Okay, it's a few minutes past 8:00 A.M. I think we should get started. My name is Ying Huang, and I'm the CEO of Legend Biotech. And on behalf of the company, we're very pleased to welcome you guys to our ASH Investor and Analyst event. With me, we also have a few members of our team, including Alan Bash, who is our president of the Carvykti unit. And then we have Chief Medical Officer Dr. Mythili Koneru here. We also have Jessie, who is our VP of IR and Finance, you guys all know. We also have Nitin from our clinical team, and Rob, and Vrinda, and also Octavio from our medical affairs team here. So with that, I'm going to run through the typical safe harbor statement. We're a public trading company. Our stock is listed on NASDAQ under LEGN. Any up-to-date information, please refer to our SEC filing and also our website. Before we give the podium to the two physician KOLs today, I would like to emphasize that given all this discussion about the landscape and also potential competition, we and also our partner, Johnson & Johnson, feel very strongly that Carvykti is the proven leader in the treatment of multiple myeloma. In clinical trials, we have demonstrated not only progression-free survival benefit, but also Carvykti has demonstrated the survival benefit. It's actually the only BCMA-targeted modality in a clinical trial setting that has demonstrated extended survival benefit compared to standard of care. As you all know, overall survival or survival is the gold standard of any oncology trial. Because any time a patient walks into a doctor's office and unfortunately was told he or she has a diagnosis of cancer, the number one question they always ask is, "Well, doctor, how much time do I have?" And this is why it's so important for any treatment approved for oncology or hematology to show benefit in extending survival. And we're very pleased to report this survival benefit in the September meeting at IMS, where we demonstrated a hazard ratio of 0.55 compared to a Darzalex-based regimen. Secondly, why do we say Carvykti has the proven leadership? Because we have treated more than 4,500 patients to date. And that includes both real-world commercial patients and also the patients enrolled into our global CARTITUDE program. And in the last couple of quarters, Carvykti has demonstrated significant growth trajectory, especially in the third quarter. As you know, we received FDA approval in April. Following that, we see a very significant uptake in that second to fourth line, where roughly half of our revenue today comes from that second to fourth line patients. We're very confident that given the recent survival benefit demonstrated in the second interim analysis of CARTITUDE-4, we'll continue to see higher market uptake. 10 quarters in, since we launched Carvykti in February of 2022, Carvykti remains the best CAR-T launch compared to the other brands. In the third quarter of 2024, Carvykti brought in global sales of $286 million. That is actually a sequential growth of 54% from second quarter in 2024. Lastly, it's very important because we all know CAR-T is not a therapy that's typically administered outside of the hospital. Yet in last quarter, we reported that up to 48% of the use of Carvykti is actually in the outpatient setting, which is a very important convenience factor for patients and also their family and caretakers. So here at Legend, we have a team of now almost 2,500 global team members. And we never forget who we're working for. So we're very pleased to see the benefit Carvykti has brought to patients. So with that, I'm going to show you one real Carvykti patient and his experience. Cycling puts you in the moment to be on two wheels, being outside. That's an active lifestyle for me, and then a torn knee changed that. When I got cancer, I was 46. My diagnosis was a day of sadness. Got an email that I had multiple myeloma, and I had to Google it to find out I had cancer. Ever since I began training in cancer, it was poison the tumor. You had to use chemotherapy. What we found with immunotherapy was a very different approach for cell therapy of cancer. I went through five failed lines of therapy. Eventually, they stopped working. That's when we went to CAR-T. I was patient number one at Stanford. They extract your T cells from your body. Cycling puts you in the moment to be on two wheels, being outside. That's an active lifestyle for me. And then adverse events changed that. When I got cancer, I was 46. My diagnosis was a day of sadness. Got an email that I had multiple myeloma. And I had to Google it to find out I had cancer. Ever since I began training in cancer, it was poison the tumor. You had to use chemotherapy. What we found with immunotherapy was a very different approach for cell therapy of cancer. I went through five failed lines of therapy. Eventually, they stopped working. And that's when we went to CAR-T. I was patient number one at Stanford. They extract your T cells from your body, modify those T cells in such a way that they became like heat-seeking missiles. They swam into my bone marrow and started eating. The cells are genetically modified so that they have in them an antibody. Now it can specifically attack cancer cells using the same machinery that T cells have naturally to kill a virally infected cell. I was in the hospital 21 days. Lisa had to carry me. I saw you at your lowest, right? And I needed to buck up and be there for you in those times. My body started to build. I looked at that bike and I said, "I'm going to ride you. I'm going to ride you." I climbed up on that bike. And I clipped in this leg. And I clipped in this foot. And I pulled around one time. And I pulled two times. And I did four. Since then, I've gone 10,000 miles on the bike. Within a year, CAR-T had done complete remission. We never had a living drug before, and that's what we have with CAR-T cells. 14 years ago, I was diagnosed. I thought I was seeing my last of my natural wonders and here we are. It's incredible. We're at the beginning of CAR-T cell therapy. I can't wait to see what happens in the next coming years. We have a reason to dance every day. And we pretty much do. This isn't the end of it. It's the beginning of it. We're going to turn the podium to our two distinguished guest speakers. Thank you very much. Appreciate it. Yeah, what a powerful movie that was. I hadn't seen it before, and I have to share, I have patients like that, patients that complete the process, go through CAR-T, and tell you, "I've never felt this good through the course of my treatment because I'm not on dexamethasone. I'm not getting infusions," so thank you for sharing that. I think it was very special, so I'll speak first, and then I'll introduce my colleague, Dr. Dhakal. And I'm going to probably just put some background context of where we are with myeloma and what the hope is, but also what the problems are, and in particular, the bigger question we have right now in front of us is the earlier use of CAR-Ts as frontline early relapse therapy for myeloma. In training, I had the capability of producing survivals, as you see there on the left, whereas with melphalan prednisone, it barely exceeded two years. That was our standard. And no one wanted to do myeloma. You were last in line if you were going to do myeloma and your fellowship. On the right side, you see now the more recent data of what we can anticipate with the advent of modern therapeutics. Now, there's three series there, each one of them with over 1,000 patients. The uniting feature is stem cell transplant and then a little bit of maintenance. As you can see, the survival can be as far as 156 months for patients with standard risk. This does not include the most recent therapeutics. It does not include quad and so forth. So really, there's tremendous hope for our patients, and precisely because of the advent of these new therapeutics. But once patients start going through their treatment and they start relapsing, our options are limited. It's a very important study. It was published in Leukemia by Dr. Mateos, the LocoMMotion study. We're using real-world evidence. She asked herself how likely it is for someone to respond once you have exposure to three classes of drugs. And it's less than 30%. So the results are not very good. And when you look at PFS, it's only 4.6 months. So the options for control of the disease are very limited. Dr. Dhakal and I have patients that we're very proud are out several years, but we remember the good stories. And it's harder to remember all the patients that we lose along the way as we go through the treatment of myeloma. Speaking of losing, this is probably one of the most important concepts I'd like to present to you today, which is attrition. I presume this exists for all cancer, but we've studied this in greater detail for myeloma. This is using real-world evidence, again, where we ask ourselves the question, of patients who complete a line of therapy, how many will go on to complete the next line of therapy? The percentages you see on the far right are the loss that we have for these patients. On the upper part is nearly 22,000 patients who are not transplant candidates. The bottom part are transplant candidates, which have a little bit lower rate of attrition. Of course, the younger, they're healthier. Now, the study was not the first, and it's not the only one. The parameters may change. It's very clear in a very conservative way, at least 20% of patients are lost through the passage of each line of therapy. So when we think about opportunities for treatment for patients with effective therapy, that happens early on. And saving dry powder for later makes no sense. When you think about it from a commercial perspective, you have to do the discounting of each one of these processes of the attrition that occurs as patients go through therapy. So I always say you've got to go with your best foot forward to provide the most durable and the best response for our patients. Using a similar line of work, we presented this recently at the International Myeloma Society, which was a model we've been engaged in several modeling exercises like this, where we asked the question, what would make more sense for survival to start with something like cilta-cel and then the BCMA standard of care for the subsequent relapse? So that is cilta-cel for your first relapse versus using the standard of care and then having cilta-cel as rescue. As you can see, our model predicts a survival that's 8.8 versus 5.5 years with a three-year difference by the early utilization of cilta-cel. This is not published. It was presented at our international meeting, and the good news too is, well, you've heard about all those patients that have been treated. But now we have the first, I would say, comprehensive report. This came from Dr. Sidana from Stanford as well, like the patient where they look at the utilization of cilta-cel in the real world. It's 255 patients. Of them, 236 can be infused. And you look at the PFS, 68%, the 12-month estimate. Those that have conforming product, 72%, conforming and get the Flu/Cy lymphodepletion, 73%, which is quite comparable to what was seen in CARTITUDE-1. And this was with a median follow-up of 13 months for these patients. And the safety, of course, is very, very important. I can tell you, and Dr. Dhakal will tell you more. When it comes down to CRS and ICANS, we recognize that. We respect that, but really are not too concerned about it. We can manage that much better. There's some very specific aspects of what we're doing for the management of this that I think will be key as we think about the minimization of long-term toxicity, but as far as an immediate threat, I think we feel like we have a very good handle on that, and of course, there was a big spotlight on some of the delayed neurotoxicity, which we'll talk more about that. 236 patients, five developed equivalent of parkinsonism or like symptoms, of which four did not improve. One patient did improve, and then there were a few patients, 5%, who developed cranial nerve palsy, and again, we'll talk more about this, but one of the thoughts is that as we move forward, we have better patient selection. We have patients with lower tumor burden than patients who present themselves a little bit earlier. Our hope and our aspiration, and also with the management of more aggressive management of ICANS and CRS, that this will continue to diminish. And of course, a reminder always that we do have the presence of infections as one of the long-term threats. The community is very proactive now in the employment of prophylactic strategies as well as the replacement of intravenous immunoglobulins. So the safety profile now in the real world is very similar to what was seen in CARTITUDE-1. So in summary, I think it's very important to remind ourselves, of course, of these attrition rates, which are very high. And we think that in the newly diagnosed myeloma patients, 57.7% of patients without stem cell transplant, that's the advanced-age patients, can be lost to attrition. And we go down to about 21% for those that are transplant candidates. I shared with you the real-world modeling that we have, that we propose, that until we have additional data, it makes more sense to use cilta-cel early on. And I talked to you also about the real-world evidence with this 16 centers treating over 250 patients with cilta-cel with results very similar to CARTITUDE-1, despite the fact that over half of the patients would have not been eligible for CARTITUDE-1. So at this point, I'm going to make a transition to my colleague, Dr. Dhakal. And Dr. Dhakal will go more into the details of the clinical trials. Please nod. All right. Thank you. Yeah, thank you so much, I think, for this nice presentation, and of course, I would say that I have two patients who were treated in CARTITUDE-1 trial in 2018, late 2018, and still doing fantastic. We are able to put three patients. One patient, unfortunately, passed away for some other reason, not for disease progression. He had underlying cirrhosis. So what I see is this is a transformative treatment. When you have a patient in front of you, especially for myeloma patients who are always having treatment and the burden of the treatment and not getting off therapy, you see that patient in front of you and then having this profound impact on their quality of life and then seeing that life transforming in front of your eyes, I think that is really satisfying to see that in the clinic. So with that, I'm going to talk about, I think, some of the important update that we have in CARTITUDE 4, the data that we presented at IMS this year. So just a background, lenalidomide is used quite frequently in multiple myeloma as early as first line. So you see a lot of patients relapsing off lenalidomide after first line of therapy. And if you look at those patients who are refractory to lenalidomide, we don't have a lot of big prospective study. But the real-world study suggests that their outcomes are actually poor. Their overall survival is less than two years. And their median PFS is about a year. So that means these patients are really in unmet need of some new transformative therapy. Now, as you know, cilta-cel is approved based on the CARTITUDE-4 study in lenalidomide refractory patients with one to three prior lines of therapy in both US and EU. And in the cilta-cel, we saw that compared to the standard of care, cilta-cel significantly improved progression-free survival. So this initial follow-up was about 16 months, where you see the PFS was significantly better in the cilta-cel arm with a hazard ratio of 0.26. Now, in this data, we're going to look at the updated efficacy and safety at even longer follow-up, almost 33.6 months, 34 months follow-up of the data. So this is, I think most of you know, but this is a brief reminder of the design of the study. This is a phase 3 randomized study. The eligible patients who are myeloma patients who are more than 18 years of age had one to three prior lines of therapy and were len- refractory so the patient needed to have a len- refractory. And this is the first trial, actually, that looked at the len- refractory patient population. Because in all the trials of one to three prior lines, they had len-r efractory patient population, but they didn't mandate for all. So really a kind of important study to be done in that context. And then they are stratified by some of the criteria there. But they are randomized one to one to either receive cilta-cel or a standard of care. We chose two standard of care regimens at that time, which is a very active regimen for that period of time, Dara-P om- Dex and Pom- Bor- Dex. Now, patients in the cilta-cel arm, they are randomized there. And then before they get the CAR-T, they were also getting bridging therapy. And the bridging therapy is one of the standard of care regimen. And that is mainly based on the physician choice. You could decide whatever you want to give based on the prior exposure. And of course, after the cilta-cel arm, the patient was followed without any treatment. The primary endpoint being the phase III study's progression-free survival. And there are some number of secondary endpoints that you can see here. Now, this is patient disposition. There are 419 patients randomized 208 to cilta-cel arm and 211 to standard of care arm. So this is the intent to treat population analysis. And patients who received any single or even one dose of the treatment will be considered under safety. There are about 208 patients in the cilta-cel and 208 in the standard of care arm. 176 patients were treated as treated patient population. The patient who progressed during that period of time had a PFS event. They were treated with cilta-cel as a subsequent line of therapy, but not as treated population. As of last follow-up, there are 117 patients in the cilta-cel arm, which were undergoing the post-treatment follow-up compared to 43 patients in the standard of care arm. This is median follow-up of almost 34 months. Now, these are baseline characteristics. I would just like to highlight a few things here. About 20% of the patients had extramedullary disease or plasmacytomas. One third of the patients in each group had one line of therapy. First line, second line, and third line. High-risk cytogenetics. If you include 1q gain of almost 60% of the patients, and 25% of the patients are triple-class exposed. If you look at the triple-class refractory patient, almost one quarter of the patients were Darzalex refractory. In a sense, that's pretty kind of a standard patient population. This is the primary endpoint data, the progression-free survival. As you can see, at median follow-up of that 33.6 months, the median PFS was not reached. The 30-month PFS rate was significantly better in cilta-cel arm, 59.4% versus 25.7% in the standard of care arm. That translates to a hazard ratio of 0.29. Cilta-cel led to almost 30% reduction in the risk of death or progression compared to the standard of care arm. What about the overall survival? I think this is the most important slide of the presentation and of the presentation at IMS. This is the first time any BCMA therapy has translated into overall survival. You can see at median follow-up the 30-month overall survival rate was 76.4% in the cilta-cel arm compared to 63.8%. That translates into a hazard ratio of 0.55. Giving a cilta-cel decreased the risk of all-cause mortality by almost 45%. That is quite profound for this patient population. I also want to remind you that there are very few regimens in one to three prior lines of therapy which have translated into overall survival benefit this early. That really underscores the profound potential of this therapy for patients in general. Of course, this is all translated because of the deep responses that you see with the cilta-cel. So this is the MRD negativity rates in both 10 to the power minus 5 and 10 to the power minus 6. 10 to the power minus 6 is the deepest level that you can achieve right now with the current technology, though there are newer technologies also being developed. But you can see cilta-cel leads to significant improvement or increased rates of MRD negativity at both 10 to the power minus 5 and 10 to the power minus 6 compared to standard of care arm. So for 10 to the power minus, it's almost twofold. And for 10 to the power minus 6, almost fourfold. So perhaps this is what is translating into longer PFS and better survival. What about the safety? I think this is something that we can probably later on discuss. But I would like to highlight some few things. As compared to 15-month follow-up, one thing that is encouraging is that there are no new safety signals that are concerning, so in this, I think there is a slide, but you can see the deaths happen in the cilta-cel arm and the standard of care arm. The first year, the deaths were higher, 13 deaths in the cilta-cel arm compared to 8 deaths, and the second year, you can see the number changed. And deaths due to progressive disease are, of course, smaller in the cilta-cel arm compared to standard of care arm. Now, in the first year, as you know, there is the intent to treat patients. Some of the patients were not treated with cilta-cel because they had progression events. So the death accounted for those as well as the patients who received cilta-cel at the time of progression, rapidly progressing disease. At the same time, there are a lot of COVID-related deaths as well that kind of accounted for the deaths in the cilta-cel arm. We can later on discuss about these issues, what could have contributed further on that subject. Now, another thing that we also need to look at is the risk of second primary malignancies. Now, if you look at the cilta-cel arm and the standard of care arm, the rate of second primary malignancies is pretty much the same if you look at all second primary malignancies. Now, there seems to be a little bit higher number in the hematologic malignancies that you can see there's seven versus one. There were two peripheral T-cell lymphoma cases as well. This is something that we need to further kind of follow-up and exploration and understanding of why that is happening. And if you look at not only this one, there is another randomized study, you know, KarMMa-3. And if you look at this, the rates are pretty much comparable. So this is nothing inherent or unique to cilta-cel. It is probably something that we need a little bit more kind of further research on why this slightly higher number is seen in the CAR-T arm. Now, one thing I would like to focus on this slide is the rates of CAR-T-related adverse events. So in that case, early and the late. So in the early, there is a CRS and ICANS. Though in our cases, we have been much better in managing this in the clinic. And that is not an issue. Just for a fair comparison, you can see CARTITUDE-4 and CARTITUDE-1. The rates of grade III and higher CRS and ICANS is much lower in CARTITUDE-4 compared to CARTITUDE-1. Partly because of two things. One is patients are going with the lower disease burden. Most majority of the patients are sensitive to the bridging treatment. And at the same time, we also are better at managing this much more than when the CARTITUDE-1 was ongoing. It's a combination of those two that has led to lower risk of these early CAR-T-related adverse events. And honestly, in the clinic, day-to-day clinic, when you use this therapy, we are not even bothered by this now than what we used to have this before. In terms of delayed neurotoxicity, that is something that is kind of in the topic of discussion for cilta-cel. You can see it's very encouraging to see that the rates are much lower than what we saw in the CARTITUDE-1. For example, one of the concerning delayed neurotoxicities is MNT or Parkinsonian-like syndromes. It was less than 1% in CARTITUDE-4 and about 6.2% in CARTITUDE-1. Perhaps these patients have lower disease burden. We are doing better because of that. Perhaps we are better at identifying that sooner and perhaps intervening that sooner. There are multiple mechanisms that could be a factor. It's very encouraging to see these low rates of both early and delayed neurotoxicity disease events. In summary, cilta-cel is the first CAR-T I showed you to show the significant overall survival benefit. You saw that with the use of cilta-cel, there was a 45% reduction in the risk of death compared to standard of care patients in those lenalidomide-refractory with one to three prior lines of therapy. I didn't show the slide, but if you look at the subgroup, cilta-cel, this overall survival benefit was consistent across all subgroups, and this is the first time when you look at the forest plot, you will see everything on the one side, and very rarely you will see that, and patients with all high-risk features and everything benefited on that, and more importantly, when you look at the PFS, the median PFS was not reached at almost 34 months. And there are very few regimens that give that magnitude of PFS benefit at that time. And this is quite impressive as well. We saw the lower incidence of CRS, ICANS, and also delayed neurotoxicity compared to CARTITUDE-1. In the real world that Dr. Fonseca just showed, almost 300 patients treated. The rate of parkinsonism was 2%. It's not a trivial number. I think we'll get better at identifying and potentially mitigating that with time. In conclusion, cilta-cel significantly improved progression-free survival and overall survival. It is an effective treatment for this patient population. With that, I would like to introduce Dr. Huang again and take the stage. Yeah. I'll invite Mythili and also Dr. Fonseca to the stage so we can take some questions. So sit here. Oh. Oh, I think so. Yeah? No. Oh, thank you. So I do see some hands raising up from the audience here. But I think before we take the question from the audience, maybe Mythili has one or two questions for the two. Yes, absolutely. Yes, please. Go ahead. So thank you. If we advance to the next slide, I think there are some key questions we'd like to understand from your sort of experience with Carvykti. So maybe first, let's go over how many patients you both have treated with Carvykti. Just to understand your sort of experience. Dr. Dhakal, would you like to go first? Sure. So if you look at both commercial and the clinical trial patient, I must have treated probably over 100 patients now. And of those 100 patients, if you ask me how many parkinsonism I have seen, I have seen one case of parkinsonism. And now I have adopted a strategy how to identify some of the potential risk factors to mitigate that. And as you know, when the Carvykti was first launched, we didn't have good bridging options. And a lot of patients were going in to get the Carvykti with a raging disease. And it's a universal fact that if you give the Carvykti to any progressive disease patient, they're not going to do well, whatever the Carvykti. Even the safest Carvykti in the world would cause damage. So now we are better at getting that disease under control. But at the same time, looking at all the data of the patients who developed delayed neurotoxicity, one of the consistent denominators or the marker was the rapid expansion of the absolute lymphocyte count. So I've been tracking that in the clinic for my patients. And I've been doing some low-cost, potentially effective intervention with the use of low-dose dexamethasone. And I'm fortunate to see that that has potentially resulted in no case of parkinsonism. So again, it's a small number of patients. It's a limited observation. But I shared that experience with some of my other colleagues. And they also have started doing it. And they are encouraged by what they have seen. So I think, again, it needs to be explored prospectively. But what we have seen so far is pretty encouraging. And again, going back to the same last question of how do I prevent and manage. So the key thing is to identify early and intervene early. But at the same time, also identifying the right patient when you offer this therapy and looking at some of these biomarkers to help prevent it. But I must say that as we start treating these more patients, I think we will have a little bit more understanding of what really is the reason that these patients develop delayed neurotoxicity. Fantastic. Thank you, Dr. Dhakal, for sharing your experience. Dr. Fonseca, would you like to? Sure. Yeah. We've treated over 100 patients at our center. I myself have not had cases of parkinsonism. I have had cases of Bell's palsy, for sure, and I know a colleague of mine has had it, so they've seen it, and we follow very similar the trajectory of the ALC as Dr. Dhakal was mentioning. To me, the key question is the very last one, and I think it's not as much the management of what gets established. It's actually the prevention, so at Mayo, we're very keen on the biomarkers, so we use ClonoSeq to monitor patients as well as the mass spec and the peripheral blood, so we really have a very good sense of when the patients are going to relapse, so even in the first relapse, we're going to take patients who will have subclinical relapse. They still don't even have full biochemical relapse. So, in theory, and this is still early. We're hoping to get the data. But assuming that tumor burden becomes a driving factor and that the prevention of this brisk expansion of the ALCs becomes preventive, I think those are the patients that I would like to say would be better treated by CAR-T. In fact, my hope is that we can do so without bridging therapy. As of now, less than 50% of our patients require bridging therapy as they go into CAR-T, which is quite different from when we were all fighting for the slots. And we had limited access. And at the time, it was a Hail Mary pass for patients. Thank you both for sharing that experience. I think one other really important question I think that would be helpful to address is really, obviously, with the CARTITUDE-1 data that was presented at ASH in 2020, almost like four years ago at this point, what have been your impressions of overall the clinical profile? And maybe also touch on what differences in terms of baseline characteristics have you seen really between the comparison of the iMMagine-1 and the CARTITUDE-1 data? I know Dr. Dhakal, Ying mentioned you were a PI in both of these studies. We'd love to get your sort of initial thoughts on that. You know, I would say this is very difficult to compare both these trials because they are done in different time frames. And then the patient profile had changed. The risk profile had changed. The way we manage CAR-T has completely changed. Because as I said, when this CARTITUDE-1 is happening, even one case of fever, you get a call and you wake up all night. Now, any grade II CRS can be managed by our APP. So I think the learning curve has quite gone up quite significantly. So I think it's difficult to compare those two studies. But just in the face value, I think if you compare it, I think it looks like CARTITUDE-1 has a little bit more heavily treated patients with the prior median line of therapy of six, more triple-class refractory. That might be a little bit differentiating factors if you just look at the baseline characteristics of these patients. Again, iMMagine-1 is still an ongoing study. The follow-up is short. We still have to wait and see what is the real benefit with the product compared to cilta-cel. Fantastic. Thank you for sharing. And Dr. Fonseca, sort of your perspective, just like looking at the data that's in front of you, what are your thoughts? You know, it's very intriguing. And I hope what we're seeing is all good news for patients because it may be a reflection of the evolution. I mean, we don't know that for sure. It's still pretty early. And people are very interested in the mechanism, this whole thing with on target of tumor effect and so forth. But I'm very pleased, of course, to see the changes. And I know Dr. Dhakal has more experience with this particular clinical trial. And I haven't seen the data. Actually, we'll see that tomorrow during the presentation with iMMagine-1. Great. Well, thank you both. And maybe I'll pass it back to Ying. Yeah. So we can take any questions from the audience and also from the webcast. All right. Why don't we give it first to Yaron. Please introduce yourself since it's a webcast, telling us your name and also your association. Where's the microphone? Yaron, can you raise your hand again so that they know where you are? Hi. Yaron Werber, TD Cowen. Maybe for both KOLs, I've got a couple of questions. Number one, maybe give us a little bit of a sense since the approval in second line onwards, how much are you using it now in second line as opposed to fourth line? And then secondly, there's a lot of confusion about what the real world MNT and PD is or all of neurotoxicity. And there's all the publications. But when you talk to different centers, some centers are reporting as much as 10%. Some centers are reporting 1 out of 100. Can you give us an explanation maybe why is it so variable? And then maybe finally, as the drug moves up the second line with a more competent immune system, do you think we're going to see more autoimmune situations like PD or colitis, things like that with Carvykti or less? So maybe I can take a first stab at the question. I think the earlier use and we have limited data. So we need to get a lot more numbers. But I think the earlier use will actually be safer. And I think that's probably part of what explains the difference with the various centers. When you look at the real-world evidence paper, the incidences were the ICANS and the use of steroids, which presumptively was to treat the ICANS. The whole notion is if you have a very brisk expansion, I think that's what makes the difference. So my hope, I can't say this is solved. But my hope is that with the monitoring of very early relapse and intervention of very early relapse, we'll see a diminution of that. No, I think. So, to a question about how the second line use has gone up, I mean, you saw the number from Dr. Ying. I mean, the use of Carvykti has overall gone up after the approval, so I'm hoping that this is some of the patients are already being considered for second line and beyond, and if you ask me personally in my clinical practice, I've definitely that has given me a lot of hope and confidence, especially for early relapse patients, those who are young high-risk patients, and I was just sharing a story recently. I have a 23-year-old patient who had myeloma, unfortunate case of myeloma, and she was showing similar. She didn't meet the biochemical progression of the relapse, but her numbers were going up, and I offered Carvykti, and she's doing fantastic so far. So I think these numbers will go up as we start seeing all these patients. And I think the one thing we have to agree is that right now, the slot, there is no limitation to the slot. So if I want to give Carvykti tomorrow, I can get a slot right away. So that is quite encouraging as well. Now, going back to your question about PD, I mean, there is definitely a heterogeneity or variability in the numbers for the centers. So I don't know what really factored into that. You have to look at the patient profile, probably the experience with the center. I don't want to go to that. But of course, we have seen less cases. So that's why we need to have these compiled cases and look at the overall burden. And when you look at these 236 patients in the high-volume centers where you're using a lot of Carvykti, you are seeing overall 2% of that. And so that is, I think, much lower than what you saw in the clinical trial with CARTITUDE-1. Going a little bit back to the referral pattern with approval to one to three, I don't think we have seen yet the change. There's still some heterogeneity in the opinion in both the myeloma community KOLs, whether you would use it there. At the moment, I think people completely agree that we have high risk, or we have functional high risk. No question, people are doing that for aggressive myeloma. The question is, if it's an effective therapy for the standard risk, those would be the patients that would derive the most benefit. Even though it's kind of justified for high risk, it would derive potentially the most benefit for standard risk. I think that's a conversation that will keep going on for the foreseeable future. Yeah. And the patients which I treated in CARTITUDE-4, they were all standard. Some of them were standard risk patients. And they are almost four years without evidence of progression. And they think that is probably the best thing. And they were very lucky. They feel they're very lucky to be randomized because it's a randomized study. Half will go into standard of care, half would. So almost four years they are in. And they feel that that's really good treatment that is improving their quality of life and on and so on. Can we give it to Gena here in the front? Gena Wang from Barclays. So Dr. Dhakal, you mentioned that you're an investigator of iMMagine-1 as well. And maybe one question is, what kind of a PFS, when the data mature, that you consider that will be comparable when we look at the CARTITUDE-1 data? And the second, you did mention that now the new evolving practice, how to using the steroids to proactively control both early onset and late onset neurotox. Can you elaborate a little bit? What is the current practice? And then how much do we know that we can control the late onset neurotox with this proactive steroid use? Yeah. So the first question is, it's very difficult to estimate the PFS. That's why we have to follow these patients. And if you ask me what the best PFS would be, I mean, as long as possible, that would be the best. But if you look at, so the problem that we have is we are comparing two treatments as if they exist in isolation. That's not what happened in myeloma. You have to look at what is happening parallelly. And myeloma is a very complex and very competitive landscape. You are seeing other therapies coming on, like bispecific coming on. Now, if I tell you the bispecific data they are going to present tomorrow, their median PFS is almost going to be 22 months. So if you have that highly effective bispecific, like linvoseltamab, going to be updated data, I heard it's going to be almost close to 20-21 months. So that is quite impressive. So if you have a CAR-T, which is almost 34.5 months in cilta-cel, and then you have bispecific already like 20 months, then you have to be competitive. You have to be somewhere in between or better than that. So I think I would say at least two years. Then it probably puts a kind of make it competitive. And two years, that's just my opinion, that it has to be at least two years and better. And the second question of yours is those interventions. And again, it is limited to a few centers. And the centers that I have shared with, they all seem to be encouraged with what that intervention is doing. To really answer your question, definitely we need a prospective large-scale study, which I think we are in the process of doing it. I'm pretty sure in the next one to two years, or at least in one year, we can really kind of show you whether that intervention is effective. But based on the retrospective, our limited experience from my side, I would say I'm very encouraged. George. Thanks very much, George Farmer from Scotiabank. With regards to the OS that you've seen in CARTITUDE-4 so far, it looks like there's still quite a few events that need to take place. Not saying that those curves are going to come together. But how do you think those curves are going to continue moving as time goes on, given your understanding of standard of care? That's number one. And number two, your comments about bridging therapy, how it sounds like you guys are reducing the use of bridging therapy. Is that common practice? How do you feel about the best compounds to use for bridging therapy? Is there any sort of standard that's evolving right now? Yeah. I mean, first, Dr. Yaron. Yeah. Maybe I'll start with the bridging therapy. I'll leave the OS for you. It's challenging because it depends when you're using it. So if we're using it for the first relapse and the patient has been progressing while on lenalidomide, then there's no question the most standard therapy we would use is a carfilzomib-based regimen. But if you're using it for the subsequent relapse, then you start getting into a little bit of a pickle. What are we going to do with that patient? And we've used anything that works. And that goes from the re-utilization of some of those drugs to some of the common practices that now will include the use of short-term bispecifics, particularly talquetamab, because of the different target we have. But I think more and more, the idea would be to be able to get patients that are well selected for that, even if they were to be used in that second relapse. We want to have patients that go into that rather clean. I know people are using chemotherapy as well too, and even recycling things like selinexor-based combinations. But the reality is, if we had such a great therapy, we probably would be using it. So that's why bridging is a solution. But the best situation would be not to have to bridge. So it's not standardized in any way? No. You don't see that ever evolving? No. No. No. The second question is, what do you think? The curves in CARTITUDE-4? Yeah. I think it will continue to evolve, and I think because the standard of care, if you look at those two regimens, their median PFS is about 12 months at the best. Now, some patients, of course, can go on for at least two, two-plus years, but based on my experience of what I have seen in CARTITUDE-4 patients, I mean, it looks very promising that this continues to evolve, and there will be seeing even more significant difference between the two groups. Leo here in front. Thanks. It's Leo from RBC. I wanted to dive in on something you said about the patient characteristics and the baseline characteristics. I think as we sort of compare all these emerging therapies, a lot of it's going to come down to how different, how sick, how pretreated were these patients? So I guess as you think about that, I guess what are the most important factors that sort of determine whether a patient's high risk, how difficult they are to treat? I mean, is it the number of lines of therapy? Is it whether they're triple refractory? Is it time since diagnosis? Is it extramedullary disease? I guess how do you balance all of those to decide what is truly the most challenging patient? Yeah. I mean, there's not a single equation. Everything you said matters a lot, of course. And in particular for us, it's going to be the status of the patient just when they're experiencing that progression, whether that occurs while on maintenance and if on maintenance, on what agents. When you look at the data front line, what we have now with PERSEUS, you have close to 90% at four years, number one. Number two is people are moving more and more towards this continuation of therapy, maintenance therapy. There was a Greek study that looked at three years of sustained MRD negativity, which is not unheard of now, 77% lack of progression. So I think we're going to have more patients that will be well controlled before and off therapy. Now, if a patient had one of those circumstances, you could argue, well, we can treat the patient adequately with a combination, either with daratumumab, pomalidomide, or a carfilzomib combination. But I always go through this mental exercise. And I'll get to the extramedullary in a second. I tell people, imagine that we have been using for five years a standard of care CAR-T for the first relapse. And I came to you, and I tell you, I have this new clinical trial which involves giving intravenous medication once a week plus this injection that is called daratumumab. No one would change to that just because of the practicalities of what we do. So a little bit of this is a historic bias we have towards the use of some of those regimens that are established. There is no question that extramedullary disease becomes still a significant challenge. There's no established practice for this. Some centers, ours included, believe that for patients that have limited extramedullary disease, there might be a role for radiation therapy for consolidation. We're doing that in patients with CAR-T after we collect lymphocytes. If they were to have a lump or a mass, we consider that patient for radiation therapy. Yeah. I mean, combination of all those factors, there is no one single. But there are a few things that definitely suggest these patients are probably high risk is time to relapse. If you are doing initial therapy and relapse early, that is definitely high risk. And then, of course, extramedullary disease are one. So it's a combination of all those factors taken into account. And then look at that, whether the patient is like I would consider this as high-risk prognostic features. And either having one of them or both of them probably put them at high risk. And Leo, I want to also add that patient selection is very important. For example, in the last two days, I and my colleagues and also colleagues from J&J have been meeting many, many centers. We just learned, for example, from one center that was one of the 20 centers in iMMagine-1 trial. It's a hospital called Northside in Atlanta. So this doctor screened 25 patients for iMMagine-1. In the end, one patient was selected. So that's a screen failure rate of 96%. And I can tell you, across our CARTITUDE-1 program, in general, our screen failure rate for all the trials is in the range of 15%-20%. So clearly, iMMagine-1 has been quite selective in terms of how they select patients. Because this PI even told us that a patient was failed because he had a headache. Here for Kelly in the left side here. Kelly Shi from Jefferies. Maybe to both doctors, how do you communicate to patients each of those novel multiple myeloma agents, including BCMA CAR-Ts and bispecifics, efficacy and safety characteristics, including parkinsonism syndrome? And how do patients take the message and make the decision on the choice of treatment? Thank you. Thank you. It's a long conversation, and we had a conversation earlier today with Dr. Dhakal, and we're saying there might be not uniformity on people saying everyone needs to use CAR-T for that first relapse, but people thought it was reasonable and probably expected that we would have that conversation with patients. And when you explain this, even if you take an hour and you go back and have a second hour, it's hard to go through all the details of what that means, but arguably, you would have the same challenges with any therapy. As an example, IMROZ, frontline therapy for transplant-ineligible, had a mortality of 10%. So how do you distill that for a patient? So we normally go and explain to them the pros and cons, the logistics, what are some of the risks. And I think it's fair to say most of us make a special emphasis on some of the toxicities that we consider of more serious consequence that would have a greater impact on quality of life. And based on that, make a decision of what they're going to do in therapy. Now, physicians carry a lot of weight. And how you talk and how you present things greatly skews how the decision is made by patients. So a lot of that depends on, let me call it, the philosophical approach of the treating physician. Yeah. I think the discussion is always going to be long. We offer all those different kinds of therapies and the pros and cons of these therapies, but especially in the CAR-T, because the patient is committing much more effort than, for example, bispecific antibody, because they are coming, staying locally for a month, and taking time off, having the caregiver for that month time. It's a lot more logistically complex and a little bit challenging than the just bispecific or other off-the-shelf therapies. We want to make sure the patient understands the risk and benefits because of that complicated process. We go off, of course, of benefits, but also we go to each of the risks and the potential risks that could happen, not only immediate, but also later on. And so, I mean, in all these treatments that the patient is getting, the patient is understanding the risks and benefits. And I will tell you, the patients want the CAR-T because of the efficacy that it has. So I think it seems to be the major driver of when you offer these therapies. We offer BiTEs. We offer CAR-T. And we offer different types of CAR-T. And then actually, my experience, I don't know, Dr. Fonseca, what you have seen. But the patient wants to go by what is the most effective treatment that is in front of him. Yeah. Very much so. Jess here in the center. Great. Thanks, Jessica Fye, J.P. Morgan. Question for the physicians. If we fast forward and think about a world where an anito-cel is available and does have a slightly lower rate of parkinsonism than Carvykti, but at the same time will never have as much survival follow-up at any given point in time, who are the patients in this hypothetical future who get an anito-cel? And kind of how do you make that call? I think that's going to be essentially the battle that will exist. Let's say that the data expands and it continues to show no evidence or minimal evidence of neurotoxicity. That would be a major value add, assuming there's some semblance of similarity with efficacy. On the other hand, by then and how the indication might come and how they might have the label, I hope that we have a very good understanding of what the things we're postulating result in in patient protection. So there is some time for Carvykti to just show the data with the earlier use with the first relapse with a better-controlled patient and to see whether this is, I mean, the key question is, is this a class effect? And I use the term double-edged sword. The sharper the sword, the more efficacious it is, but also the more dangerous. Or whether there's something about the construct that makes it different. And I know people will kind of hypothesize for years about those things. But I think the empirical data is what's going to be critical. So I would say that that may happen. And if it was available for earlier on and there was no neurotoxicity, of course, that would be a value add. I would hope we have, by then, a very good understanding of what the implications are of these approaches towards Carvykti. Yeah. I agree. I think just looking at the data right now, I don't think there is any differentiating feature that would offer one versus another one. Because I think most of the thing that relies on is how to mitigate that and then potentially trying to see what is the long-term effect that this particular product has. And then I think both products can be used in any patient. And of course, we have to see the long-term follow-up of the anito-cel and see how that pans out in that larger. You have to give the time and number. Those are the two important things you have to do for any treatment. And you say that this is what it looks like. But as you start treating more patients, you really see what is the real kind of impact of that treatment. So I think we just have to wait a little bit longer. And that's the fact in medicine. And you just have to, at least right now, we have seen Carvykti being used for almost five years. And we have seen all the plus and minuses of that therapy. Jess, maybe I'll add that in the last two days, again, we have met many of our top 15, top 20 customers, centers like Mayo, Medical College of Wisconsin, Hackensack, which used more than 140 commercial slots. They don't really see that as a problem. We just met with also Colorado Blood Cancer Center, part of the Sarah Cannon. Again, they try to use ALC as a biomarker and then track that and then use a three-day short course of steroid. They don't see the problem. In fact, that data hopefully will be published soon. So I do think that in real world, what we're seeing is that many physicians are learning how to manage that. And that's also taking learning from the selinexor program. And I also want to say that I know there are so many centers. We have today 90 centers in our certified network to prescribe and use Carvykti. Some of the brokers kept using one single center in Boston to talk about the real-world experience, which I don't believe is representative. In fact, we also spoke with a doctor from the University of Wisconsin who enrolled three patients in the iMMagine-1 trial today. He told me, so far, out of the three patients, two already had HLH, and one was a grade 5 HLH. Unfortunately, the patient died from that. A lot of these details in those things may not be in the abstract or posters. I recommend you guys talk to more centers and more doctors. I think the other thing I think it's important to mention is the outpatient use. Being able to penetrate into outpatient clinic early and have that capability, I think, is going to be really important. And I think cilta-cel lends nicely to that opportunity. I totally agree. I think cilta-cel is the product that is best poised to give outpatient. I mean, because you can tell the patient on day seven, you're going to have fever, and the patient will have fever. If at all, that is CRS going to happen. Because for the first seven days and plus three days of lymphodepletion with the one day of rest, almost 10 days, the patient will be completely outpatient, even if they don't have the outpatient management program. But for Mayo and us, we do completely outpatient, and we have the resources to kind of treat them completely outpatient. But in places where even they don't have the completely outpatient management program, you could administer this product outpatient and monitor them for almost seven days without any issues. So, I think of all the products we have right now, I think cilta-cel is definitely the best poised to be given outpatient. Of course, not all patients will be outpatient. You have to select the patients. Somebody with a rapidly progressive disease, of course, and or comorbidities, you don't want to give outpatient. You have to select them. But of eligible patients who can get outpatient, I think cilta-cel is probably. Mitch here in the back. Hi. Mitchell Kapoor from H.C. Wainwright. Just wanted to ask if you could quantify, if you had to, thinking about anito-cel, could you quantify what you would be OK with in terms of PFS trade-off to have no SPMs or neurotoxicity, parkinsonism particularly? I'll just start. No. I said, I mean, it's a very difficult question to estimate what PFS you would want to trade off with. Of course, we don't want any patient to have parkinsonism, and you cannot measure that with the PFS benefit. I mean, you see the cilta-cel PFS is right now the queen, is like 34.5 months, and nothing has beaten so far. So I think the next strategy is to, rather than looking at the number, how we mitigate that and prevent that. I think that's really the key. So the patient get that same 34.5 months or even longer and don't get this delayed neurotoxicity. Even the small risk, you don't get it. So that's what I would go by. I don't know whether we can get that number and then say on that. The difference in patient populations matter a lot. We've seen that with every single clinical trial in myeloma. As much as you try to adjust, sometimes it's very hard to know precisely with the numbers. I would just say a rough equivalency would be probably enough. OK, and then on stringent CR versus MRD negativity, could you just talk about how you weigh those two when you're thinking about a therapy coming to market? Sure. I can take that one. So there is no question that MRD negativity is moving in to be the goal of myeloma therapy. More and more, it's clear that there's no significant or substantial difference between the various response categories to IMWG. And the only one marker that truly predicts this achievement of MRD negativity, there's still this ongoing conversation whether it's 10 to the minus 5. I believe it's 10 to the minus 6 that is going to be ideal. And one of the things we've learned, and it's maybe too much detail beyond what we want to talk today, but now we know that the protein electrophoresis and immunofixation, when you have small proteins, is totally unreliable. Any M-spike less than 0.5 cannot be counted to be 0.5. The reason I say that is because we're using now routinely mass spec analysis to measure small monoclonal proteins. Patients that are said to have monoclonal proteins don't have them. When they have them, sometimes they get a 0.4, and then it's 0.02. It's totally unreliable once you look at small monoclonal proteins. I've made the argument that as we look at these clinical trials, we might not even need to have the response category. As long as we report the MRD status, that might be sufficient. I use the analogy like you're doing rounds, and you spend half an hour talking about the X-ray, only to say, now let's look at the CAT scan. That's really how we're thinking about MRD negativity. It gives you the precise view of what's going on. Asthika in the back. Thanks. Asthika Goonewardene from Truist Securities. Thanks for taking my questions. To the two physicians on stage, I was wondering, you both described how slots are no longer a limiting factor for getting Carvykti to patients. So could you maybe talk to us a little bit about what the bottlenecks are that you're seeing today? And also, when you think about capacity at your centers, how many patients can you leukapheresis each month? Yeah. I think the slots point of view, definitely no limitation. As I said, if I want to give a Carvykti tomorrow, I can get the patient right away. I think the bottleneck probably would be the availability of apheresis space at the center. At our place, we are a medium to large volume center. We do about 400 kind of Carvykti/stem cell transplant. So we probably can do about 10 a month, five to 10 a month. At the maximum capacity, I have done like 12. But in addition, we have our own Carvykti program and the clinical trial going on that. So with that, I think that probably is going to be the major limitation. So that's why there is a talk, at least at our center, trying to how to expand that and how to use the other spaces to utilize this for leukapheresis and all those stuff. So the institution has to work on that. But otherwise, beyond that, I don't see any bottleneck from my point of view. Honestly, it shouldn't be because the centers have a good line of business with the Carvykti as well too. The leadership of the hospital pays attention to this. I would say the leukapheresis sometimes give you a hard time. It's just a one-day collection. We don't have to use growth factor. It really should be greatly simplified. I would argue that given what I've said about the line of business, we should expand capacity as well too. Now, moving to the outpatient releases a lot of hospital beds as well too. Right now, we're in the range where we're going to be doing about 10 per month as well too. I think that should be highly doable. And if I can just add another question on Carvykti and anito-cel here. As you said, you're going to be in a position where you're most likely going to have access to both. So what would you think is the ideal patient to give Carvykti? And what is the ideal patient you'd want to give anito-cel? I think this is the same question that I was, and the answer would be the same. We still have to see the long-term data from anito-cel to see what subgroup of the patients or what is the overall benefit, and then I think based on that, you probably decide, but at this point of time, it looks like there are patients that would get either of them. So would you characterize these two products are similar in your hands in safety and efficacy? Yeah. I think I would say pretty much the same. I mean, we have to still use the real-world patients, the anito-cel, right? So it's two. And then we need to have the real-world data to emerge to really have. I think the clinical trial data is one thing. But I think the real value of the product will be seen in the real world. And the crucial piece of information, people don't miss it. And I think that really has to come up and then try to compare how they look like. Curious, how many patients did you screen for iMMagine-1? And eventually, how many were you actually enrolled? I don't remember because I was the first one to enroll. So I think I enrolled quite a bit. I had to look at that number, how many I screened. But I don't think the number is not like that, what you reported. It's definitely way, way less than that. Thank you. We do have a question from the webcast. Caroline, can you read? Yep. So this is from Justin Zelin. And I think he's asking if you can discuss the reduced incidence of neurotoxicity in CARTITUDE-4 being related to earlier lines of therapy or from introduction of mitigation strategies. And how are the trends in the real world? We think it's mostly related to the earlier introduction, better control, more proactive approach. At the beginning, when we were doing Carvykti, we were holding quite a bit on the decision to use tocilizumab. Back at the first kind of phase on how we're using Carvykti, there was a more conservative approach towards the management of that. So I think that's probably the biggest factor that makes that difference. Yeah. I think when these delayed neurotoxicities were observed in CARTITUDE-1, then there is a CAR-T wide program initiative to have fewer strategies. One of them is decrease the disease burden and also more aggressive monitoring of the CRS ICANS and also monitoring these patients a little bit longer. So that was adopted in all CAR-T program in CARTITUDE-4 and the newer CAR-T studies. And I think one of the most kind of important factors in those CARTITUDE-4 patients are probably decreased disease burden. And at the same time, in addition to identifying these CRS ICANS early on and treating them aggressively, must have contributed. Thank you. I think we're at time, everyone. OK. And now we're 10 minutes past. So again, thank you very much for coming to this event. And I'm sure our team will be still around here if you have more questions. Thank you. Thank you.