Good evening. Welcome. I'm Rami Elghandour. I'm the Chairman and CEO of Arcellx. It is my pleasure to welcome you this evening to our investor relations event here in Orlando, Florida at the 67th annual ASH meeting. Before we get started, a look at our forward-looking statements. In terms of our agenda for this evening, I'm going to kick things off by talking a bit about our company. I'll particularly focus on the evolving multiple myeloma landscape, which I know is of interest to a lot of folks in this room and around the world listening in. I will then of course talk about how excited we are and some of the plans we're making for our commercial launch. I then have the privilege of inviting Dr. Krina Patel to the stage. She'll share the latest results from our iMMagine-1 registration phase two study. She presented those results earlier today at the ASH Medical Congress, and we're fortunate to have her share those results again with us this evening. We'll then be joined by our Chief Medical Officer, Dr. Christopher Heery, who will moderate a physician panel where he'll be joined by Dr. Patel, Dr. Frigault and Dr. Anderson. And last but certainly not least, we'll be joined by our Chief Financial Officer, Michelle Gilson. And we'll open it up for your questions. At Arcellx, we are a different kind of company delivering a new class of CAR T. I joined Arcellx almost exactly five years ago and I joined precisely because of this image. What you're looking at is one of the earliest patients treated with an anito-cel. This patient had extraordinary amounts of extramedullary disease, 95% bone marrow plasma cells and was really truly months away or had only a few months left to live. This particular patient resolved all of their disease within one month of dosing with anito-cel, and truly when I saw that, I thought it was nothing short of miraculous. This patient is now approaching six years of progression-free survival and stringent complete response. And that miracle wasn't a one off. What you just looked at was patient three in our phase one study. This is patient one. Patient one had a very similar course or prognosis. He was also an elderly gentleman. He had extensive extramedullary disease and coincidentally the same level of EMD. This particular patient, you might ask yourself why would they volunteer to be the first person ever treated with a new modality like this? Besides being fortunate enough to being Dr. Goggins' patient and having an excellent physician that gave him this treatment option? He was a photographer and still is a photographer. He wanted to travel the world and be able to pursue his hobby. He was concerned that both, A, the alternative therapeutic options available to him might compromise his vision and B, he wanted the freedom to be able to live his life. We are so grateful for Dr. Frigault for giving that patient and for us this opportunity to prove out this therapy, which has been, again, to me and to a lot of the patients who have had the benefit of it, nothing short of a miracle. Five years later, I am beyond confident that we are creating a new class of CAR T that is absolutely the best treatment option for patients suffering from relapse and refractory multiple myeloma. I believe that because we're bringing the best of both worlds together. From the CAR T side, as we just talked about, the ability to deliver that treatment-free interval in a single dose, the depth and durability of response that you just saw is something truly the benefit and the idealism of what CAR T can deliver for patients and the physicians treating them. However, from bispecifics, we also are able to deliver the low CRS, low ICANS, the ability to broadly deliver a therapy and to make it abundantly available. And combining those two things is why I believe anito-cel is truly and uniquely differentiated in its ability to deliver efficacy, safety and scale and broad adoption, which we'll talk about quite a bit. And you can see that. Oops. Hang on, we got some technical difficulties here with the slides. There we go. We can see that in the data. So on the right hand side of this slide, you could see that from an efficacy perspective, A, CAR Ts are well ahead of bispecifics and B, anito-cel is clearly at the top of that stack in every measurable way. On the left hand side of this slide, on the safety side, if I blinded the purple bars and I asked you what modality you think that is, you probably would have guessed that it was a bispecific. But it's actually a CAR T certainly as it relates to CRS, ICANS, and delayed neurotoxicities. But when we get down to infections and non-relapse mortality, we actually feel like we are at the top of the stack again in a very differentiated way, whether it's from bispecifics or CAR T's. Now, with all the caveats about comparing, you know, cross-trial comparisons, this is a very compelling data set that again uniquely positions anito-cel in a different class from everything that is available for patients and physicians. The other thing that we know about bispecifics is that their results don't hold up in the real world in the same way that CAR T's do. And the reason for that is they have a fairly narrow therapeutic window. Meaning that what we see in the real world is that perhaps in clinical studies the protocols are written in such a way to maximize efficacy, but it comes with a fairly serious detriment in safety. We saw a recent study with an over 50% infection rate as an example, so maybe in the real world, when you're trying to titrate and spread out some of those dosing regimens, you're going to certainly address some of those safety issues, but you're going to compromise efficacy, and we don't see that sort of degradation with CAR T for all its promise. There's one other thing that I find curious about the bispecific category, which is this perception that it could drive or sustain broad adoption. When you look at things like this, like a two times increase relative to CAR T increase in mortality, a three times or threefold increase in ICU hospitalization, and a three- to four-time increase on a relative basis again to CAR T and non-relapse mortality again. If I asked a casual observer who happened to be knowledgeable in this field, do these appear to be the characteristics of a therapy that can be broadly adopted? I think the answer is decidedly no. Now, now some of you are probably thinking, I knew that I knew this about bispecifics. I mean, I'm in the know, I follow these things. But. We've certainly seen some combination studies that at least on the surface appear to be intriguing. Now, if you know all of these things about bispecifics relative to CAR T and you're suddenly seeing results in a combination study that appear CAR T like, where might those results come from? It's not magic, right? They're not coming from the bispecific. They're coming from one of the most incredible drugs in the world, Dara. Dara is so incredible that if you add it to almost any regimen, you get a two to two and a half times increase in pfs. So it's not magic, it's Dara, which is kind of magical. It's an incredible therapy. Now the challenge with that is that if the more Dara refractory patients you add to a clinical study, naturally, the less effective Dara is going to be. Right? We already know that. What is the challenge with all this? Well, the challenge is that Dara is so incredible it is being overwhelmingly used in frontline therapy, right? DVRD induction, DVRD maintenance, that is the standard of care. So the question is, if you're running studies in a population that is not at all proportional to the real world in its third-refractory participation, how realistic or how clinically relevant is that? I want to close with a couple of different thoughts. First, this is exactly why we ran iMMagine-3 the way we did and designed it the way we did. As a reminder, we are running iMMagine- 3 in a dual-exposed population, anti-CD38 and IMiD-exposed patients. There are no restrictions on Dara refractoriness unlike we've seen in other studies. And we made a real world control arm in that we've offered KdD as one of the control regimens for all of these reasons, the profound impact of anito-cel, the real world applicability of the study. This particular trial is enrolling at an incredible rate and we're very excited for its potential. Two more thoughts before we transition into the commercial landscape. CAR T for all of its challenges pre anito-cel, the delayed neurotoxicities, the. Relatively limited footprint, the launches that have been challenging has continued to grow in a really meaningful way, even beyond the scope of its footprint. Conversely, bispecifics, for all of the excitement, have been relatively flat, and they're actually a little bit worse than flat because as you could see, the number of centers that bispecifics are offered in are significantly higher than CAR T and they keep growing. So if you have a growing install base and flat revenues, it means that you are declining on a case by case or an account by account basis, right? Which speaks much more to the reality of the data that you just saw versus perhaps the percentage. Then the last point before we transition to commercialization is that again, we truly believe that anito-cel is uniquely positioned beyond anything else out there in terms of modality. It really is a new class and it doesn't happen often, but every once in a while you get a therapy or a product that truly redefines a category and is mass adoptable. So I've got an iPhone in my pocket here. I've had an iPhone since the first day they came out in 2007. Before the iPhone, believe it or not, for those of you who are old enough, there were smartphones out there. I had a Palm Treo. Some of you might have had some Sony Ericssons. So smartphones existed, but everyone didn't have them because the unique combination of attributes required to drive mass adoption did not exist. Same thing happened when Windows came out. Drove PC adoption in a huge way. And going way back, since I'm a car guy, the Model T scale manufacturing changed the automobile industry. An interesting tidbit that might be somewhat related to CAR T. Believe it or not, Ford had greater than 50% market share in the U.S. at one point because of that manufacturing advantage. In the therapeutics world, the same thing does happen as well. Think about checkpoint inhibitors, right? Yervoy existed. They weren't broadly adopted in the way they are today, thanks to Nivo and Pembro. And there was a point in time where people didn't believe that checkpoint inhibitors could be adopted beyond the academic setting. And they've since come on to become the greatest oncology drugs of all time. That's how we feel about our anito-cel. It is that different. It is that differentiated. It is that good in our view from a patient and a physician perspective. And it has that kind of potential to be a category defining therapy that can impact enormous amounts of lives. And that is why we. We are so excited to launch anito-cel. As I mentioned, I'm approaching my fifth anniversary here. It'll be in January, and going way back, my first hire when I started five years ago, which some people thought was a little crazy, was our Chief Commercial Officer, Neeraj Teotia. Now Neeraj and I are good friends. This is our third company together, and we vowed we would launch this therapy, and here we are, and we are really, really excited to do it for the reason that I mentioned. We really believe we can make an enormous impact for patients and physicians, and this therapy is the best available option for them. To do that we have to deliver in a big way, and we're fortunate to be partnered with Kite, the best in the world at doing that from a scale reliability and abundant supply perspective. Of course we are going to continue to run the right kind of studies that are going to actually impact clinical practice and lead to expansive use of anito-cel. So let's touch on those three points. The first is a slide that should be familiar to most of you, hopefully. We presented this slide at EHA and it helps you build how we arrive at our $12 billion second-line+ market and $20+ billion frontline+ market. And you can see that because we've outlined for you here our class share assumptions, not anito-cel share, but class share in each of those lines of therapy. And one thing that might jump out at you for everything that I said about our anito-cel is that our class share assumptions are actually quite conservative. All right. We are not assuming massive share capture by CAR T at this point in time. That's something that we do hope and expect will come with time. But the way we've built our market model leaves plenty of room for bispecifics or bispecific combinations of any sort to play in the market. That is not necessary for us to realize from a business perspective a significant market opportunity. Having said that, if you ask me, I do believe we are going to overachieve these assumptions because again of the uniqueness of anito-cel. And like all disruptive innovations, we are going to expand the market because as I gave you in all these examples, that is what disruptive innovation does. Again, to be able to do that we have to deliver and we have to deliver in a multitude of ways. First, supply. And we believe that we're going to have abundant and enormous supply. You've seen this from our partners at Kite. Again they have the capacity of up to 24,000 plus doses across all of their products, including anito-cel. And that capacity is something we believe we will need over time given the strength of this program. But you have to be able to be reliable. You've seen that Kite's commercial manufacturing is in the mid- to high 90s% in terms of in-spec rate. We expect again in line with our commercial experience with anito-cel, you have to be able to turn it around quickly. We expect a median turnaround time approximately around 17 days. One of the most incredible things I've seen, frankly in the last five years I've been here, is take this technology and this therapy and immediately hit this mark of 17 days from the very first patients enrolled in iMMagine-3. No adjustment period, no time, just immediately from the ground up to be able to do that. And that kind of competitive advantage is hard to quantify but I can tell you it is very, very real. We also expect to launch in the largest footprint at launch of any CAR T therapy. And the way we're going to do that is to make it incredibly convenient for our clinician partners. We've been in a lot of physician meetings over the last couple of days and I can tell you the excitement is palpable for this therapy to come to market. But one example I'll share with you is that a physician was going down this train. "I'm so excited for this. We're holding patients for anito-cel. We can't wait. But oh no, we're going to have to integrate a new system and we're going to have to figure out new slot booking," until one of our colleagues at Kite in the meeting gently just jumped in and said, "you're going to be able to still use Kite Connect." And to tell you the visible physical relaxation that this particular physician experienced at the reminder that they're going to use the best system that they're most comfortable with to utilize anito-cel was pretty incredible. We're also excited to share some new information with you as it relates to our clinical trials. First, as again you're going to see here momentarily, Dr. Patel will share the latest results from iMMagine-1. I already commented on iMMagine-3 and how incredibly that study is going, but there's two new pieces of information that are very relevant and we're excited to share. The first is Anito-First. Anito-First is our phase two safety lead-in for our frontline study, iMMagine-4. And that study is now fully enrolled thanks to Dr. Mateos and the team in Spain. They've done an incredible job of prioritizing the study and it is going to be really a valuable forward step for us to utilize anito-cel again for every patient who can benefit. iMMagine-4 will start once the Anito-First study reads out. We're also excited to announce that we'll be running iMMagine-5. That study will be run post approval and it is meant to engage the community again. We've talked a lot about the community over the years. We believe we have the kind of therapy that can be adopted in the community if you can dose bispecifics. You saw again from that safety perspective that we are in line or better than bispecifics across every safety metric. You're likely going to be able to dose CAR T at some future point in time. So this is an important opportunity for us to demonstrate that anito-cel is the kind of therapy that can travel and can really impact many more patients than even we have forecasted to date. From a commercial perspective, there's a couple of updates that are very relevant. Again, we just could not be more excited for this commercial launch. Especially we felt like after this data presentation, given the strength of the data and that given that the launch now is measured in months, not years, we're really, really excited to be here and I will first share that we have built an incredible sales and medical affairs leadership and team overall at Arcellx. We feel like we have the best in category therapy and it should be represented by the best in category team. And we absolutely have that, so excited to have them on board and so excited to see the team they are going to continue to build. We've also just felt incredibly grateful for the response we've seen as we've engaged accounts to bring an anito-cel to the market as rapidly as possible upon launch. As you can see here, some of the numbers, 82% of ATCs engaged via our pre-approval information exchange already, which tells you again, we are going to be ready to go at launch to make sure this therapy gets to the patients who need it most. We've also had an incredible reception from payers, administrators and physician partners to help us make sure that this therapy again is going to be massively accessible at launch, and then lastly, we're just also incredibly grateful for the feedback and support we've received from advocacy groups, from a patient side, from physicians, from investigators. They certainly are supporting us in bringing this launch again to as many patients as possible, but also giving us great feedback so that we can continue to do our very best for this community. You've heard me talk a lot about the therapy and about the impact and that is something that we certainly get up every day and feel excited. It is really, truly fulfilling to know that every effort we're putting forward is in the best interest of patients and physicians, and at the same time, there's another very meaningful thing that we're chasing from a legacy perspective and that is to build a meaningful business. We feel like if we can do that, which we're confident we can do, we can attract more investment in this space and that can help further impact many more patients. Are there any House of the Dragon fans in this room or listening on the webcast? I'm a big fan of that show and one of the lines that always sticks with me is what is this mortal life if not the pursuit of legacy? We have two amazing legacies from a patient perspective and from a future innovation perspective that we're pursuing. To wrap it all up, we could not be more excited about our anito-cel, which we believe establishes a new class of CAR T. It is leading from an efficacy, safety and deliverability perspective. We cannot wait to get it into the market and into the clinics in the United States and around the world. It is my absolute pleasure to then turn it over to Dr. Patel to share with you the results that are of the underlying basis for that belief. Thank you. All right, it's been a really long day today and so I'm going to sit, if that's okay. So I don't fall off the stage. At least our slides are here at this time. For those of you who saw that today. So thanks again for having me and I'm excited to present the data again. Maybe a little bit differently, but you know, again, lots of different options. The fact that this phase one study had 100% response rate, the depth of response is always really important. And 79% stringent sCR rates is fantastic with that 30.2-month, you know, PFS which again this lines up to our CAR T therapies and where we really think our BCMA CAR T therapy should be at. And so again this was a phase one study that did have, you know, different patient population. So going into the phase two, these were patients that were triple-class exposed. So prior IMiDs, PIs, anti-CD38s had to be refractory to the last line of therapy, had at least three prior lines or more and had evidence of measurable disease. So now we had to have the IMWG measurable disease and the overall response rate was the primary endpoint. And again depth of response, stringent CR rates and then overall response rates in those patients that are prior to three lines of therapy. And something I didn't mention earlier today, with this patient population, obviously even in early line therapies, our patients are much more refractory and exposed to a lot of these therapies, you know, instead of sixth, seventh line by the time they get to penta-refractory, because our practices have changed that patients get these things a lot earlier and they tend to have more aggressive disease earlier. And so, out of the patients that were enrolled, we have a median follow-up of 15.9 months by the IRC evaluation now, and 129 enrolled and leukapheresis, and then 118 got lymphodepletion. There were patients that discontinued for multiple reasons, but again, 118 got lymphodepletion and 117 dosed. Only one patient that did not get dosed, and manufacturing was 99% successful, which was fantastic. So again, looking at the patient population, of course, as an academic physician and researcher, you know, we don't ever do this, but people ask me about it all the time. So here are the numbers for you. I think, you know, the age patients, the 70 or above I think is really important considering myeloma is diagnosed for most people at the age of 69. So it's really important that we know how our patients that are older do. African American patients, 15% represented here, similar to what we see in the U.S. population, and again depth of amount of disease, 18% had 60% myeloma or more in the bone marrow. Lines of therapy are lower, but you can see that most of these patients were still refractory for the last line. Triple refractory 87%, penta refractory 41%. Our patients are becoming much more refractory sooner because of the way we practice in first and second line, and then median time to diagnosis was seven and a half years, but bridging therapy was not required, but 76% of patients did get it. And again at least some patients were able to get it outpatient for the study, so overall response rate again fantastic, 96%, and stringent sCR are very comparable to the phase one study at 74%. Again, just like all CAR Ts, we see these responses very early. One month to get the first time to first response, best response by 4.8 months, and then time to that deep sCR 3.2 months. An MRD is very important for us in myeloma. Of course now we use it as a surrogate endpoint to get approvals hopefully very soon. But 94.8% at 10 to the minus fifth for our overall evaluable patients and then again 78.2%, 10 to the minus six with next generation sequencing. And then sustained MRD is obviously very important too. So we think PFS is related to MRD, but only for those patients who have continued MRD undetectability. And again at six months it's been 83.1% for all patients. And then, to look at the PFS, you know, again, you know, we are seeing the 24-month calculated PFS estimates that are around 60%, 61.7%. Currently, the same thing with overall survival at 83%. And then safety again. This comes back to, you know, how applicable is this for the outpatient side? You know, my patients really want to come. Are they going to get of toxicities? And really the CRS is what helps us make things outpatient. And so the fact that, you know, 95% of patients have either grade one or no CRS is really important for us. We can do that with our eyes closed when someone has grade one CRS. And then the fact that there's not really much ICANS, very little ICANS, and if it was, it was grade one two is really, really important. Then of course the no secondary primary malignancies, no other deaths that we've seen since our last presentation and then really the no Parkinson's, all the delayed neurotoxicities that I do have to tell my patients about right now. We didn't see any Parkinson's, cranial nerve palsies, Guillain-Barré and again, one of the more recent findings in the last year to immune effector cell-associated enterocolitis. You know, in the myeloma world, we are saying that we're coming up with new diagnoses now. And in this CAR T with the anito-cel we haven't had to deal with any of that, which has been actually really nice. And so again, coming back to the CRS, 85% of patients who did have CRS, the onset was four days and then 83% had less than grade one, including 15% of the patients with no CRS. And again it resolved within 10 days of an anito-cel infusion. So it all happens in that first two weeks, which again with the REMS approvals at two weeks, that makes it a lot easier for us to get these patients back home. So I'm not having to wait for all of this stuff to, you know, resolve by the time they get to day 30. And then again, no ICANS is actually very, very exciting to see. And then the 0% of delayed neurotoxicity. So again having anito-cel being a different in terms of the D- Domain splitting, high transduction efficiency, a lower cell dose and the majority of those cells being CAR positive, which I know what I'm giving to my patients, that overall response rate still improving 96% with that deepening of that CR and stringent CR rate now at 74%. Again, great MRD data, 95% patients who are MRD negative at 10 to the minus 5th and 83% that were sustained and then again median PFS, overall survival not reached, but 24 months, we think it's about 62% and overall survival at 83%. So really the lowest rates of safety, high-grade CRS and low-grade CRS is very low as well. And then none of the delayed toxicities that we are currently seeing as standard of care CAR Ts makes this really, really promising for our patients. So again, we've talked about the iMMagine-3 already, but we are part of that as well. And I think it's a great study design. Yes, these patients are different. All of them have had an anti-CD38, which is what we do right now, and newly diagnosed. But I think the standard of care options are good options that I would be giving if I didn't have anito-cel for me to give otherwise. And so hopefully we'll have this data for you in the near future. Now I can have everyone else come up. I know that's great. Thank you all for joining us. Could I actually? Maybe I'll ask everyone to just introduce themselves so that everyone knows who everyone is. Dr. Anderson, could you start? Yes. I'm Dr. Larry Anderson. I'm the director of the myeloma program at UT Southwestern Medical Center in Dallas, Texas. Hi everyone, I'm Matt Frigault. I'm the Clinical Director of the cell therapy program at Mass General. I'm Krina Patel, myeloma section chief at MD Anderson. Krina might be losing her voice from giving so many talks. But maybe we could start out with something that's really high level. And I'm actually going to turn to you, Matt, to try to address some of those patients that we saw earlier. Could you just talk a little bit about what that experience has been like now six years on since the first? Patients enrolled in the study. It's actually. It's hard to explain. Very rarely do you get to give a therapy for the very first patients treated dose ever. First time a drug has ever been in a human being before is still in a response almost six years later, and we're having conversations with them. They're coming back. The biggest problem this person lives on one of the islands off of Massachusetts. In getting him to come back for a long term follow up, he's so freaking annoyed because he just wants to get his labs done locally, doesn't want to take the ferry, but he comes back and you know, the other patient we showed was patient number three, no, that was somebody who during most of his visits still to this day is so very thankful. He's like, I have my life back. I'm able to go places, I'm able to do things. You know, he is a big advocate for CAR T cells and we're seeing like those stories get passed on from one patient to another and then patients are asking for it and patients are looking for it and patients can't wait for that approval. So it's really powerful to be able to change someone's life like that. The last heartwarming part of it is I had one patient who just got a CAR T cell. Unfortunately she wasn't in the anito-cel study but she fortunately had a great response and she actually bought an RV and had her and her best friend drive to the West Coast together. This is the first time she didn't need to be getting therapy every two to three weeks. So I think we forget when we're thinking about overall response rate, PFS, CRS. We forget how much of an impact this actually has on people's lives. Krina, I think you told me a similar story, not necessarily about it in the patient, but why some patients and some of the things they've done. Could you share that? Yeah. No, I think they feel normal again. So the fact that they don't have to come see me every week or every two weeks for an infusion or making sure their counts are okay, making sure they don't have an infection, they can actually go hang out with their grandkids because they can get vaccines, and it works because they're not on therapy. And these are little things that our patients get to do now. But then one of my patients loves to travel, and he hadn't been able to travel for four and a half years, and the first thing he did after his CAR T is he went to Japan to go watch a sumo wrestling match, because that's when he loves sushi. And then he's been six times since in the last couple of years. So, you know, again, I take that for granted that I get to travel everywhere, and that's one of my favorite things to do. And I love Japan and Tokyo now. He's given me restaurants to go to. And so, again, it's just. It's so different than what the rest of our patients go through when they get to really feel normal and have an immune system and, you know, be able to be with their family and not worry that Christmas, if someone's sick, they can't hang out with them. And my CAR T patients are the ones that actually go and hang out with their families and have family reunions. So I think it's really, really big. From the small to the big. That's great. Dr. Anderson, do you have any similar experiences? Yeah, I mean. I guess I've treated 16 patients with this product on study, and I have nothing but really good results in these patients. And pretty much all of them have had great remissions and the longest time they've ever had off therapy. And I think the most important thing is just not having to deal with the delayed neurotoxicity. It's just such a relief to not have to see that in any of these patients. Yeah, that's really helpful because we've, you know, we've spent the better part of our conference as members of the Arcellx team meeting with physicians and trying to frame up what we're hearing about new data from different clinical trials, and so I'll ask sort of the same question to the three of you and we'll reverse the order this time, but you know, given data that's just from freshly becoming available, does it affect your decision making about when and how you might think about using CAR T or other agents, you know, just based on data available at this meeting? Yeah, I could start. Yeah. So the data that we have so far is so highly encouraging and personal experience as well. I have no hesitation moving forward with this product. So. And if it's available for anybody that, you know, I mean, certainly there may be, you know, it's always going to be a discussion with patients, the pros and cons. And you know, we don't have necessarily long, long term data yet, but we know the safety profile and many of our patients have a lot of hesitancy around the risk of adverse events with other products. And so I think there's going to be a lot of uptake just based on that. Can you repeat the question again? Sure, yeah. I was asking, you know, based on data that are available at this meeting or just over the last month or so, is there anything that changes the way you think about how and when you might use a CAR T? Yeah. So I think again, the safety piece of it is really important. And then the last couple of years, you know, we've seen again last year and a half maybe where we didn't see the colitis before. And now in our group, we've seen it in about 10 or so patients. And it just sort of, you know, again, the stories I just told you about these patients had such great outcomes. And then our patients that have MRD negativity and great outcomes but then have this horrible thing happen and the 40% mortality rate, it crushes us. It's like we were trying to do something so amazing for you, we thought we were going to kind of beat the disease down. But now I just shortened your life. Right. Or I gave you such morbidity. And even if it's not a high rate of it, when you see it again and again, it really puts you at pause. And so again I talk to my patients about it. I still say like, this is amazing. You can be off therapy. However, there are certain patients that might get this and I don't know if that's going to be you or not. And again, we usually go forward, but if I had something where it was different you know, again, amazing responses. But I think our goal is always to make things safer and then again increase the efficacy over time as well. So that's what I'm looking for now as the next, you know, CAR T's come through. And I think early line versus late line, there's a lot of differences of what we're going to be doing over the next couple of years. Yeah, for my standard risk patients, there are patients who are waiting to go to our selects, make sure they're to go to make sure that they don't have any potential side effects like that. I think in the last couple of years you've seen kind of the view of myeloma change a little, that I think over the last year. It's probably the first time I heard a myeloma doc say cure, which like when CAR T first came out, no one really believed. They thought it was like auto transplant. Eventually patients are going to relapse, and then we see with cilta-cel that the five-year PFS is, you know, over a third of patients are basically typically in ongoing responses, and then we start thinking, well, is this actually effectively a cure, but if you're going to be giving these non-ICANS neurotoxicities to one out of every 10 people, it's kind of a rolling of the dice, and so we're stuck between a rock and a hard place. For us and for patients, and patients see this too, you know, I'm excited to have a product one if I can get the patient on for clinical trials. Clearly we're going to be putting them on anito-cel if we can. But to have something that potentially has that same track or at least is looking like it's trending at least equivalent to, if not better than, what we're seeing with long, durable responses. As I said, I have patients now almost at six years without having to worry about all those other side effects, being able to send patients back to the referring docs without having to have them come back in four or six weeks because you want to screen them for these strange neurotoxicities. I still think we're underappreciating how often they're occurring because they can happen one or two months later. They're very subtle at first and usually they kind of, they're insidious in that way. I think that was probably one of the reasons why we didn't pick up on them at first. So I don't really think we're identifying the true population of patients that are being affected by that. Yeah. There's been a lot of discussion around the MajesTEC- 3 data too. Right. So I think it'd be helpful to get just your own framing of what you understand about the study, whether it impacts how you would practice and specifically how you see it in the context of what is the current standard of care in your clinical setting. So we can start with whomever is excited to answer that question. I remember the question right now maybe. Yeah. Like a fly. No, I think the MajesTEC data is fantastic. Again in myeloma where we've had, we haven't had a cure for very long. June was the first time we really started saying it, but it's always been continuous therapy. We want to do better than what we had before in the rest of oncology world. That's what we're known for. We're known to make better and better therapies, get better hazard ratios, get better PFS. I think applicability of this study though is a little bit different, especially in the U.S. Again most of these patients have not had anti-CD38 on MajesTEC- 3 while in the real world even our smoldering patients are getting anti-CD38 now. So how does that really affect the efficacy piece? But I'll say the infection part, that is such a big, big deal. 96%, 90-something% that had infections, almost every patient got an infection. But then 50-something% that are grade three, those are, you know, patients that need antibiotics or hospitalized IV antibiotics, those aren't just simple infections. And when you're on a bispecific, vaccines don't work. So our recommendations are always let's get the vaccines before you start the bispecific and hopefully you get some coverage. So to be on something like that for three years and it's not just BCMA, even anti-CD38s, they actually cause a lot of hypogammaglobulinemia. And so again applying that to our patients probably are going to have that maintenance and have some hypogammaglobulinemia and adding this. It's really hard to keep someone on this for long-term. So I think if it becomes fixed duration, we'll see. But based on the way this is, I don't think the majority of my patients would actually be able to tolerate it. I think I feel the same way. If you look at the data, you know, the data are amazing, say, but they probably would have been more applicable five years ago before quad induction kind of became the new standard of care, and if you look at the, you know, the number of patients, you know, not an insignificant number of people are going to have an inadequate response to a quad or become refractory on maintenance, and so that basically puts you at the level of monotherapy with teclistamab, which is probably closer to PFS of about nine to 12 months, and so you're putting that all together. It's. I think it's more applicable to an older generation of patients that we're currently treating, and I think we need to look at the patient populations in the sense that is that reflective of what we're doing now. You know, if things are like single digits in terms of exposure to Dara, is that really going to give us the same benefit in terms of what we're seeing in the clinical trial now, so great data, great options for patients who may not be able to access CAR T, but our hope is that we're able to expand CAR T in the future so everyone can have access. Anything to add to that? Yeah, I mean, obviously the, you know, the MajesTEC-3 data looks really good too. But I think there's two key things that drive my decisions to do CAR T before that would be one, as mentioned, the treatment free interval is very priceless for patients and not having ongoing therapy and ongoing risk of grade 3 infections for years and then also preserving the ability to have a second BCMA therapy. Because if we do. Unfortunately, have a patient that relapses after their CAR T, most of those patients will still respond to a bispecific BCMA bispecific. Whereas if they've had failure of a BCMA bispecific earlier, those patients do very poorly after BCMA CAR T. Yeah, I. Think that's a really good point, and we've seen. retrospect, or, you know, case series in the real world indicating that this. Matt, could you maybe fill in, like give a little bit of the science behind why that might be true? Yeah. So, you know, you look at bispecifics and CAR T's and you're saying you're targeting BCMA. Why don't you see very similar infection rates? Right. Same target, you're depleting plasma cells. And there's a couple of things that I think are different. The first thing is that when you're giving CAR T, the percentage of those cells are transduced or not, and they're not activating every T cell in that patient's body all at the same time. When you're giving a bispecific that infused product will bind to any single T cell receptor that's available and continually just hit it over the head. And what we know with chronic stimulation in the immune system is that leads to what we call exhaustion, where those T cells can't replicate. They're hyper inflammatory, but they don't function well. In that type of a setting, you start seeing a lot of immune dysregulation. You see increased infections, and you still have the plasma cell depletion, which leads to hypogammaglobulinemia. So at the end of the day, you have this compartment of T cells. We're always talking about fitness, fitness of T cells earlier line fit T cells, combining therapies that make T cells more fit, but when they're exhausted. You're going to manufacture a CAR T product but not going to work the same way. Counterpoint to that is when you give a bispecific after a CAR, you weren't targeting and activating every single T cell in their body. You still have a population that can be responsive to T cell engagers. You know, we see lower infections and you actually get to see more viable and functional T-cells if you go with a CAR T before T-cell engager. So I realize, you know, not everyone here has medical training and so based on what Matt just described, could you also maybe put a little more meat on the bone about why vaccines don't work then? Yeah, so again, the health of the T-cell is so important and when you've exhausted these things, I mean, it's like they're just, it's like me today, I'm an exhaustive T-cell right now. In the morning with coffee, I'm amazing. I could do great things even without slides. I could give a talk. And right now I'm like, oh my God, I'm going to die. And so really the product, whatever T cells you have, it really matters. Doesn't matter what the CARs are, it's the T cells themselves. And we call it naive T cells. I wish I was younger, in my 20s. That'd be better, right? But, and I think the other thing afterwards that's really important is the fact that you're not on treatment. Your own immune system comes back. So my own NK cells, your own T cells, your own B cells, your immune system is back to normal, which is huge. Myeloma knocks the entire immune system down. So when patients are relapsing on bispecifics, that's actually the highest time point when they actually get the worst infections because their innate immunity just goes horribly. And we had already depleted everything with the bispecific the entire time. So both ways, the immune system gets affected from the beginning all the way to the end of both treatments in complete opposite ways. Yeah, thanks. That's super helpful, I think, you know, just to also share that, you know, one of the challenges that you get with ongoing therapy like that is as opposed to something like a CAR T that is going to eliminate very deeply the quantity of all plasma cells in the body, and then it can recover. You're consistently putting pressure on those plasma cells, so they're going to continue to be suppressed such that even if you could generate that T cell response, you can't make antibodies. So you really just are constantly in a situation where you are at high risk for additional infections versus a CAR T. We see most of the time, patients who have pretty good bone marrow reserve will recover that bone marrow by the first or second month after treatment. Their immunoglobulin levels will start to return to normal again, depending on where they were when they started. They can return around six months or nine months or 12 months in most patients. I'll just give an example of a patient. We just had a young woman in her 30s who was treated elsewhere and was put on a bispecific Tec, and she came to us looking for CAR T cells, unfortunately, and had already had been progressing. She had three active viremias, meaning she had three viruses reactivated inside of her body all at the same time, and we're trying to get her apheresis. We're trying to treat her for her progressive disease, and we're trying to get her to T cells in eight for CAR T, and she's got three active viruses and a bacterial infection going simultaneously. That's not the optimal patient to be treating with a CAR T cell. We did it, figured it out. We actually gave her a stem cell boost from her old auto to try to give her some passive immunity. We did all these crazy things, but that's just one example, which you never see that type of immunosuppression outside of bone marrow transplant. Not only do you have constant pressure to suppress plasma cell production, but constant pressure to mutate the BCMA binding domain that causes the lack of subsequent response to BCMA therapies as well. Yeah, thank you for pointing that out, Dr. Anderson. So there's a concept in oncology that I think we probably all take for granted. But constant pressure typically will lead to outgrowth of resistance mechanisms versus an extremely potent initial active approach. So for instance, in adjuvant therapy and breast cancer, we don't slowly give therapy, we give all guns blazing to try to eliminate the last cancer cell. And that might be a reasonable analogy between CAR T and bispecific. I don't want to take that analogy too far, but I think it's, it's a similar concept in terms of potent killing. It's the same reason why we always tell people to please finish and take all of your antibiotics. Because if you just take a low dose or you miss every other dose, you're just breeding resistance. It's the same concept. As far as I know, doctors are the worst at that as patients. So I'd love to come back to this topic about cure because we've talked about data and we've talked about how you. But I think it's clear, like you guys all are CAR T fans. You're all looking forward to using the best CAR T for you, your patient, when you can. But what do you imagine like five years from now and ten years from now looks like for patients? Do you think there's a world in which the majority of patients who are newly diagnosed with multiple myeloma that you could think about? I could treat you for some fixed amount of time and you're done. I'll start with you, Dr. Anderson. Yeah, I mean, certainly the first time we've seen any glimpse of that is with CAR T-cell therapy. You know, we have many examples of long-term remissions beyond five years. I have a seven-year remission after a different CAR T. But before that we didn't really think that was possible. Now we're all excited that it's definitely possible. I think we can definitely see hopefully at least a substantial minority if not a majority of the patients in a long-term remission, whether or not they're completely cured is maybe irrelevant. As long as they have several years of remission. You know, that's also the next best thing. I'll put it simply, like what, what would you want your mom to go through multiple weeks and years of chronic therapy again and again and again, or one and done one time therapy that's potentially curative up front? Because I see, I imagine five to 10 years from now we'll be ideally using it either in high risk patients or all newcomers getting a CAR T-cell frontline therapy and hopefully curing a substantial number of them. Those patients never have to go on maintenance long term, beyond a certain stage-defined time period. They're never going to have to cycle through different therapies, they're never going to have anxiety about their light chains coming in all the time. They're not going to have pathologic fractures and have morbidity associated with that. I think, you know, it's an easy decision for me because it's what I want my loved ones to get. I think it's the best quality of life overall. Yeah, no, I agree with everything. I mean, cure to my patients is time away from treatment, no active cancer and not being on anything. Right. We sometimes call cure. The IMWG is going to come up with the answer what the definition of cure is. I don't know if I'm going to agree with all of it. It'll be complicated. But really what my patients want is I don't want to be on treatment and I want to be able to do whatever I want. Sure, you can watch me. But I want no symptoms and the only thing that's done that is CAR T. So I'm hoping we'll figure out ways to increase that cure fraction. Right. Right now we've seen that glimpse, but how do we combine some of our therapy sequencing? I mean, even some of the bridging options? Like in the real world, I get to give anything I want for bridging on studies. I can't do that. So being able to see what I can do with some of these new therapies. But like you said, stopping after and seeing how many patients we can actually get all the way through, and then let's say seven years from now, now we have a different CAR T where we can do it again with a different target. Yeah. Actually, I thought we might finish on that because that ray of hope was nice. But I just wanted to touch on one point that you've all kind of alluded to, which is something that you can see in the data in iMMagine-1 a bit. But we haven't done the full analysis yet, so we will. Which is what is the impact of how you prepare a patient for CAR T. Right. And so Krina, you were just sort of alluding to. And Matt, you did too. Using a quad up front puts patients into a really well situated approach to CAR T receipt. Right. Like so they are now the minimum tumor burden. They're ready to go. They're not in a hyper inflammatory state. Can you guys just talk why that makes sense and what you've seen with CAR T's maybe even in lymphoma and how that's played out over time? I'll start. I think you know the best time to do a CAR T. And as I explained to patients, you want to land a plane and you don't want to crash it. And so we want to sequence and time everything out to basically do the treatment on our terms and on our timeline. And the ideal patient to treat is the patient that has the most minimal disease going in. Those patients are going to have. And we've seen this in leukemia, we've seen this in lymphoma, and we're seeing this in myeloma. But the better that you reduce the patient's disease burden, the better the patient's going to do overall. The fact that we're seeing durability in patients who have 95% plasma cell involvement is like, mind blowing for me. But I think the big movement now is really tough disease burden. Using highly effective therapies in earlier line patients that have better quality T cells. Cells going in, all of that's going. To add up to more durable responses long term. Yeah. So I agree. Having disease control at apheresis seems to help because again, your T cells aren't just falling apart, but then having minimal disease going into the actual cell infusion. And in relapsed/refractory patients, for instance, we know that those are the patients. Not only do they have less toxicity and better efficacy, there's lots of data that shows that, but it makes it more applicable for outpatients. So 30% of my standard of care patients right now get such great bridging, they don't get CRS or ICANS. I can't do that on a trial, maybe with prophylaxis or something. But in the real world, I have that control on that bridging, which really just makes it so easy for those patients. They don't ever go to the hospital, they didn't have fevers, they get to go home after two weeks. And those are the patients that did really, really well and never had any issues. So that's our goal too, is make more patients not have any CRS so that they can just fly through this and again, make it more applicable to other centers that can do CAR T instead of just ours that have to deal with all the potential side effects. So, Dr. Anderson, I'll ask the last question to you, which is along those lines. Have you been able to incorporate any newer agents into bridging strategies? Whether, obviously not in iMMagine-1, but in commercial product. And have you seen that play a role in late stage patients to help manage outcomes? Yeah. So now that we've moved beyond trials and the limitations, we're becoming a lot more creative. And you know, Krina and I are both in a consortium that has published this data recently with talquetamab for example, as a bridging agent. You know, whenever possible we try to collect the T cells before giving a bispecific. But then that's really been instrumental in decreasing the tumor burden and decreasing the patient's risks of not only short-term post-infusion toxicity, but also as we've seen from CARTITUDE-1, the patients with the lower tumor burden have the highest chance of the long-term remissions as well. Just a cycle or two of bispecific, usually with a different target than the CAR T to try not to down regulate expression of the target and then with a washout period to allow the T-cell fitness to improve over about a month or so has been really helpful in getting more and more patients to CAR T that otherwise would not have been able to get to it safely anyway. Awesome. Thank you all for these comments, and the physicians will stay with us in case there are questions that anyone wants to address to them as well. Rami and Michelle are going to join us up on stage for the Q&A. Thank you so much. Hello. Hello. Thank you so much for the presentation. Very thoughtful event and thank you for the perspectives positions. I guess I wanted to dive in a little bit more as it relates to the differentiation on safety. There have been a lot of theses put out there as it relates to. The different products and what may be. Driving the differences we're seeing both with respect to the enterocolitis and also the ICANS. What is it? What are your latest thoughts? Maybe start with the physicians and then also love to hear how Arcellx. Is thinking about the differentiation. What's driving that as well. Yeah, I'll start. I think we're getting closer to understanding exactly what's going on. I think there have been a few, you know, there's a whole research field now around what causes cilta-cel toxicity, which is great for us, bad for patients. And I think, you know, what we're finding at the single cell level is that there seems to be a unique population of CD4 positive CAR T cells and this has been reproduced in multiple, multiple data sets that seem to be pathologic and seem to be potentially driving the enterocolitis, seem to be driving the Parkinsonism and they're associated and enriched in those patients who have toxicity. So they're really trying to define what they're doing and how they're doing it. You know, when it comes down to what's the difference? I think it comes down to what is the. These are all 4- 1BB-CD3-zeta CARs. They have the same signaling domains. They use lentivirus, and it really comes down to the binder where that's the only difference structurally across these three CAR constructs, and so when you put it all together, we may have a potential reason for why there's a difference, but I think we're actually really honing in on exactly what's happening. I hope in the coming months we'll be able to show that. I guess from our end I can add that a couple of things. I want to reiterate what Dr. Frigault shared, which is we certainly believe that it's binder related. I think all the data would suggest that, you know, there's one particular therapy that has the overwhelming, you know, number of these particular issues, and secondarily that our teams both at Arcellx and Kite, along with a number of clinicians have been working towards finding this answer, and we do believe we have an answer, and stay tuned. Hopefully in the next couple of months that will be public. Hey guys, Oscar from Truist, just talk a little bit about ALC monitoring for a second here. So in the discussion today in the morning, feedback was that it might not just be enough to look at the absolute lymphocyte level, but you also need to look at how quickly the cells are increasing. The presenter from Stanford suggested that they are only monitoring ALC every 24 hours and that might not be sufficient to capture the ALC growth rate. So to the three doctors on the panel here, how often do you currently monitor for it and what actually do you need? If you need to actually try and capture that growth rate as one of the indicators that you might expose the patient to DLTs. So I'll take it. So with Carvykti, we monitor ALC daily through day 14 and we give steroids if it rapidly rises, you know, above 3,000. But I think the key difference there with that product is that mainly you're trying to decrease your risk of delayed neurotoxicity, not the immediate toxicity. And so with this product, since you were not seeing that, I don't think with this product we really have to worry as much about that. Yeah, we do it a little differently. For us, we have the CAR T expansion we can follow in blood. And what we've seen for the enterocolitis is actually the patients who. It's not the expansion that happens in the middle, like where it's supposed to expand. A lot of our patients expand crazy. And they come right back down. Those patients do fine. It's the ones that expand and keep expanding at day 30 when they're high, the CAR T levels are high and we have some cutoffs that we use. Those are my patients that are at high risk of these delayed toxicities. We're mixing things up. We're sometimes giving a little bit of steroids. We're trying to see, and I monitor them very closely. I don't know if we need to intervene at that time or not yet. But again, those are my patients that we're seeing enterocolitis in. So if I see diarrhea, the second that I know that patient has a high level, I just, I treat with aggressive therapies to knock it down. So I think we're learning. I don't know that intervening with steroids just because ALC went above three or five will decrease some of these other, like ventriculitis for instance. I don't have enough data. It's such a small, rare phenomenon. I don't know how many patients you need to treat to really show that it will improve. So we don't give steroids in that first 10 days, 14 days. If we do anything, I think we're treating our own anxiety about it. Like, I've yet to see, like I've had patients on steroids who've gotten bilateral cranial nerve palsies and Parkinson's. Right. Like even before they had a high ALC. So I really don't think, I think ALC is a marker for a high risk patient because it's a marker for CAR expansion, which is just a lottery game where you have more cells around to do bad things. And so I think that's probably why that's the same associated with more toxicity. But the only thing we've ever seen work is basically ablating the CAR T cells with high dose Cytoxan as early as humanly possible, which then leads to cytopenias, delayed count recovery, more infections, more viral reactivations, and maybe an impact on efficacy to the point we're having to give stem cell boosts back. So ideally we have something where I don't have to do that. Then if you can ask, you know, a lot has emerged last couple years about sequencing bispecific and CAR T. With what you know today, if you say you had a patient who's seen a BCMA T cell engager and it's been six months since they've last been treated with that BCMA T cell engager, would you consider giving that patient an anito-cel? Yeah, I mean we don't have data for an anito-cel specifically, but if I again, if I had the chance to go backwards and give the CAR T first, I would definitely prefer that. Six months seems to improve the PFS for at least ide-cel and cilta-cel in our real world data. It's still not back to what we see with naive patients. And so it's all that sequencing is about that PFS 1 and 2 and I think especially people are going to get bispecifics for long term. I don't know what's happening to that mutate the mutations for the BCMA and that's what I worry about with long term and BCMA bispecifics. So a lot of us are actually trying to get sequencing data before we ever give that CAR T know because we're afraid that they're just not gonna have a response at all. And then we put them through all of this, you know. This is not what we want. But yeah, I would wait six months if I can. But in late-line patients, they can't wait, and then I just have to do something else, like another T-cell engager, which makes their T cells even more exhausted after. Exactly. Same thing, more time away. Shorter duration of T-cell engager are typically associated with better outcomes with cell therapies afterwards. But ideally we get the cells in first. Yeah, same. And we try to sequence them if they've relapsed after one BCMA therapy and try to see if they have mutations that might preclude another response. Although we don't necessarily know if the different BCMA products bind to the same BCMA binding domains. So that's a little bit to be determined. Maybe just some foreshadowing. That's a question we like to help answer in the not too distant future, but be on the lookout for that one. Great. Thanks very much for the presentation, Tyler Van Buren from TD Cowen. I'll try to ask a couple quick ones. First one is obviously encouraging data out to 24 months response rates. PFS all seems pretty similar to Carvykti. However, looks like we might be seeing a divergence in survival at 18 and 24 months between anito-cel and Carvykti. Do you think we could be seeing something real here or is it still too early? And then the second question is, you guys just slipped Anito-First in there. The lead into iMMagine-4, which I believe you said was fully enrolled. So we'd love to hear a bit more about that study and if we could get data next year on that. I'll answer the first one to protect our physicians from having to make cross trial comparisons and just say I think we're optimistic that that could be true related to non-relapse mortality issues that could have happened in CARTITUDE-1, for instance. But it's probably too early to say that definitively. Chris, why don't you go to the geometry? Yeah, I was trying to flip back. I think it's forward. Clicker is not cooperating. Can we go back on the slides? Yeah, I don't know why. Oh, there it goes. Okay, almost there. We're going to. Keep going. There you go. Right, Great. Yeah. So maybe we should just give a high level overview of what the intention of this trial was. We know that there are a few scenarios that can exist within this frontline setting. And so, you know, the idea was to establish that it is both safe and has some level of efficacy to enroll patients in these populations. And this was something that we were able to do in a collaboration with the group in Spain in order to move things along very rapidly. And as Rami already mentioned, it's already fully enrolled, so we're still waiting on all the patients to get through the process of. And so as you can see, they get an initial induction either with DVRD or Isa-VR d. And the reason for that, just so everyone understands, is that even though I think it's reasonable to assume that Dara and isatuximab are pretty similar. They are used differently in different geographies. And so that's something we wanted to make sure we covered to show that these can be used essentially interchangeably. So those cycles that you see for each one are given first and then leukapheresis is given. The reason for that is largely because what we expect will happen in a frontline study is that patients will start treatment before they start having a conversation about a clinical trial. And so the assumption is that patients will have already received a cycle or two by the time they enroll and can think about leukapheresis. So we wanted to cover for that scenario here. And then the patients go on to additional cycles of therapy before they start lymphodepletion and anito-cel on the back end. I just want to point out this is an open question that's still one that is really important in the field. So we talked about cure and we talked about treatment free interval. We know that if we asked patients if you could get the same outcome with no maintenance versus having maintenance, they would all choose no maintenance. Right. What we don't know is whether giving that maintenance or not giving that maintenance will result in the same progression-free survival. So that's a part of this study, to say is this safe to give? How does it look? So those are all things that help feed into some of the other decisions that are being made around a frontline study. If we poll the group here, I think you'd probably hear the same thing from all three. Although I can let you all speak for yourself that if you could find a way to get away from maintenance therapy, that would be a preference. So that's all things that are part of this consideration. Hopefully that gives you the background about the study and you know why it's being conducted. Hi, this is Sami Corwin from William Blair. I'm curious for the physicians, in what line of therapy are you currently most commonly using Carvykti and ide-cel? And a couple of you mentioned how you already have some patients that you're holding off and waiting to use anito-cel for. So I guess how are you thinking about specific characteristics of patients and those that you would be more inclined to treat with Carvykti in the second line setting versus waiting to use anito-cel and then Rami? I was wondering what exactly you're looking to see in iMMagine-5. Thank you. I'm happy to take. So I think it's my standard risk patient that I wait. If someone has high risk disease, I don't have time to wait. Those are the patients that they go. They blow through all therapies really fast. So I will use whatever I have. And the best therapy we have right now is CAR T and second line cilta-cel for those high risk. But it's my standard risk patients where some of those are patients who are kind of like second, third line. Like okay, well I don't know what's going to be approved, but I'm doing well on my current therapy. I'm okay, I'll wait. I will say that the majority of my patients for cilta-cel go in second and third line and the majority of my ide-cel patients go in third, fourth line. But my ide-cel patients are my frail patients. The renal failure, the older patients, other major comorbidities. But I think you know when hopefully with other therapies, other CAR T's coming in. I will go as soon as I can. So depending on when I get approved I can get going to get more of our patients in that first four lines. Completely agree. I think we're mainly using it in third, fourth line except for say cilta-cel primary refractory high risk patients like you can't really mess with that. But those are also really high risk patients for toxicity too. They tend to be refractory high disease burden going in. So I think you know, when you look at actual commercialization and how we can use things we don't have to follow IMWG. I don't have to wait for true biochemical relapse or progression. I can wait if the light chain is slowly rising. I can treat at 50 as opposed to 100. So I think we'll be looking at lines of therapy and progression a little bit differently when we have a commercial product than say when we're trying to do it for a clinical trial of eligible patients. Yeah, basically the same. We have. We're, you know, mostly third and fourth line, but we do have those patients that are either pretty resistant or right after their induction therapy that we're using a second line or patients that relapse within a year or two of their front line therapy going to second line CAR T. We don't mess around with those. But anybody that has more long term first remission and has good options for second and a third line, then certainly can wait a little while. I just think it's important to point out that we have three docs from three different institutions and I think the sentiment holds across the board where we're really excited and we're talking about cure from CAR T cells but we're still not using the current CAR T cells in the second line setting. Despite all those benefits because of the toxicity that is the only thing preventing us from using this more broadly. I think the rest disagree. Yeah, I mean, if patients are relapsing early, high risk, and induction failure, then okay, it's a no-brainer. It's worth taking those risks. But for other patients that have known five, 10 years of remission with frontline, you know, why they don't necessarily want to take these risks. If you were fishing for another study schema slide, Sami. There isn't one for iMMagine-5. And I think the purpose of that study, as I kind of alluded to, is look, we feel like we have a really unique profile within anito-cel. As you've heard from the physicians, there's a real opportunity for a functional cure with this kind of therapy. And so we want it to be as broadly adopted as possible. And part of that is demonstrating that given the uniqueness of the safety profile and the patient management with an anito-cel, that it can be adopted in the community. So that is obviously the thing that we want to show that it is amenable in that setting. Hi, Daina Graybosch from Leerink Partners. I want to talk more about bridging therapy. Excuse me, Krina. Something you said is really interesting. The study had a bridging regimen, and then there was a protocol amendment and that allowed different bridging. And you talked about more creative bridging you can use in the real world. So I wonder if you could frame those three different types of bridging and how much you think each of those could contribute to the overall survival benefit we're seeing for early patients. And iMMagine-1 late patients and then the real world. Yeah, no, that's a fantastic question. I think in the beginning, when we first got CAR T's, everyone said, oh, bridging, none of it matters. We don't know. And now we know it's complete opposite for our CAR T therapies. Again, efficacy is much better in patients who have better bridging. And then the same thing with toxicity is usually much better in patients who are responding to bridging. So in the study, just like all their CAR T studies, patients had to get something that they had already been exposed to. And this is how ide-cel and cilta-cel started as well. And most patients, you can combine things differently, but most patients aren't going to respond to those. We're just trying to hold them, basically. Right, please just don't explode so that we can get you to your T cell infusion. And so that's the goal at the beginning of the study, when we know that these patients have already been exposed to these drugs. And then because of safety issues, again, when those patients are having increasing disease, that's where the toxicity happens. The FDA looking at all this data said, okay, you guys can use other therapies. We still couldn't use bispecifics and, you know, other mechanism of action. But at least we could use something that patient hadn't had before so that hopefully they actually have a chance to respond some and keep their disease controlled. And so again, the safety profile improved. And my patients that had a better response had better safety and, you know, efficacy. We'll see long term. But again, with Sarclisa and Pomalyst there is data that shows those patients that are responding to bridging do way better, both safety, toxicity wise than if they weren't both on trials as well as standard of care. So now that in the standard of care I can use even better therapies like potential talquetamab, I can really make sure these patients get a great response by the time they go to their CAR T so more patients will respond and a deeper response before they get their T-cell infusion. Real world makes it so much easier. And then earlier line I have more things that will work, so that makes it even better. Dana, maybe to help answer that question, where I think you might have been going to is, you know, obviously with limitations on bridging that we know has a negative impact on patient outcomes early in the study that could have. Somewhat disproportionate impact on some of the patients that were enrolled earlier in the trial compared to later, and so, you know, we obviously have to follow those patients for longer to know, but we do know that relatively early in the study there were three patients who died early in the trial and that didn't happen as the trial went on, so the impact of any death is only mitigated as more and more patients reach threshold points for PFS or OS, and so it just takes more time and more follow up to see what the final numbers look like. Hi, this is Josh Cesario on for Cory at Evercore ISI. This is for the docs on the panel. For your second and third line. Patients. That are getting cilta-cel today, which ones do you think are like. The best fit for those second or third line? Are there particular qualities you look for in those patients, and if anito-cel is approved next year? Do you expect to have patients wait to get anito-cel? Wanna start? Yeah. So, I mean, I think, you know, the best quality earlier line, if they want to go for CAR T early, then have a good bridging option that they're not refractory to to get them to a low level of disease to avoid the toxicity. You know, ideally to go really early to have some sort of high risk feature or functional high risk disease. And then those that can wait are the ones that are maybe, you know, you can do all sorts of things like, you know, give some pulse, dexamethasone, things like that to use as another line to for a couple months to see if that can stabilize their disease for a while and then you can say they've had three lines. I guess a lot of this will also depend on how the FDA. Determines the labeling. You know, we don't know what that's going to look like yet. So that could come into play. Is it three lines? Is it three therapies? Different things like that. So we'll have to see what that. Looks like, you know, for us and the patients who are getting the earlier line cilta-cel. Again, the primary refractory, the really sick folks that we don't think can wait and we don't think other therapies are gonna be that effective, to be honest. I actually don't think we can actually truly predict the risk factors for these delayed neurotoxicities as well as we think we do. We have patients who you would think should not have any of those: very low tumor burden, no extramedullary disease, no high risk features, and they still get these delayed neurotoxicities. There's a study in smoldering myeloma. It was presented last year at ASH: smoldering myeloma, not active myeloma, very, you know, low disease burden going in. And they had two or three cranial nerve palsies. So, I think this concept of disease burden and whatnot. We think that we can predict it, but I don't think we truly can. Yeah, right now. So we actually had an increase in our second and third line, you know, in our standard risk patients, because again, it's a potential cure. Patients want that time off. And I will say because of some of these toxicities, our numbers have gone down a little bit. Not horribly, but they're not going up still. They should have plateaued or gone down just because of that toxicity piece. A lot of my colleagues, my junior faculty especially, are just like, wait, I need pause because I've had a couple patients now that, you know, have this bad thing happen. Hold on, I got to figure this out again and make sure I'm telling my patients the right thing. So I think we're seeing a lot of that where we're going like, woo. And then, okay, hold on. So I think, you know, right now it is my high-risk patients. I will say with cilta-cel, I usually make sure my patients don't have major comorbidities. I worry when they have renal insufficiency. We have data that, you know, those are not the patients that do as well. So I am actually a little bit more excited that anito-cel is going to come in that group where I'll be able to see how those patients that aren't represented on trials because right now I use ide-cel in a lot of those patients thinking that okay, at least they'll be safe for them. They'll still buy time even if the efficacy is a little bit lower. But it'll be safe because we don't have data at all for the other patients except standard of care where those patients don't do as well. It's hard when the patient uses an MRD negative complete response and they're telling you, I wish I hadn't done this and that has happened, and so I'm at the point with some of our patients when we are talking about using it in the second and third line. I say we're going to do this only if you assume you're going to have potentially those awful toxicities that we talked about and you're not going to have regrets that you have to be okay with that possibility because you've got to be frank with them because you really can't predict who's going to get those side effects. Biren from Piper, maybe a question for the company. When can we expect the BLA submission for anito-cel? And then maybe a question for the physicians. We talked a lot about MajesTEC-3 and Tec Dara and how you know, your perceptions of that and how you. Would physicians it to the CAR T's. But if you put on your, the. Community hematology, oncology. What do you. Think your peers would do in the. Community setting given that they don't have the infrastructure to dosing a CAR? And then I have a follow-up question for Dr. Frigault. After that. You guys can go. Yeah, I mean the BLA submission is as we've said, we expect to be on the market next year and you kind of can work backward from there. So we think everything's looking right on track. Yeah. So in terms of the community doctors, it totally depends on where you are. So we might have different answers here, but in Houston a lot of my colleagues aren't using bispecifics. They're still sending patients to us to do the step up dosing. Some keep them with us, some take them back, you know, eventually, hopefully they learn how to do that. But I will say they run out of options and then they don't know what to do. So if I tell them, if you send me this patient after bispecifics and I can't do this, they really do listen to me. So again, it's, you know, myeloma is not just what's my next therapy. It's what am I going to do for these patients long term. And I think that's changed compared to let's say 10, 15 years ago because everything's so new for everybody all the time. They really do ask our opinions for the most part. Okay, which way should I go? So for me, I don't think that because they can do bispecifics that they're all going to do it. There can be certain, you know, certain community practices that can do it and they will. But the second they try to send me CAR T patients and I can't make their cells or they have bad outcomes, usually that gives them a little bit of pause. But I agree with you. There are going to be some communities out there that are just going to say, nope, we're doing bispecifics for everyone because I can do it. You're not going to see my patient. But again, for me in my area, it's not as likely that that's going to happen. Dallas. I guess I'll add one other thing on the BLA submission we've discussed. We'll announce acceptance, not necessarily submission, but I would just use the word imminent. How imminent. Don't push your luck, Biren. All right, maybe a question for Dr. Frigault. You're a co-author on a poster earlier today detailing five patients that received cilta-cel and had developed colitis and they were treated with ruxolitinib. Do you view that as a solution? For these colitis events? Also, I think there was a. Patient that had developed T-cell lymphoma. Is there any correlation between development of colitis and T-cell lymphoma? I think as I was kind of alluding to earlier. Well, first to answer the straightforward question, I don't think RUX is a cure for enterocolitis. I think it helps a certain subset of patients for a period of time. But I really yet to truly feel that I've reversed and gotten so much bowel back to normal. Like no one's really ever normal after they get enterocolitis. But you know what I was alluding to earlier was a single-cell data with that kind of atypical CD4-positive population on single-cell. The New England Journal of Medicine enterocolitis and T-cell lymphomas paper that have been presented are typically CD4-positive atypical CAR-positive T-cell lymphomas. The predominant cells we look at when you look at that, the poster rehab enterocolitis first CD4-positive CAR T cells in the gut. And so there's something atypical about that cell population that I think this is probably all linked together. Right. We're talking about persistence of a CAR in some cases for upwards of a year. That's upwards of 30% of the patient's lymphocytes. That's not normal, especially in the absence of antigen. So there's something about that process that's probably leading to all of these things happening, just different manifestations related to the CAR construct. Yeah, thanks. Stephen Willey from Stifel. Maybe just a couple Anito-First questions for the company and then a question for the physician. So how many patients are you planning to enroll in Cohort C of Anito-First and I guess how confident are you that a 12-month evaluation will be sufficiently indicative of. Longer term outcomes without maintenance therapy in the frontline setting? And then I think we saw from the Gracell AstraZeneca presentation this afternoon that only two cycles of induction therapy administered either before or after leukapheresis was sufficient to drive really good longer term outcomes. So does that change the way that you're thinking about the design of iMMagine-5 where I think you're planning for maybe four cycles of induction? Yeah. Okay, so I'll try to get those in order. So in terms of Anito-First, that's supposed to be essentially equally randomized between those arms, so should be about the same number. I'm not 100% sure if that slide had the numbers on it, so I'll just defer that question for now. But it's not a huge number, but enough patients for us to make some solid inferences. Right. And then to the second question around the 12-month follow-up. That's a time point that has already been acknowledged in an FDA ODAC where MRD negativity should be highly predictive of outcome and is associated with data that we already have with other regimens at that same time point where we know what the bar is. So your question is, I think, a very good sort of philosophical question like is that enough to tell you the answer? The data says that it should be enough. And the question, the goal that we have with our prior studies leading into this is to demonstrate that that time point and that that endpoint is predictive of outcomes. So, we believe that if we can do that with data from iMMagine-1 and iMMagine-3, that you can take what the ODAC said before and cement it with actual data from your program, and then add these data to that, and then that gives you more credibility when you try to use that for a primary endpoint in a subsequent randomized trial. Does that help? I mean, there's no endpoint that can otherwise tell you the answer definitively without waiting three, five years. Right. So that's why it's the 12-month. And I know I probably forgot one. No, and then just on the four cycles of induction that you're proposing versus the two that were used in the Gracell AstraZeneca study to date. Oh, that's mainly a practical thing to be totally honest with you, like that. It's, it's just going to be really unlikely to capture a patient consistently who has not already gotten some therapy. You know, they're going to show up, they're going to have a diagnosis, somebody's going to knee jerk, start the standard therapy. And so this is the primary intention here is to follow what we think will happen in the real world. Overall. Could it have an impact? Maybe marginally, I think that's possible. But these are really good regimens that have excellent cytotoxic capabilities. Two cycles is clearly not quite as good as four, I'll acknowledge that. But I think we already feel very confident that an anito-cel is a highly potent CAR T. If we had two cycles it would work. If we had four cycles it would work. But this is a practical solution to a practical problem. And then just for the physicians maybe just to level set ahead of Tuesday morning, I know the company talked a little bit about this in the presentation. What proportion of frontline patients that you treat are currently seeing a quad, are then receiving Dara as maintenance and are then subsequently progressing with Dara refractory disease? Probably, excuse me, 75% of my patients receive quads. Even my older frail patients, I'll just do really low doses and then eventually take off the PI, the bortezomib, and I will say 50% of my patients probably go to transplant. Again, part of it's are they eligible or not? Most are, but a lot of patients just don't want to do it. In my practice we then continue the Dara Len especially if they didn't do transplant and so they just keep going until they relapse. The other 50% of the ones that actually go to transplant, there are some that I'll do just Len maintenance but the majority high risk patients, anyone that's not sCR, MRD undetectable yet will do the Dara Len for two years and then stop the Dara over time. So I'll say, you know, everyone's Dara exposed. Probably at least 50% of my patients will be Dara refractory at relapse, and then the other 50% will be exposed. That's conservative. I think that's gonna, that's probably a standard practice for a lot of. The community docs are already doing quads. So, like, more and more patients, it's not just our practice. I think more and more of the community docs are starting to use quad induction regimens. There are other abstracts here at ASH looking at, you know, an Emory cohort of 400 or so patients and, you know, the percentage of patients who got a quad induction with maintenance in Dara who didn't achieve a VGPR or better or progressed while on that was around 25%. So that kind of gives you an idea of just the ballpark for kind of what's happening today. Yeah, pretty similar, I think. You know, majority are getting quads up front. High risk patients will get it long term. Patients that don't do transplant are going to get it long term and be refractory when they relapse, whereas the ones that do transplant, probably half and half would do two years of Dara and then most of them will be off of it after two years, though, unless they're high risk. So there'll still be a substantial number of patients that aren't Dara refractory at relapse. Yeah. And I think also it's important to keep in mind when we see those data that it may not just be refractoriness, it may just even be exposure. I mean, I'm sure a lot of people have heard a lot about this trial, and everything we hear is that the large majority, very, very large majority, hadn't even had exposure to Dara. So while a patient may not technically be refractory to Dara by IMWG criteria, multiple years of exposure has some. Impact on the likelihood of efficacy of. Dara in a combination setting. And we've seen data to support that across other studies with Dara prior exposure and the impact it has on PFS, for instance. Yeah, I would say, like said another way, if that study happened to be overwhelmingly a Dara naive population, how relevant is that data set? Hi, John Newman, Canaccord Genuity. One question for the physicians and one question for the company. The question for the physicians is, given what we know about the safety profile of anito-cel and what we know about the safety profile for daratumumab at. Some point in the future, would there? there a reason why you would not consider Dara maintenance? And then the question for the company. Are you considering testing that at some point? Why don't I answer that one first? That is a really important question. There are two ways to look at that. There's the treatment free interval part that we know people want, and then there's the how do you run a trial that you know will beat everything else? And I think you can tell by the way we are talking about this that we believe that if you gave an anito-cel in an early line setting and then gave Dara as part of maintenance, it would be exceptional in terms of PFS and OS impact. However, there's a significant trade-off there to be considered. So we're not ready to answer that question directly about how we're going to do it. But it is definitely a significant consideration. And in the end, a lot of that comes down to what do patients and physicians say they really want? And you know, we talk a lot about these numbers and we often forget that at the end of the day it's a doctor and a patient who make the decision about what they want to use. And I'll say this. If it were me, if I were 70 years old and I had multiple myeloma and someone asked me, would you rather have therapy today and then nothing for three years or maybe five years. And you will maybe relapse at that point, five or six years later, I would still say, yeah, I'm 70. That sounds great, right. So that's just me. But patients and doctors make these decisions, right? So those are the things we have to weigh and we try to come up, as Rami said earlier, with trial designs that solve for not just the best numbers, but the best reality that we have to get for the patients and the doctors. So I'll let you all answer the other part. I think it's an important question. We're going to have to answer it and we're going to have to do a study. And as long as it's some defined time interval of maintenance, I think that's tolerable and still consistent with a treatment free period. And there's also a difference between maintenance therapy and active therapy for measurable disease you're trying to keep at bay, right? If you're on like a triplet and you're having side effects and you know, it's different than say just a monotherapy in a maintenance setting. So, and you can take a month off, you can go and do different things, you're not worrying about your disease exploding. So there are differences in the maintenance setting versus, like, active treatment or active disease. Yeah, sorry. I agree. I think there's gonna be patients who do really well, like, who are the ones that get the five years and who are the ones that relapse earlier? And I think it's that group of patients that relapse earlier. And again, I think MRD does actually tell us a lot in CAR T that people get to MRD negative or they're sustained MRD negative, they tend to do much, much better. Or if they're MRD positive still in that first three months or become MRD positive in the first six months, those are patients that usually relapse. So maybe that's the group that we actually do something like Dara for. And again, I would still like to stop it after a while. So we want to increase that cure fraction, but it's in. How can we actually stop that therapy? So once they're MRD negative for longer, can we stop it? Yeah. I think another question is if, you know, maintenance Dara is one thing, but maintenance IMIDs could potentially not just keep the myeloma in check, but also help activate the T cells and improve persistence. And maybe, you know, they may not mind as much being on oral medicine, you know, as opposed to coming in every month for a shot. So that might play into that role as well. All right, well, with that, I want to thank our physician panel. Thank you for your time and certainly for your insights. It's incredibly valuable. We know you have a lot of demands on your time, so thank you for spending this evening with us. I want to thank you and the audience for joining us. It's nice to see a full room here in Orlando, despite what appeared to be torrential rain. I want to thank our team. You did an incredible job just executing across all phases of the game, as they say, to make the best ASH yet. And finally, our exhausted T cell, like, she got an infusion and finally rest. Thank you all.