of time, but I was fascinated by Adam Cohen's study of doing a CAR T cell therapy and then giving limited duration cesvostamab to get patients into MRD negativity. Yet another bispecific antibody being used, but with this idea of a short-lived space, that cassette that Dr. Lonial commented earlier. And that almost made my top five here. But there's just obviously so many things to discuss. So with that, I'll just comment that I love this slide even though it's hideous and it's getting more complicated and it's filled with words. I just love that we are growing and growing our numbers of options as we treat patients. But let's turn to our experts here, and Donna, floor is yours. Donna, what do you want to comment on? Feel free to comment on any of these. I hope you're as excited as I am about the future of myeloma and maybe how in vivo CAR T could be a part of it.

- So the in vivo CAR T is actually my favorite abstract of the conference. Again, three patients with the fourth one which, or some follow-up there. But it just shows the innovation that's happening and that it's moving us into the future where we can get CAR T therapy quicker to the patient, eliminating the apheresis, eliminating the lymphodepleting chemotherapy, which you know, that chemotherapy also has side effects and causes low blood counts. So this is just showing, it's a proof of concept that this is something, it's innovative, and access to care so more patients will have access to CAR T. So that's what really excited me, but this was my highlight of ASH, is showing innovation is still happening. And then we have anito-cel and-

- [Dr. Joseph] So Donna, just before you jump to anito-cel, let me just add to what you just said. We probably should have figured out how innovative they were when they came up with the name of the trial. I saw that someone asked that in the chat and they asked it probably 'cause they know that I love the name of this trial. I don't know if you saw it when I put the title slide, but it's called "inMMyCAR" with two Ms. I mean that in itself, you know, has to make it a pretty cool abstract. But anyway, I didn't mean to interrupt you.

- No, no, no. I love it. And then you know the novel CAR T, so the dual targeting CD19 BCMA, which I thought was interesting that patients who failed BCMA CAR T responded to this CAR T. So it shows that patients can get more than one CAR T. So I think again, another being innovative and approved that we can do multiple CAR Ts. And in addition to the anito-cel, I think our biggest fear with CAR T, especially in the earlier lines, some of those late neurotoxicities. And yes the numbers are still small, but we're not seeing those late neurotoxicities in these next-generation CAR T. So really excited to see more follow-up on these two assets.

- That's fantastic. Tom, what's your take on all this? Are we entering into a new era of, you know, the next wave of CAR T in vivo dual targeting, D-domain binders? I mean, does this excite you? I know you're a nerd like me and this stuff does excite you, but tell me about what you think about all of this.

- Yeah, I agree with Donna. So the in vivo is probably also my favorite abstract at ASH, just for CAR T to be off the shelf is pretty amazing, right? And it also begs the fact that can you do it more than once, within a short period of time? Can you give 'em an in vivo CAR today and then three months later target a different antigen and give 'em a second if they still have any residual disease. I mean the future is just so, so bright with the things that we have. It's amazing. I do think that you point out two things. One, I think the CD19 BCMA CAR may actually end up being best in class just because of the rapid manufacturing. And we hopefully will not need bridging-based therapy. They're gonna be able to get us back that CAR T-cell product within 14 to 17 days. So that'll come sooner than in vivo CAR 'cause it's already in, you know, clinical trials and in phase three clinical trials. And then the etentamig, that actually, that antibody was made by a UCSF pathologist's dad's company and he left UCSF to go work at his company. And so, the special sauce there was that you can give it once a month. Now you could go right to once a month and that you wouldn't actually have to do any step-up dosing. They are trying, they are testing step-up dosing now. But the truth is, is you might be able to do that CAR with... Without a step-up dose, one dose that you have to watch out for CRS, and then it's monthly thereafter. That could be the easiest in class for BCMA bispecifics. But I think it shows the point that again, combining bispecifics and even CAR T-cell therapies with other drugs to make them more effective, whether it's BCMA CAR T-cell therapy with a cevostomab or iberdomide, a CELMoD, or combining BCMA bispecific or GPRC5D bispecific with iberdomide or pomalidomide. I think that's gonna be the way we move forward. We have a trial at UCSF that is the combination of talquetamab, the GPRC5D with iberdomide. We're just starting the trial and we're still looking for more people to join. But that is again an excitement where we take something that's gonna activate the T cell together with one that's gonna bind to myeloma and bring the T cell there and hopefully get a better kill. Amazing. What we're doing is really fun.

- It's amazing. I mean literally if we'd had this conversation five years ago, you might've thought that Tom and I were a bit crazy. You know, Donna was asking us these questions. We'd be like, "What? You're actually gonna be doing that?" And we are doing it. And I think the themes that everybody are hearing tonight is that we have, you know, newer versions of the treatments that we have, but we're also trying to use them more intelligently in combination and hopefully for limited duration. I know this has come up a couple of times and I just cannot help but think about our patients who have had, you know, CAR T and are off therapy. Or some of our patients now have been on bispecifics for 12 or 18 months and come off therapy, how they love being on nothing. I was joking with a patient in clinic yesterday that it's my favorite prescription to fill. Nada. You know, it's amazing. Every insurance company covers it. Everybody's 100 percent adherent to receiving nothing. You know, and Donna, with so much of the great work that you do at the nurse leadership board, as you track patients' quality of life, it is exciting to talk about all these great and sometimes intense therapies. But maybe you can comment for a minute on that idea of being able to give people nothing.

- Right, and that's what we saw with CAR T therapies. Those patients who are long responders, five years out, they're on nothing and they're back to their pre-cancer diagnosis quality of life. And then speaking to the point of bispecifics, that fixed duration, we have plenty of patients here at Mount Sinai where they received a, you know, they're no longer on bispecifics, yet a year or two out, they're still in remission. And again, returning to that quality of life. So I think, you know, moving forward we need to figure out how long do we, you know, how long are we treating with bispecifics. Patients are really getting their quality of life back to pre-diagnosis. And that's so great to see. And I think that's important too when we consider, you know, our treatment options.

- Yeah, and let me add to that 'cause I know that tonight I didn't have a chance because there weren't any oral abstractions. 'Cause we've heard so much about belantamab over the last year and we saw it just approved. I want to bring belantamab into this conversation because when you talk about quality of life, you know, it is an agent. I know we have some challenges with the eye-related side effects, but you know, I think we've really overcome the vast majority of those. And I know Tom, you and I have talked about this a lot about how, you know, if I were to give it to someone tomorrow, give it today, give it in four weeks, and then every eight to 10, 12 weeks thereafter, we all have patients in our practice. I joke about one of my patients who literally smells the bottle of belantamab every six months. She only needs to be dosed twice a year. That's also something I think to factor in because it's such an easily delivered drug. We don't have to worry about CRS, we don't have to worry about, you know, ICANS and these other things. I mean, do you think Tom, there's still going to be an important role in place for belantamab?

- Absolutely. And the other thing is that with belantamab, it's a much lower signal for infection compared to these other BCMA bispecifics and also CAR T cells. And so the convenience plus the low risk of infection, I think will actually promote its use, especially in patients that... So the approval is for two or more prior lines of therapy. So they've had two or more prior lines of therapy, they can get on belantamab, bortezomib, dex. You know, the combination of bortezomib, dex did show in DREAMM-7 a really good PFS of over 36 months and an improved OS compared to the competitor arms. But we worry about the neuropathy. And what I would say to that is then you have to either dose reduce the bortezomib or you could potentially have people come off the bortezomib and just give belantamab, because belantamab is given quote unquote maintenance, and I think it's going to be a well-used product. I think all of these products have its place in myeloma therapies.

- Donna, any feelings about belantamab as well?

- Yeah, and I think it's another good drug that we can give easily in the community and not necessarily dosing as frequently. I have patients on every three months and are doing fantastic. Multiple years out on receiving belantamab. So I think this is an easy drug to give, great for community settings if patients don't have access to the large academic centers, you know, and we're seeing really deep and durable responses with belantamab.

- Fantastic. Well, this was great. I mean, I wish we had time to answer all these questions in the chat. Someone asked, by the way, that tec-dara is not yet FDA approved. The FDA has received the file, it's being reviewed. So we hope that in early 2026, we may see it approved. But one last question I'm going to ask you, Tom, and I say this a little tongue in cheek because Sagar now has left. Someone asked really a fantastic question here and said, "In light of all of what's come now with these BCMA products, where does autologous stem cell transplant fit?"

- That's a really good question. So, and I think it is good that Sagar's not on here because he's very pro autologous transplant, but it is our most toxic therapy, unfortunately. And, you know, we are getting very good progression-free survival in patients just getting quad or even triplet-based therapy with CD38 plus lenalidomide and dex, and PFS is over five years. If you take that and you say, well then I'm going to give them tec-dara after that, and the PFS is now going to be maybe longer than that, maybe seven to 10 years. Then those two lines, line one and line two together, we're looking at a pretty good duration of remission during those periods of time. And does autologous transplant add to that? I don't know. I'm still doing autologous transplants in those that I think are a good fit, young. If anybody's not young or not fit, for sure, it's not in the algorithm anymore.

- Yeah, I think that's a fair thing to say. You're the champion until someone knocks you out, and we'll see these coming studies where they're directly compared. But I agree, I think we want to be careful in how we use it and we don't want to overuse it. Well at this point, believe it or not, our time is just about gone. I'd like to take a moment quickly to thank our sponsors again, AbbVie, GSK, Johnson & Johnson, and Sanofi. And I noted this before, but please provide feedback if you can. And also for the 60 of you whose questions I didn't get to, please don't worry. We capture all of these questions. In fact, I'm going to spend the day tomorrow in the studio in Los Angeles answering a lot of these questions. So we love questions at the IMF. Please interact with us on every social media possible, whether it's X, LinkedIn, YouTube, Instagram, Facebook, TikTok. Just find us and ask a question with the hashtag, #asktheIMF or at these live meetings or virtual meetings. We'll do our best to try and answer as many of these questions as possible because we know that that is really important. But we do want to hear your feedback, and of course, this is being replayed. If you've had the chance to watch it live with us tonight, great. If you're watching the replay already, thank you. Share this with your friends, it's easy to find at myeloma.org. Look under IMF videos and you'll see the IMWG conference series. And with that, I just want to close by saying it's been a privilege to share the stage with you, Donna. I love every time we get to work together. Tom, BFF for many, many years. Thank you both so much for your commitment to your patients, for your commitment to the myeloma community. It's been a privilege to have you with us tonight.

- Thank you, Joe.

- Thank you.

- It was nice seeing you, Donna.

- Nice seeing you.

- And thanks everybody for joining us. Please stay tuned for more live and in-person meetings that we'll be having over the course of 2026. We've just planned out all of our patient family seminars, our regional community workshops, our virtual workshops, the post-conference series, our Living Well series. I could go on and on. There's so many different ways to interact with us at the IMF. We're very grateful for you. Thank you again for joining us tonight, and have a great night.