Welcome to this Legend Biotech Investor Meeting, which we're holding on the sidelines of the sixty-third annual meeting of the American Society of Hematology. I'm Tina Carter, Senior Manager of Corporate Communications and Investor Relations at Legend Biotech. Before we begin, on these slides, you'll find our forward-looking statements. We encourage you to review this cautionary statement regarding information and remarks included in today's presentation, as well as the company's Form 6-K, which identifies certain factors that may cause our actual results to differ materially from those expressed in these forward-looking statements. The information in this presentation speaks only as of the date hereof. Legend assumes no duty to update the information to reflect the subsequent developments. To see the progress and updates announced today in further detail, you can access our SEC filing and the presentation slides in the investor section of legendbiotech.com. On slide three, you'll find our disclosures. We have the pleasure of being joined by two key opinion leaders to go over the latest developments on CARTITUDE-1 and the CARTITUDE-2 studies for cilta-cel. Today's meeting will begin with opening remarks from our CEO and CFO, Dr. Ying Huang. Dr. Sundar Jagannath, one of our key opinion leaders, will provide important data on the CARTITUDE-1 and CARTITUDE-2 studies for cilta-cel. We'll open up our panel discussion with the doctors and several members of our leadership team. Now with that, I'd like to introduce you to the CEO and CFO of Legend Biotech, Dr. Ying Huang. Thank you, Tina, and good evening and welcome to Atlanta. Thank you for joining us today. We're very happy to be live and in person here in Atlanta at ASH for the first time since 2019. Tonight, we'll be sharing the progress made on the CARTITUDE development program, including the latest on the pivotal CARTITUDE-1 study and also the multi-cohort CARTITUDE-2 study. Joining us to bring that data to you are two prominent key opinion leaders in the field of multiple myeloma treatment, Dr. Sundar Jagannath and Dr. Saad Usmani. Dr. Jagannath is the Director of the Center of Excellence for Multiple Myeloma and Professor of Medicine at the Tisch Cancer Institute at Mount Sinai. Prior to joining Mount Sinai School of Medicine, Dr. Jagannath served as Chief of the Multiple Myeloma and Transplant Program at St. Vincent's Hospital. Dr. Jagannath has published more than 180 peer-reviewed articles in New England Journal of Medicine, Blood, the Journal of Clinical Oncology and Cancer, and other leading journals. Dr. Sundar Jagannath will provide the latest data on efficacy and safety results from the CARTITUDE-1 study, and also from cohorts A and B in the CARTITUDE-2 study tonight. Dr. Usmani is the Chief of Multiple Myeloma Service at Memorial Sloan Kettering Cancer Center, and is a Professor of Medicine at the Weill Cornell Medical College of Cornell University. Prior to his current roles, Dr. Usmani served as the Director of the Plasma Cell Disorder Program and the Director of Clinical Disorder Program, and Director of Clinical Research in Hematologic Malignancies at Levine Cancer Institute of the Carolinas HealthCare System. Dr. Usmani is a specialist in hematology, medical oncology, and bone marrow transplantation. His clinical and translational research has been focused on plasma cell disorders in general and high-risk multiple myeloma specifically. Now with that, please welcome Dr. Sundar Jagannath to discuss the CARTITUDE-1 clinical development program. Dr. Jagannath. Thank you for that, kind introduction, Dr. Ying Huang, and it is a pleasure to co-chair this session with my colleague, Dr. Saad Usmani. Today it's my pleasure to talk about CARTITUDE-1 study, which was reported in the ASH meeting. Tom Martin presented the two-year update on CARTITUDE-1 primary efficacy and safety. Marie-V Mateos from Spain, she presented the comparison of CARTITUDE-1 with the real world data, which is called LocoMMotion study. Then my colleague from Chicago, Andre Jakubowiak, he had a poster presentation doing the subgroup analysis. These were all presented, and it's my privilege to actually review them for you. Just as a backdrop, you know, cilta-cel is a CAR T-cell therapy for relapse and refractory in multiple myeloma patients. The CAR construct is very unique for this product, you know. It is shown on the right-hand side of the panel. It has two BCMA targeting single-domain antibody to confer avidity, and has a CD3ζ signaling domain and a 4-1BB costimulatory domain to optimize T-cell activation and proliferation. In the phase Ib/II CARTITUDE-1 study, early, deep, and durable responses were observed with a single cilta-cel infusion in heavily pretreated patients with relapsed and refractory multiple myeloma. Last year in the ASH, we gave you the results at a median follow-up of one year, and we are very happy to present you this year an updated results after a median follow-up of 22 months or almost three years. Now, CARTITUDE study design is shown on this slide. The primary objective in the phase I-B portion was to characterize the safety of the cilta-cel and confirm the recommended phase II dose that came out of China. In the phase II, we had to evaluate the efficacy of cilta-cel. The key eligibility criteria are shown there. The patient should have progressive myeloma with three or more lines of prior therapy, or they should be double refractory to PI and IMiD, or they should be triple class exposed. Everyone should be triple class exposed to prior PI, IMiD, and an anti-CD38 antibody, and they should have measurable disease and in good performance status. On the right-hand side, it showed the flow of the patient in the study. You know, following screening, the patient underwent apheresis, bridging chemotherapy, if it was indicated, it happened in 73 patients. Approximately three weeks later, the patients received lymphodepletion chemotherapy, which is cyclophosphamide and fludarabine given over three days, followed by cilta-cel infusion. It was not a fixed dose. The cilta-cel dosing was, you know, based on patient's body weight. The patients received a median of 0.7 million viable CAR T cells per kilogram body weight. Now this slide shows the CARTITUDE efficacy response. I've been doing myeloma for 30+ years. These are really incredible responses in relapsed and refractory myeloma patients. Overall response rate of 98%, we don't even get that in the upfront situation. That is indeed very remarkable. The responses deepen over time from one year during the last one year follow-up. If you look at what we reported last year, the best response after median one year follow-up, stringent complete response rate was 67%, but this year, Tom Martin updated it and said after a median of two year follow-up, it is 83%. Okay. Not only that, these responses were durable. The median duration of response was not estimable. 60.5% of the patients are still progression-free at two years. Of the 61 patients who were evaluable, 92% were MRD negative by next-gen sequencing. The next slide shows the CARTITUDE-1 progression-free survival and overall survival. What do you see here? The median progression-free survival and median overall survival are not reached after a median follow-up of 22 months. The progression-free survival was 60.5 months at two-year mark, and the overall survival was 74% at two-year mark. You can see the progression-free survival and overall survival improved in patients with MRD negativity sustained for six months or greater than 12 months. This was shown as a slide by Tom Martin in his presentation. Let's go to the subgroup analysis. This was presented as a poster by Andrzej Jakubowiak. What you see, the responses to cilta-cel was durable up to two years in most subgroups of patients with heavily pretreated relapse refractory myeloma with consistent safety across the subgroups. The patients which are in a box in the red, you could see the patients with high-risk disease, ISS stage three at baseline, and presence of baseline plasmacytomas had similar high overall response rate, but the duration of response was shorter. Now we look at the CARTITUDE safety. In the past one year of extra follow-up, no new safety signals were observed now with a median follow-up of 22 months or approximately two years. No new events of neurotoxicity or movement and neurocognitive treatment-emergent adverse event, what we call as MNT, was reported in CARTITUDE-1, you know, during the last one year of follow-up. After implementation of an MNT patient management strategy, approximately 200 patients have been dosed with cilta-cel across CARTITUDE clinical development program, and MNT incidence has decreased to 0.5%. I will share the data when I show you CARTITUDE-2 data. No new treatment-related death occurred during the past one year. This is indeed remarkable. That means the patients who went into complete remission, deep remission, et cetera, and then made it past one year, they are all being still followed. I personally have patients who have made it to three years in complete remission MRD negative status because it is now coming to that phase, because we started in the phase I safety first in human study at our center. This is indeed remarkable safety signal here. Now we'll go to LocoMMotion study. What is this one? You know, we wanted to put CARTITUDE-1, what it really means in relapse and refractory myeloma patients. As I said, they should have had more than three lines of prior therapy or should have been double refractory and should have been progressing, you know, after the last line of therapy. You know, we set all that, and everybody should be exposed to the three classes of drugs. What happens to this patient in real world as compared to what CARTITUDE can offer them? This is where you had a real-world comparison, LocoMMotion study. It is a first prospective efficacy and safety study of real-world clinical practice. It's an observational study in heavily pre-treated triple class exposed patients with relapse and refractory myeloma. Patients were included from nine European countries, 91% of the patients came from there, and from United States, 9% of the patients were coming from here. Ninety-two unique regimens were used. This is not uncommon. They include carfilzomib, dexamethasone, pomalidomide, Cytoxan, dexamethasone, pomalidomide, dexamethasone, just to give you a flavor of all these different combinations that have been used. You could see how they are bridged. There were 113 patients enrolled in CARTITUDE-1, 248 enrolled then died, progressed, or withdrew consent, and then 97 patients went on to CARTITUDE-1 and were infused with the drug. There were 97 patients on CARTITUDE-1, and similarly, there are 170 LocoMMotion patients, progression-free, alive 52 days post-therapy, and they were the ones who were compared. Now, what do we see in the comparison? You could say the observed rates of overall response rate, very good partial remission or better or complete remission or better, were all significantly higher in cilta-cel cohort. You know, 82.5% of cilta-cel patients achieved complete remission or better, versus only one patient on the real-world clinical practice with the currently available agent can even dream of achieving a complete remission. Okay? Patients treated with cilta-cel were 3 times more likely to achieve a response and compared to real-world clinical practice and at least 5.5 times more likely to achieve very good partial remission or better. This one shows the progression-free survival and overall survival. You know, cilta-cel, I don't even have to speak to it, you can look at it. Cilta-cel significantly reduced the risk of progression or death by 85% and risk of death by 80% compared to the real-world clinical practice cohort of patients. Now let us look at the safety. Cilta-cel patients experienced more adverse events of any grade, but they were all manageable. Following cilta-cel, most frequent adverse events were hematologic. Of course, unique to cilta-cel or the CRS and neurotoxicity that were seen there. Treatment-emergent adverse event, you know, if you look at it, treatment-related death was 6.2% on cilta-cel and 19.7% in real-world clinical practice. That is why we feel that I could use the term that the, you know, the toxicities were manageable on the cilta-cel because treatment-related death was no worse on cilta-cel versus real-world clinical practice in these patients. Now let's talk about CARTITUDE-2. CARTITUDE-2, we had several cohorts in this one, and you have cohort A, results were presented by Yael Cohen from Israel. This is progressive myeloma after 1-3 prior lines of therapy, and they were lenalidomide refractory. Cohort B results were early relapse of myeloma within one year after initial therapy. These results were actually presented by a Dutch person, Dr. van de Donk. He made these presentations. Let's review what did they have to show in the ASH meeting. The study design is shown on this slide. The primary endpoint is, you know, instead of overall response rate, they actually went for minimal residual disease by next-gen sequencing. The secondary endpoint included overall response rate and duration of response and, minimal residual disease negativity, time, and duration, and adverse events for safety. On the right-hand side, you see the sequence of events, which is exactly the same. Screen the patient, do the apheresis, give bridging chemotherapy if necessary, lymphodepletion. Everybody got 0.7 million viable CAR T cells per kilogram body weight. Then they were followed. In Cohort A, these are patients with progressive myeloma up to 1-3 prior lines of therapy, and they had to be lenalidomide refractory. That is considered to be adverse event. In the cohort B, we have early relapse within a year, in a frontline therapy that included PI and IMiD, because we all know VRd, KRd are the frontline treatment strategy right now. Now we go on to look at the CARTITUDE-2 cohort A. There were 20 patients, and look at their response rate. Again, overall response rate is 95%, and most of the responses are complete remission or better. 85% is complete remission or better. You know, 6-month PFS was 95%, 12-month PFS 84%, you know. And of the 13 patients evaluable, with evaluable samples, 92% were MRD negative by next-gen sequencing. All of that was very good. And safety was manageable, and such that even one of the patients was actually treated in the outpatient setting. They got the CAR T-cell given in the outpatient setting. The CRS all grade you could see was there. 95% of the patient had CRS, and grade 3 was only 10%. The neurotoxicity was there, 20% ICANS, but grade 3 was none. No cases of MNT was encountered here. There was one treatment-related death, but that it was due to COVID-19 at day 100. That's unfortunate at this time. Now, CARTITUDE-2 cohort B, 19 patients were enrolled on the study. Again, look at the overall response rate, 95%. Complete remission or better, 79%. It is still remarkable response rate. Six months PFS 90%, 12-month PFS 84%. You know, all of them are very good. Of the 13 evaluable, you know, 13 patients with evaluable sample, 92% MRD negative by next-gen sequencing. Again, manageable toxicity, you know, CRS 84%, grade 3 5%, neurotoxicity 26% ICANS, grade 3 5%. One patient did have MNT on this one, but there was no treatment-related death at the time of data cutoff when they were presenting for the ASH. If I have to summarize and put them all side by side for you, so you can at a glance look at what cilta-cel can really do. Consistent response rate, whether you go to relapsed refractory myeloma patient, CARTITUDE-1, you know, triple refractory, group or, penta-refractory or penta-exposed patient, 98% overall response rate. CARTITUDE-2 cohort A, 1 - 3 lines, 95% overall response rate. You know, again, in CARTITUDE-2, those who have really poor prognosis progressing within a year after getting IMiD and PI, they went on this and they got 95% overall response rate. Across the board you can see stringent complete response rate is 80% or better. It is indeed a. This is gonna take the field by storm. It is unprecedented results that I had the pleasure of actually sharing with you. These were all presented by my colleagues already in ASH. I'm happy to be here with Saad Usmani, my friend. We were going to be together, but I decided to stay out of Atlanta for the time being. I'm all virtual here. Thank you, Dr. Jagannath. We'll now prepare for a panel discussion on the CARTITUDE-1 and CARTITUDE-2 studies. Joining us to answer these questions are the doctors, Dr. Lida Pacaud as well, our head of Clinical Development, Yu-Hung Chu, head of Regulatory Affairs, Tanya Nishwat, head of Medical Affairs, and Steve Gavel, head of Commercial Development, as well as Dr. Ying Huang, our CEO. Okay. If you're in the room today, please raise your hand and you'll be provided with a microphone. If you're joining us virtually, just put your questions into the chat and we will try to answer everything in the remaining time. Hi. Yeah, this is David Dai from SMBC. Quick question on the CARTITUDE-2 cohort B, the one patient with the MNT. Can you just tell me more about that patient and what's the patient characteristics look like? And did he also have any kind of CRS or any kind of you know other AEs associated with MNT? Excellent question. You got from the Cohort B was actually patient with poor prognosis because they were progressing on frontline therapy within a year. This was a patient who was actually treated in one of the centers in Europe, I believe. He was a young man, 40 years old. You know, in MNT we have said, one way to avoid this particular complication when we said we wanted to put in, is that if the disease is out of control, you try to give bridging chemotherapy, get the disease under control, and then you move on. The young man whose disease was already progressing on frontline therapy, they did collect the, you know, they did the apheresis, but then they gave him a bridging chemotherapy, but the disease still progressed. You know, this is exactly where we said we could run into trouble. This was a young man and, you know, as physician, at the end of the day, you hear it all, but when you are a bedside physician, you know, you really are compassionate. I don't blame the physician. I would have done it too, but we kind of take a little bit of risk. This patient, you know, later on developed a you know MNT symptomatology. He did have CRS, so it was all expected. He did have a good proliferation of the T cell, and it was sustained. We had expected that these few patients who ran into trouble are in whom there is a rapid expansion of the T cell, very high level, and it is sustained, and it was also sustained in the patient. But because of that and the expected. But he was managed, and he's doing all right. As I told you, there has been no mortality in the study. You know, I can't be, you know, I can't tell you more than that, day to day, but all I do know that the patient is doing well as the, and, you know, ongoing, whatever, physical therapy or whatever. But he we were able to manage him successfully and get him out of trouble. We have a few questions here on expected updates. What are other cohorts presented from CARTITUDE-2? When can we expect that? This is Lida Pacaud from clinical team. We will report data as they mature. Some cohorts probably next year, and then some other cohorts started enrollment recently, and they are not mature. We will report some probably mid next year and end of next year. Similarly, when can we expect first updates from CARTITUDE-4 now that enrollment is complete? Yes, I think we are very excited obviously with the cohort A data with prior 1-3 lines from this presented here, and this is exactly the same population in CARTITUDE-4 trial. With response rate we see here as well as durability of response we see in CARTITUDE-1, we are very excited about CARTITUDE-4. We have completed recruitment and yeah, as soon as data are mature for phase III trial, we will report. We cannot comment and speculate on exact date right now. For the doctors participating today, once cilta-cel is available, how do you expect physicians to choose between commercially available BCMA-targeted CAR T products? We can start with you, Dr. Jagannath. I mean, once cilta-cel available, you saw the data and, you know, I'm maybe also a little bit biased in the sense the responses, as I told you, are unprecedented. I've not seen in relapsed/refractory situation these kind of response rates. I think cilta-cel will be really taking the field by storm. There will be a lot of patients who will be clamoring for access to this particular product. That's my feeling. Even as a physician, if I had a choice, I think this is good. You know, the future is also very, very good in the field, you know. We will see how it goes. Dr. Usmani, who's joining us currently from this Zoom, would you like to add anything? No, I would echo Dr. Jagannath's impressions. You know, we are very impressed with the cilta-cel data, and I think CAR T-cell therapies would be the preferred choice for us, you know, for a BCMA-directed therapy. You know, I think that the only piece would be the logistics, you know, of making sure that we can keep up with the number of patients that may require them. Otherwise, you know, I think all of us are quite impressed with this one and done kind of an approach. You know, I agree with everything that Dr. Jagannath has said. What do you think it will take to enable outpatient use of cilta-cel in the real world? Well, you know, we have to be cognizant of the fact it'll become a center-dependent experience and how you are structured. You know, in the center which is able to provide 24/7, there is an expedient way of bringing the patient in or managing the patient. You know, that in those centers you can start giving the lymphodepletion outpatient, and you can give the cilta-cel. The beauty of cilta-cel is you don't get CRS within 24-48 hours, which is what we see in other products. Typically, they are seen very early. Different products has different time frame, I found. There is one product which gives you within 24-48 hours, ide-cel. There is another product from BMS next gen CAR T, which is about three days, 3-5 days, and this one is more like closer to seven days. You would be able to take a patient, including infusion of the CAR T-cells, and manage the patient up to day five or six, and you have the option of electively keeping the patient for just another five days or so. If they don't have any significant, then you can discharge. This gives you a lot of flexibility and the predictability, so that's also important, you know, of the product. I think cilta-cel is unique in the sense that you can predict that it is somewhat delayed, and then you can, you know, manage it well. I think. I'm not saying that every center is gonna immediately do it as an outpatient. The center experience. Not only the physician experience, also the facility provider, which depends upon the hospital and the institution. There is more to it rather than just coming here and saying that, "Oh, this could be done as an outpatient." I don't wanna give that kind of an impression. Yes, you know, I think, you know, Dr. Jagannath is hitting the point, you know, for centers who already have the capability of doing, you know, outpatient transplants and have that kind of outpatient support algorithms and SOPs in place. Some have already, you know, started to do CD19 CARs in the outpatient setting. For those kind of centers, you know, they may opt to do cilta-cel because of the predictability of when to anticipate the CRS in the outpatient setting. For others, it may be a learning curve. Okay. Did we observe a negative correlation between EMD and response rate? Extramedullary disease, is that what you're talking about? EMD. You know what, as I showed you, the response rate is phenomenal. We couldn't show the response is poor in patient with EMD or any particular subcategory because the response rate, once you are at hitting 96%, you know, 97%, et cetera, you don't have response rate. I did show that yes, durability of response would be an issue. This is where we are learning in this particular ASH. There were sessions where people showed that there could be RAS mutation in patients with extramedullary disease. You know, there are drugs for RAS. You already have combinations coming with bispecific, you know. There are other ways to tackle it. We have not fully explored the maintenance strategy or keeping the CAR T-cell much more active, if necessary, in the patient with extramedullary disease. There are other strategies have not been explored because you got to remember, this is a rapid development towards FDA approval type of an approach. I'm pretty sure we will be able to tackle those EMD also effectively. Tumor cytoreduction is phenomenal across the board. At 96%, you cannot say the EMD patient won't respond. Our challenge is, okay, how are we gonna keep them and how to cure myeloma. We have a question, another question for you, Dr. Jagannath. How would you describe the change of toxicity profile, including both CRS and MNT, from late line to early lines of patients treated with cilta-cel? That's an excellent question. Actually, we actually saw the data. You know, here we have, you know, 1-3 lines of therapy. Patients went through it, 20 patients, no EMD, impressive response rate, like fantastic. You know, you were able to give easily tumor cytoreduction. When you move into one-year rapidly progressing patient who was refractory to IMiD and proteasome inhibitor within a year, and his disease is progressing. When those doctors tried to give, you know, after CAR T collection, when they tried to give the bridging chemo, the bridging chemo didn't work, you know, in that particular patient. He ran into trouble. My feeling is, cilta-cel in earlier phase of disease will do phenomenally well, but you have to respect and have the strategy. If one bridging chemo didn't work, maybe you should look at a second bridging chemo, bring the disease down and then give cilta-cel, you know, so that you can completely avoid MNT. You know what to do, how to avoid it. You know, at the end of the day, we are physicians taking care of patient, and you sometimes make the decision on the spur of the moment because, you know, what you're going to do with a 40-year-old young man who's, you know. In this day and age, to lose a patient within two years is so heartbreaking in myeloma because you have myeloma patients who are being cured, myeloma patient doing so well in relapse refractory, bispecific, this, that. Now a patient comes to see me and looks me in the eye, it'll be heartbreaking for me to lose that patient within a year or two, I tell you. Tina, do you want to repeat the question so Dr. Usmani can also weigh in on the same question? Sure. How would you describe the change of toxicity profile, including both CRS and MNT, from later lines of patients treated with cilta-cel? No, I think, you know, we would anticipate that we have gone through this learning curve in the late line setting and how to cytoreduce patients effectively like Dr. Jagannath has stated. That would be, you know, the optimal goal. But there are going to be situations where you may not have that kind of optimal control, yet you do want to get your patient to an optimal response. I think it's not a one-size-fits-all kind of an answer. You know, we do anticipate better management and recognition of CRS and ICANS. But there are going to be instances where there will be, you know, high-grade events that we'll just have to manage as good clinicians. Hopefully by then we'll have bispecific and others, so we would know how to bring the disease down. Yes. Yeah. We are getting smarter. We are still going to medical school. Another question for the doctors. How do you envision deploying cilta-cel in multiple myeloma upon approval? In which patients would you envision using cilta-cel? I think you've spoken to this a little bit, but we'd love some elaboration. I think, you know, Saad can speak to it more. Right now, when they approve, the FDA is gonna approve in with patients who have failed three lines, you know, therapy and should have had PI, IMiD, and anti-CD38 monoclonal antibody, et cetera. Just because it becomes commercially available, you know, I don't think it is gonna move. I mean, all the clinical trials have to be done appropriately. I think it'll be mainly for me at our center, there are patients still dying who have failed all treatment, et cetera. The patients who have failed and meet this criteria, as I exactly said, the inclusion criteria for cilta-cel in the CARTITUDE-1 trial, those patients would be the ideal candidate right now for me for this study. I'll defer to Saad, who has a little more clinical perspective. What do you wanna say, Saad? I think, you know, we'll have to comply by, you know, the indication that the, you know, that cilta-cel gets approved to. I'm also, you know, interested in seeing, you know, how the data will look like in patients, you know, who may not have met the criteria for CARTITUDE-1, such as renal, again, on basis of renal insufficiency status. Dr. Jagannath, you and I know that many of those patients in the relapsed refractory category do not meet those criteria. I would really hope we can generate data to benefit all of those patients and include them. The other group where, you know, I hope that the field moves into is for frontline high-risk patients. I think in CARTITUDE-2 there is a cohort that's looking into this question and that is something that I'm really looking forward to, you know, getting some of that data, in the coming year or so. Yes. You are right. You know, some patients who would not have qualified for clinical trial could still go on this one because non-secretory myeloma. There had to be measurable disease to be on this particular study. Some leeway on some renal impairment. Renal impairment may be a little bit of a challenge because the third-party payers may also insist on the eligibility criteria meeting exactly what was in the, so, you know, what was there in the CARTITUDE-1. Yeah. That one we will have to go to pharma to Legend and to Janssen and say, "Hey, you need to give us a study whereby some renal impaired patients could be tried in a, you know, in a small run of 20 patients or 40 patients or something like that." I agree there will be a lot more patients who would not have gone on the clinical trial for some other reason would be eligible to go on the study, on the treatment once it is commercially available. Okay. Further questions online. We've seen some significant impacts of MRD negative status on patient survival generally. Could you share the information of the patient baseline characteristics of the MRD group? Sorry, I was a little distracted. Go ahead. There's a question regarding the patient baseline characteristics of the MRD group. Baseline characteristics of MRD group. The MRD, as I told you, in those it was evaluable, it was already over 90% of the patients were MRD negative. This is almost like asking me about who will respond, the response rate. You know, I can't find out a subset who will, would respond. Likewise in MRD negativity, the depth of response is phenomenal. Those in whom they can do the next-generation sequencing, et cetera, over 90% of them did achieve MRD negativity. I don't see there is a unique characteristic to say who would achieve MRD negative status. Saad, do you have a little different take on that or insight? No, I agree. You know, when we have such a high overall response rate, it's you're really comparing to only one or two patients who've, you know, in fact, just one patient, if I recall correctly, you know, who was not evaluable for that response. You don't have that denominator in that category. You know, it's very difficult to say that certain subset benefits more on one arm than the other. Yeah. This is David Dai from SMBC again. One question for doctors. For CARTITUDE-2 especially in the earlier line setting, you know, we're looking at what, you know, 1-3 prior lines cohort A and then early refractory patients in cohort B. Mm-hmm. Just help us understand just sort of the PFS rates and survival rates in those patients. You know, what's really the clinical benchmark that we should be comparing to? Of course, cilta-cel has shown about 84% PFS rate which is, you know, really impressive. But what would be sort of like the clinical benchmark in those patients, standard of care? That's an excellent question. You know, the one short answer is this is preliminary data, early data. You need at least two years, because then by that time we have done so many doublets versus triplets was the standard clinical trial in the 1- 3 prior lines. I mean, Saad has talked on the umpteen number of those cocktails, I'm pretty sure. You know, Rd data, Pom data, you know, KPd and KRd and, you know, all Rd versus KPd and elotuzumab plus Pom dex and elotuzumab with Rd. So there you have a lot of benchmarks. This one is a preliminary safety, exciting. The way the CARTITUDE-2 was structured, if I'm not mistaken, they had like a smattering of 20 patients or whatever. This was not the idea behind it. The idea behind it, okay, now are we ready to do randomized clinical trial? This is a safety run and, you know, this gives them assurance before they invest their $ millions to run the phase III international trial. They wanted to know whether it is a go, no-go signal. So far, the signals are all go. All right, Saad, it's your turn. No, it's this was a mic drop moment. I think you know, Dr. Jagannath has covered this very nicely. I think you know, we have you know, the safety and efficacy signal from you know, the late relapse setting, the CARTITUDE-2. You know, all these cohorts have set the stage up for these larger studies. In terms of benchmark, you all have been these triplets. Depending on the patient population that we're you know, examining questions whether cilta-cel can be you know, better than some of the standard of care treatments. You know, those benchmarks will be different for each of each of those categories. Another question for the doctors. What are your thoughts on BCMA antigen loss as CAR T moves up the treatment paradigm? What impact might this have on BCMA targeting bispecifics? Oh, that's easy. Slam dunk. Only 2%-3% have this, you know, BCMA disappearing 16p deletion along with 17p. Even the Dana-Farber, which published on it, acknowledged it, and now there is a lot more data, you know, coming out. I don't think that is the show. As a matter of fact, there was a presentation from my group from Mount Sinai group of sequential T-cell redirection therapy. Those who had failed first one line of bispecific antibody, subsequently going on to a bispecific antibody or a CAR T-cell therapy. These patients all respond beautifully. One of the questions in that was somebody who had failed BCMA, have they been rescued on another BCMA? Yes. Somebody who had failed a BCMA ADC or BCMA bispecific went on to CAR T and had an excellent response. We do know that also as a fact, and vice versa will be happening too. My feeling is, this loss of antigen is not a common phenomenon, but it was a good basic science investigational, you know, publication from Nikhil Munshi and group from Dana-Farber. There was a recent case report of a patient in CARTITUDE-1 who developed a progressive movement disorder with features of parkinsonism. Could you provide additional details on this patient and whether this case is unusual? Okay. There was a patient who had a movement and neurocognitive treatment-emergent adverse event encountered in our place. That was, I think the third patient. One in Chicago, one in UPenn, and one at our place in the early stage of the drug development. In our patient, he had an adverse outcome. He, you know, passed away. We did autopsy, and we studied the brain in great detail. This was published in high-impact journal. Probably that's what Samir Parekh and the neuropathology group at Mount Sinai you are alluding to. What did we learn from that? Yes, you know, under stress condition, this BCMA was expressed in the frontal brain area and also in the putamen area or caudate nucleus area there. We all know from even CD19 study as well as BCMA CAR T-cells do go to the spinal fluid. In this patient, we did show there was CAR T-cell in the spinal fluid. This patient met all the criteria for mitigation strategy, which we had. He had high tumor burden. He had a very high CAR T-cell, you know, proliferation, and it was sustained beyond day 100, even up to day 180. He encountered that particular toxicity. This is not just to cilta-cel. It is more like class specific for BCMA because it's a matter of BCMA. It turned out, even on cilta-cel package insert, they did say that they had encountered one patient with the, you know, the same parkinsonism type of neurotoxicity. What is more important is once we implement the, you know, identified what causes this, two of the three things which we noted, you know, not controlling the disease before bringing them in, so good anti-tumor bridging chemotherapy was recommended. Sustained and high CAR T-cell proliferation, very. You know, patient had high CRS grade and high and also had ICANS. These are the patients who are likely to get it. Follow this patient with the handwriting regularly, so you can pick that up early. Once we implemented it, as I told you, then in the next 200 patients, the incidence of MNT has come down to 0.5%. My feeling is, yes, there is BCMA expression. We showed it in our manuscript after detailed examination of the brain with all the special. That's how it came out in a high-impact peer-reviewed journal. But at the same time, it is not something that's gonna happen in all these patients or we got to worry about it because we found out the mitigation. You know, in the ide-cel, that's already commercially available, so it does not become a problem. I don't think it is gonna be a major hurdle. Right. You're referring to the ide-cel package insert? Yeah. We've seen some usage of the gamma secretase inhibitor in combination with both autologous and allogeneic BCMA CAR Ts. Would Legend consider exploring the use of these in combination with the GSI agents? I guess we all have seen this data, and it's potentially can be discussion with our experts like Dr. Jagannath or Dr. Usmani. We can probably discuss and- Oh, you can get two different opinions right away. Yeah. Go ahead. My feeling is CAR T cells, you know, it is able to get rid of even few number of antigen expression. They are all quite susceptible. They tried many different ways to find out, is the level of expression as any correlation. Again, once you have 96% response rate, you couldn't say. This was true even for ide-cel. They tried very hard, and they actually studied with the special immunohistochemistry and other method. There is a methodology problem. There is also soluble BCMA coming out and things like that. I do not know for CAR T cells whether this gamma secretase inhibitor is as important as in a bispecific antibody trial. In bispecific, I think this is a good. That's my pick. Now, you wanna hear the counterpoint. No, I think, you know, it really depends on the product. For cilta-cel, you know, the first time you're infusing it, you may not need it. The only other situation where I can think of where. Again, I agree with Dr. Jagannath. I think it's probably more relevant for ADC and bispecific-based strategies, you know, where GSI may actually improve the efficacy for patients. This is. You know, if you are reinfusing cilta-cel in a patient who has benefited from it and is relapsing, and you're concerned that you may not get the same bang for the buck, we have to ask that question in that setting. That, you know, with the second infusion do we use GSI so that we get, you know, more bang for the buck? That's my thought. You know, like, what do you think about that idea, Dr. Jagannath? Hey, you are agreeing more. You are coming to Sloan Kettering, and you are agreeing with me. I am a city slicker now. I am a city slicker. The New York City is going to have an apoplexy. The thought leaders are agreeing so much. I got to send you a Christmas gift. I'm looking forward to it. I will text you my address. Thank you. We only have time for a couple more questions. Next one, are there any material differences between cohort A and CARTITUDE-4 studies that are ongoing? How do the doctors think this therapy will be implemented in patients in 1-3 prior lines if CARTITUDE-4 data is as strong? You know, I think the data will be strong, but obviously you said that it is studies fully approved. You know, I think this is something I'll leave to Legend medical director to speak on it. But I have a feeling it should be strong data. I don't know. I mean, this. It's difficult to say, right? I mean, we don't have the data, and, you know, we won't be able to, you know, say anything until we've seen the data. So maybe next year you can ask us the same question. That is not a guidance from the company. That is- the year after that. How about that? Who knows? Final question for you doctors. How do you, the physicians, think about novel endpoints for trials in earlier line studies, in order to try to get answers quicker and potentially enable accelerated approval for MRD? Do you believe regulators have any interest in seeing these? I think you know MRD will be revisited again. I know they had all tried, and earlier the surrogate marker MRD was not quite accepted by FDA. Then the sustained MRD you know now the studies are getting more mature. We are reporting six months and 12 months sustained MRD. I think we need even more sustained one year apart and two year apart sustained MRD data, and that would be critical for this thing. Another thing is there is also new development in the field. There are you know other methods to measure serum free light chain or heavy chain by mass spectrometry and other method, very very small quantity. Once you have these kind of technologies, not just the bone marrow trephine biopsy and MRD negative in the iliac crest, you know, sometimes it is false. You could have a focal lesion in the left clavicle, and your bone marrow could be MRD negative. There is some inherent fallacy also in the field. That needs to be overcome, and I think it could also be overcome because of the newer technologies coming in. Putting it all together, that is a reachable goal, but is it something that will happen in 2022? I doubt it, but I think the groundwork is being, I mean, put in place. Saad, what is your feeling about some of the newer technology and what do you think? No, I think the sustained MRD endpoint at least 12 months apart is something that will be relevant to the regulators in the future. I think all the trials in the front line as well as early relapse setting are kind of looking at that endpoint. There are even studies in the cooperative group setting that are trying to question the definition of duration of treatment and maintenance based on that goal. That data is being generated. I think it may be ready for prime time in 3-5 years, but not just yet. You know, what we've learned from some of the trials is that response or PFS, again, you know, those are different kind of therapies, but there are some trials in myeloma that showed early promise but then did not deliver. With that in mind, I think, you know, we just need to, you know, build robust data sets so that we can, you know, when we go to the regulators that they don't, you know, question the intent of what we are trying to do with all the data at hand. Before we close for the evening, there are quite a few questions on combination and sequencing studies, specifically looking at FcRH5 or GPRC5D. Just wanna answer that quickly before we close? Yeah. Those are also open questions, you know. There is a lot of activity with BCMA target therapies, but GPRC5D and FcRH5 are also coming. The good news is, you know, just like Dr. Jagannath had mentioned, you know, we have patients dying in our clinics because of how aggressive their disease may be and because of lack of options. Seeing these new options is, you know, brings hope for those patients. We need to learn a lot about those targets too. You know, they have their unique side effect and safety profiles that we're just learning about. You know, with GPRC5D, you know, some skin and nail things. With FcRH5, they were concerned about, you know, neurotoxicity as well, kind of a little bit unique. We, we'll just have to learn what's happening. Yeah. I think you all should listen to Tarek Mouhieddine's presentation from our group this evening on sequential treatment with T-cell you know redirection after failing one bispecific antibody. That will kind of give you a flavor. Patients have failed one BCMA, had responded very well to another BCMA. Somebody asked the question, is duration of the first bispecific predict for the next T-cell redirection? No. There are patients who had failed quickly on one bispecific antibody, had a very sustained response to the next T-cell redirection therapy, so it did not preclude it. Whatever it was, that sequencing really did help patients in terms of longer duration of disease control. I think I'm very... Exactly like Saad said, we are very happy that there is more than one target coming into the bedside. I'm sure we would still have to tackle patients. I can actually say patients who had failed CAR T-cell, ide-cel therapy, we have, you know, successfully retreated them with a bispecific antibody. I think Ajai Chari talked about the bispecific plus the daratumumab combination or TRIMM-2 study in which patients have had prior CAR T-cell failure, and they have responded well. I think this is a new burgeoning area of research and data coming in. You know, very exciting time. At least I wanna stay tuned to all the excitement because I wanna see myeloma cured in the next few years. Okay. That brings our Q&A to a close. Before we end tonight, I just want to thank both Dr. Jagannath and Dr. Usmani for your insights. You two have been very valued development partners for the CAR-T program. As everyone can see, these results show that in CAR-T studies to date, cilta-cel consistently demonstrate deep and durable responses in patients with multiple myeloma across different settings. These are exceptional results for a patient population that has been heavily pretreated and also in need of options. I hope you agree with us that we are changing the paradigm of care for the relapsed and refractory patients. If you look at the CAR-T data, which demonstrates the potential for cilta-cel in earlier lines, both cohort A and cohort B patients show early and deep responses again. We're very excited to see the 95% response rate and also more importantly, a 79% CR rate in the cohort B here. Regarding safety, we're also encouraged by the 0.5% of movement disorder and neurocognitive treatment-emergent AEs, with more than 200 patients dosed across the CARTITUDE program. This patient management strategy is implemented by Legend and Janssen clearly have worked well in the clinic. We're continuing to explore the use of cilta-cel in early lines of treatment and are actively preparing for commercialization as we near the U.S. PDUFA target date of February 28. None of that, what we have achieved, would have been possible without our motivated team members, some of those who are actually sitting in this room. They're very committed to translating the best of science into innovative treatments. Without our collaboration partner, Janssen Biotech, who shares our commitment to patients. We also want to extend our thanks to the investigators who have dedicated their time to bringing this paradigm shift therapy to a patient. Finally, we owe our deepest gratitude to the patients who participated in the clinical studies. Thank you very much for attending tonight's event. I hope you guys all share our passion about fearlessly exploring the possibility of CAR T-cell therapies. Hopefully we'll see you in New Orleans live next year. This brings us to the end of our meeting. For those of you who have joined online, you may now disconnect. Those of you who are here in person, we do have some refreshments to the left. Thank you all, and have a good night.