Arcellx, Inc. (ACLX) Earnings Call Transcript & Summary

Good evening, I'm Rami Elghandour, I'm the Chairman and CEO of Arcellx and it is my privilege to welcome you to our Investor Relations event here in Milan. Thank you so much for those who joined us in person, you get extra credit and thanks as well for many of you joining via our webcast. Before we get started, a look at our forward-looking statements. In terms of our program for this evening, I'm going to kick things off by sharing a little bit more about why we're building a different kind of cell therapy company. I then have the pleasure of welcoming Dr. Kaur to the stage. She'll share the latest results from our registrational iMMagine-1 study that has been selected for an oral abstract presentation here at EHA that she herself will be presenting tomorrow at 5:00 p.m. Dr. Chris Heery, our Chief Medical Officer, will then share -- lead a physician panel and he'll be joined by both Dr. Kaur as well as Dr. Patel. Dr. Kaur joins us from Mount Sinai and Dr. Patel from MD Anderson, and we're very much looking forward to hearing their wisdom and insights. And then lastly, we'll open it up for your questions. As I mentioned at the outset, we are building a different kind of cell therapy company. We endeavor to match the clinical differentiation that you've seen from our anito-cel program with operational and commercial excellence and execution. And I'm really excited today to share with you a little bit more about our plans and progress as we gear up for our anticipated launch of anito-cel in the United States in mid- to late 2026. But first, a quick look about how we got here. Arcellx was founded around the principle of addressing some of the limitations with biologic-based binders. And we've developed the D-Domain, our proprietary novel synthetic binder, through which we've been able to demonstrate what we believe to be a best-in-class profile in myeloma. And that addresses both the primary limitations that we see with biologic-based binders, which are namely safety and scale and reliable manufacturability. We've leveraged this binder to generate what we believe is the strongest data set in the relapse and refractory myeloma population. And when you look at the profile of anito-cel combining the efficacy, safety and again, that scale and reliable manufacturability with Kite, the leader in cell therapy. We believe we can have a huge impact for the multiple myeloma community and build a significant business. We also believe in leaving a lasting legacy. If you've been following the CAR-T space over the last couple of years, particularly over the last 4 years, it's been a particularly challenging space, both from an entrepreneurial as well as from a public company perspective. And that challenge has existed despite a significant amount of clinical success, broad-based business success has been harder to attain. But we are committed to proving that you can build a meaningful business in the CAR-T space by doing the good of helping patients. And that starts by focusing on areas of high unmet need. And certainly, we believe myeloma is 1 of those spaces. As we've shared with you before, we believe that the second line plus population or second line plus market for multiple myeloma is $12 billion. As these therapies advance into frontline, which we believe they will, that market is size of approximately $20 billion. And importantly, the fourth line plus population is approximately $3.5 billion. And the reason that, that is notable is that we expect to launch in the fourth lines population, again, in mid- to late 2026. So how do we arrive at these figures? So for the first time, we're going to share a little bit with you about how we've built our models, some of our assumptions into our launch and some of our pillars have launched going forward as we approach again this commercial launch in 2026. And this is that first piece of information. So if you look at this, the first starting point for us as a assigning class share for myeloma CAR-Ts across different lines of therapy. And you can see that there's a range in those class shares that ascribes to the 2 different market opportunity sizes that you see here. The first that is $9 billion is based on the currently approved therapies for myeloma, excluding anito-cel, and the $12 billion figure is inclusive of a anito-cel in 2028 and beyond. Now one of the primary differences between these 2 market estimates is actually our iMMagine-3 trial. And there are 2 distinct features in iMMagine-3 that we believe will help drive this market, help us, help a lot more patients and generate this greater market opportunity. The first is that iMMagine-3 is a dual exposed population, specifically, it is an anti-CD38 IMiD-exposed population. And that is different than some of the labels that exist with current therapies, specifically, for example, a len refractory PI exposed population. And that difference in population, we believe, can lead to a sizable -- sizably larger population to address. The second difference is that iMMagine-3 has a contemporary control arm meaning that in the control arm, there are multiple dara regimens that we believe are going to be critical in driving engagement in the community physicians and again, expanding the patients that can benefit from these therapies. Digging a little bit deeper, we're going to share with you some of our primary market research, and this is fairly substantive market research that included over 300 hematologists and oncologists over the last 2 years. And you can see here, including treaters and referrers in this research, that the market share assumed, and this is peak share, not necessarily penetration as of today, but the peak share assumed with the existing class of therapies can go up substantially in the future with the introduction of newer therapies like anito-cel for some of the reasons that we discussed. You can also see that the share in that future case is fairly consistent across our studies in terms of that substantial increase, whereas the share for the existing therapies fluctuates a bit more. We believe that's a function of the end market experience, some of the things that we've all heard about in terms of delays and toxicities that may be impacting the end market experience and causing greater fluctuations in those assumptions. In totality, you could see, however, that anito-cel can drive significant expansion, and we believe it will help expand this market and again expand the number of patients that can benefit from BCMA CAR-Ts. So we spent a lot of time talking about how we've arrived at this market, its size, the class share assumptions. Let's dig a little bit into how anito-cel itself performs within the BCMA class of CAR-Ts. You can see here, again, citing our 2024 research that anito-cel garnered a 58% market share, both in our qualitative and quantitative elements of our research and that increased substantially to 83% in our 2025 research. We believe that increase is really reflective of the profile that you saw in our iMMagine-1 results, which, again, Dr. Kaur will share a little bit later today. And specifically, the replication of the efficacy profile in our Phase I, which led to a north of 30-month PFS as well as the safety profile where we again saw no delayed neurotoxicities in a patient population that's approximately 3x the size of that of our Phase I. It's also really encouraging to see that the patient research led to an 83% share coincidentally as well. We know we live in a world where patients increasingly are taking more charge of their journey, of their treatment options, and having this level of patient advocacy, we believe, is going to drive a significant role in the adoption of a anito-cel. Two other things I want to mention. The first is if you think back to those share assumptions that we talked about, they still account for a significant amount of alternative therapy use, whether they be bispecific or otherwise while still resulting in significantly large markets in the myeloma CAR-T space. However, we also expect that the CAR-T class share in myeloma will continue to increase because of the unique durability and particularly the quality of life elements of CAR-T therapy. Now everything I've showed you so far relies on asking physicians to look at different profiles and ascribing share based on these profiles they see whether in the present moment, again, with only the existing therapies, or a future time point inclusive of therapies like anito-cel. But another way you can ask this question is to simply ask them, based on this profile, what is your likelihood of prescribing? And what is your motivation of prescribing this therapy? And you could see that stands at 90% for anito-cel and the reason that question is important is we know with a anito-cel, the ease of delivery and use given the safety profile, the combination with our partners at Kite, who are the best in the world at what they do in terms of delivery, it's going to be a therapy that the more you use it, the more it's likely going to be adopted. And so this is a really important data point for us, informing our launch decisions. And so with that, I think I can summarize that this is a very large and expanding market that we expect a significant class share for myeloma CAR-Ts, and that within that class, anito-cel is poised to be the leading CAR-T therapy. So that informs our launch decisions. And the first pillar of our launch that I want to share with you is how we expect to expand into the U.S. ATC market. We expect to launch into 160-plus ATCs in the United States within our first year of launch. And you can see how substantially different that is from prior myeloma launches. And the reason for that, again, is that market research that gives us the confidence that this is a highly desired therapy that is likely to be rapidly adopted. Now part of the reason that these historical launches have been staggered is because supply has been a significant challenge. So the second pillar that we want to share with you is that we're planning to have manufacturing capacity to capture the majority of the fourth line plus population at launch, scaling to be able to cover the entirety of the fourth plus line population in 2027 with a global potential of greater than 24,000 doses within the Kite network. Now you're going to hear from some physicians later today, and I'm sure they will tell you that capacity just isn't it. There are other challenges that impact adoption of these therapies, turnaround times, in spec, out of spec rates and logistics and planning. So let's talk about those things. We expect a turnaround time of less than 17 days with anito-cel. And what's great about where we are today is that Kite has been able to deliver on that. We've shared this previously that we are seeing a less than 17-day turnaround time with anito-cel in iMMagine-3. So this isn't a hypothetical. This is a real operational achievement that Kite has been able to deliver. And in terms of in-spec rates, Kite's in spec rate, I believe, is somewhere around 96%, and we expect a similarly high in spec rate when we are commercial. The other element that's going to be really important is that we're really excited to share that anito-cel is going to be part of Kite Konnect. Kite Konnect is the leading platform in cell therapy in terms of patient onboarding tracking and logistics. And again, it reduces significantly the friction of the adoption of these therapies. So we are introducing a new therapy to the market but imagine introducing it in a way that doesn't just take physicians to something that they're used to, but something that they yearn for that they're excited for that they want to use because it helps them run their programs in a much more efficient and reliable manner. We also wanted to share with you what this launch is going to look like on the ground. While myeloma CAR-Ts have been on the market now for 3 years. Amazingly, there are still a number of centers that haven't had access to these life-saving therapies and we're excited alongside our partners with Kite to be the first company that can bring these therapies to these patients and particularly not any therapy, again, anito-cel with its unique profile across safety, efficacy and scale manufacturability. We're also really excited to share that we are very ready to take this market with our partners at Kite, working together to bring a best-in-class experience and service. When you think about Kite, you think about the brand, you think about their expertise and with Arcellx, we bring a knowledge of this particular agent and a focus and a track record of execution that I'm confident together we are going to be the best-in-class service organization alongside the best-in-class CAR T that we're looking to deliver. Now again, to recap, we've talked a lot about the size of the opportunity, the class share, the specific anito-cel share, some of the elements that are going to drive the launch from supply to ATC onboarding to Kite Konnect. So let's spend a minute on market access. We are in the process of initiating our pre-approval information exchange, which we believe will allow us to have access to 80% of covered lives within 30 days of launch, and 90% of covered lives within 90 days of launch. And as you'll see, that will continue to tick up towards that 99%, 100% level, over time. It's also worth mentioning that the payer mix for BCMA CAR-Ts is not too different. It's actually quite similar, maybe a little bit favorable relative to the more broad myeloma therapy payer mix. And the reason that's important is that it means that there aren't any payer issues that are significantly skewing the payer mix, which tells us that there is generally access to these life-saving therapies for the patients that need them. All right. Well, let's shift gears a little bit and talk about -- what I said at the outset, which is the type of business that we're building. And when you look at the capital that we've raised over the last couple of years, we've been public since February of 2022, and you look at how much of that remains on our balance sheet as of Q1, which is $565 million, over half of that capital. When you look at that relative to the achievements and the value that we've been able to create, and relative to our headcount, approximately 170 team members, that really speaks to our operational differentiation. We talk a lot about people, culture and specifically diversity as our superpower and what makes us different and you can see that reflected in how we operate our business. That also informs how we think about the future. We expect gross margins that are greater than or equal to 70% at launch, and we expect to reach profitability at less than $1 billion in anito-cel shares. Now a big component of our differentiation certainly is our partnership with Kite. This was really a win-win deal and partnership with Kite. They are able to drive this myeloma therapy through their infrastructure and through their expertise, which is incredible for patients and physicians and for their organization. And we're able to leverage that infrastructure as well. Mainly, it reduces cost of goods for us and eliminate capital expenditures in a way that again helps us achieve significant margins at the time of launch and to drive profitability in the near term. I will say also going back to what I said at the outset that it is really important that certainly, our mission and why we all chose to be in oncology is to make a difference for patients, right? We could have chosen a lot of different fields. We chose this even though it's hard sometimes because ultimately, we want to do something that makes the world a better place. But it's also really important that we build good and meaningful and valuable businesses because that will help drive more and more investment into this category that I believe will be a forward pillar of medicine. So this is certainly important for Arcellx but again, from a legacy perspective for us, it is informing hopefully, more and more attraction and investment in this space. So lastly, before I wrap up, we do want to share with you an illustration of how this all comes together. And so we've put together this illustrative P&L in a future state when we achieve, and we hope to achieve $1.5 billion in sales. And you can see through this example that we get incredible leverage both due to our commitment to operational excellence as well as our partnership with Kite that drives significant variability. To orient you to this graph, you could see the shaded portions are the range for each of these bars and particularly the profitability bar you could see there at the end. And that is compared to a cell therapy peer at a similar stage, and you can see the differential in the overall profile as well as in the profitability line. So with that, I'd like to conclude with sharing that anito-cel is expected to be the preferred CAR T based on our experience. I can tell you that I've conducted and our team has conducted this type of research in the past for other launches, and it has been incredibly accurate and instructive. So we're very confident in it. And as you can tell, it informed a lot of our commercial decisions. We do expect anito-cel to expand the market for the reasons that we shared. We're expecting a broad launch based on the combination of the belief in these 2 attributes. Hopefully, today, you know we have incredible confidence in our therapy and our clinical differentiation. Hopefully, today, you've got some more belief into why we're also incredibly confident in our commercial plan on our execution. We will launch with the excess capacity we need to address patients and to make sure this life-saving therapy is available to as many patients as can benefit. And this is a different kind of company. I know a lot of you get the opportunity to interact with some of our team, but it is really truly a super team. It is an honor and a pleasure to get to work with them every day, and we are committed, again, to bringing this incredible therapy to as many patients as can benefit and building a differentiated company that we certainly really value being a part of but can also help drive more investment and attraction to this incredibly important space. And with that, it is my pleasure to invite Dr. Kaur to share the latest iMMagine-1 data.

Thank you, everyone, for having me. My name is Gurbakhash, I am Mount Sinai Hospital in New York City. Before I delve into the Phase II portion, namely iMMagine-1, I'd like to remind everyone of the Phase I study and the data. In the Phase I study of 38 patients, it was over 100% overall response rate and 79% complete response that was observed. At a median follow-up of 38.1 months, anito-cel achieved a median PFS of 30.2 months for patients and a complete response are better in 79% of the patients. Median overall survival was not reached. And the highlight is that the safety profile of this CAR-T product is predictable and manageable with no delayed or non-ICANS neurotoxicities, including no Parkinsonism, no cranial nerve palsies and no Guillain-Barré, seen until date. This is an overview of the anito-cel iMMagine-1 Phase II study design with patients, which is pretty standard for this patient population. 129 patients were involved, and ultimately, 117 patients were dosed with this product, anito-cel was successfully manufactured in 99% of the patients. These are the demographics of the patient population enrolled onto this clinical trial, which is on par with CAR-T products at a similar stage of development. And now in terms of efficacy, at a median follow-up of 12.6 months, the overall response rate was 97%, and the complete response are better was seen in 68% of the patients. With the VGPR, which is Very Good Partial Response, or better of 85%. The median time to first response was 1 month. And in the myeloma world, we often evaluate the depth of response because we believe the depth of response translates into duration -- long duration of response. And anito-cel sees comparable depth of response to other BCMA CAR-T products, namely 89.3% when measured at 10 to the minus 5, and patients were able to demonstrate this and we're able to reach this depth of response within 1 month of dosing. The estimated 6-month PFS is 91.9%, and the 12-month PFS weight is 79.3%. The estimated 6-month overall survival rate is 96.6%, and the 12-month overall survival is 95.2%. In terms of toxicity, namely cytokine release syndrome. 85% of the patients experienced grade 1 or less CRS, including 15% of the patients who experienced no CRS. The median onset of CRS was 4 days lasting and with the median duration of 2 days. In the 85% of patients, as I said, the median onset was 4 days. And 97% of patients either had no CRS or CRS that are resolved within 10 days of anito-cel infusion. In terms of ICANs or neurotoxicity, 92% of the patients had no ICANS. So it was observed in 8% of the patients of any grade. All cases resolved and the median onset of ICANS was 7 days, and the median duration was 4 days. No delayed or non-ICANS neurotoxicity was observed, including no incident Parkinsonism, no cranial nerve palsies and no Guillain-Barré Syndrome at a median follow-up of 12.6 months. And similarly, none of these have been observed in the Phase I study as I have alluded earlier. And I have already mentioned, 92% of the patients did not have any ICANS. And I think this slide highlights the safety and profile of anito-cel very much so. There were no cases of delayed neurotoxicity observed with anito-cel in the Phase II study. Until this date, 150 patients have been treated with anito-cel between the Phase I and iMMagine-1 studies, 38 patients have a minimum follow-up of 25 months. no delayed or non-ICANS neurotoxicities have been observed. And most importantly, no secondary primary malignancies of T cell origin, no cases of immune effector cell enterocolitis have been reported. So anito-cel has shown a differentiated safety profile in the Phase I and iMMagine-1 studies to date. In conclusion, anito-cel utilizes a novel synthetic compact, stable D-Domain binder, which allows for high transaction efficiency, car positivity, CAR density and T cell surface -- on the T cell surface and has the fast off rate. It has demonstrated deep and durable responses at a median follow-up of 12.6 months. The overall response rate was 97% and with a CR or better response even 68% per IMWG criteria. 93.3% of the -- 93.3% of the MRD valuable patients were MRD negative at 10 to the minus 5, and they were able to achieve that within 1 month of dosing. Median PFS and OS was not reached, the anito-cel safety profile is predictable and manageable, no delayed or non-ICANS neurotoxicities, were observed, namely no Parkinsonism, no cranial palsies and no Guillain-Barré Syndrome, and no immune effector cell-associated enterocolitis , have been observed to date with the anito-cel which, to me, as a conviction, is very important. 85% of the patients did not have any CRS or had a MAX Grade 1 CRS and 92% of the patients did not have any ICANS. And this is the ongoing anito-cel, iMMagine-3 study schema, which is a global Phase II trial, and that is currently enrolling. Thank you for your time. I'd like to welcome Dr. Chris Heery to the stage.

We're going to come over here and conduct this panel. I'm going to start just with a little more context to some of the things you shared, so that we can dive in on some of the questions that I think are relevant to clinicians. We get questions quite commonly to us as the management team. And we say, well, we talk with clinicians all the time, and this is what they tell us. But it's really important for people to hear it directly from you all. So I'm going to just here a few of the points that do come up quite frequently. And namely, the last topic that you really touched on, Gurbakhash, was these delayed neurotoxicity events and enterocolitis events. From the now multiple published real-world studies, we see that the incidence of these delayed neurotoxicity events as well as cranial nerve palsy putting that in that broad bucket, Parkinson, cranial nerve palsy, and then now seeing these immune enterocolitis events. We see them happening at a rate that seems quite high relative to other CAR-T, particularly with Carvykti. And the feedback we often hear is that, that has become a bit of a challenge. That's one of the topic. So I'm going to ask you all about. The other topic I want to ask about for you both to just think about right now is when you think about use of a particular product, do these events affect your conversation with your patients, does it affect the trade-off, the risk-reward consideration and then maybe weigh that for us between Carvykti and Abecma as the currently approved products. This is more data from the FEARS database, which I think really just complements what we just saw from the real-world evidence data.

So I'll pause there, and I'll ask maybe Krina, could you start with the questions that I just listed for you?

Yes, no, I think it's an exciting time that we have these treatments for myeloma. I will say cell therapy is -- I do research in cell therapy, that's my COI but to really see these patients off treatment that we've never had in myeloma, that quality of life piece is so exciting. However, this is what we start talking about when we talk about consent for CAR-T. Right now, I have 2 options. I have CILTA-CEL and anito-cel. And when I'm talking about the different options, also therapies are not the same. So for my patients who are fit and I can do CILTA-CEL and not worry as much about these neurotox, I still talk about all of the potential toxicities. And I think we talk about patients who get bridging therapy and they have less toxicity, which is great. But unfortunately, even patients that have minimal disease going in, sometimes we'll see the colitis happen. Sometimes I'll see the cranial nerve palsy. And I think there's a distinction between what serious neurotox versus colitis versus not but it does take more therapies. It does take more management that those patients don't get that quality of life piece for as long as we would like if they get these side effects. And I'll say the Parkinsonism and the colitis are the 2 big ones that I talk about with CILTA-CEL. I don't really talk about with anito-cel because again, I have never seen it with anito-cel, it's very rare but with CILTA-CEL, not just myself not just myself but my friends and colleagues around the country, we text each other about it to say, what do we do now? What have you tried? So again, it is something that I talk about in terms of consent for CAR-T. Sometimes patients will pick anito-cel for the safety profile, right, especially if they have standard risk disease. I think that the risk benefit is really important, putting in context of both the toxicity as well as the efficacy.

You want to take that one, too?

Yes. As Dr. Patel highlighted that we are -- very fortunate to have these therapies, and they very much have a space even and CAR-T continuing to evolve. And I think with each evolution of the product, we're getting safer products. We know that these products are efficacious as highlighted by the success of their counterparts. And now we're sort of wanting to focus on CAR-Ts that not only just provide the safety -- the efficacy but also the safety. And these I would say my conversations over the 1 year has shifted greatly actually. I would say, especially in the last 1 year, as there has been more data that has come out about these toxicities. And the scary thing is we do not know how to manage these toxicities. So that's why we still think that there is a need for products that can offer similar efficacy and yet not put the patients at risk for them. And we are also similarly texting each other, "Hey, how do we manage this?" And sort of is like winging it as we go along actually. But yes, it does play a role in my patient selection and how I counsel them. I would -- the T-cell malignancies that is now emerging as a possibility, that also but multiple myeloma patients in general get a lot of treatment. So it's hard to tease out what is contributing eventually but that's a discussion that I also have as well.

All right. No, that's super helpful. I think along those lines, I'm very interested to hear how that's affected where you choose to start cell therapy. Obviously, we've seen the approval of Carvykti in second line, Abecma in third line. Are you using cell therapy in second line commonly? Or if not, what are the -- what's the limitations there?

I think we were all -- we all have been enthusiastic as CAR-T moved up. And at the beginning, I thought I would be using much more than I had. I am doing right now. And especially because there are other regimens that can give you long-term PFS such as the [indiscernible] when you give when that is available in the second line. So right now, for me, I reserve CAR-T in the second line mostly to patients who are functionally high risk. These are the folks who relapsed within 1 year, 1.5 years or even 2 post auto transplant or first-line therapy, people who are young and they have high-risk cytogenetics or they have a very aggressive clinical relapse. So I think that it's a small subsection of patients that I really thought who would be going for CAR-T.

Yes, I agree. I think we started with the high-risk patients, again, risk benefit ratio matters for the of high risk or standard risk. If you're fit or frail and if this is early line or late line, I think the -- I'm excited about the possible plateau that we're seeing with CILTA-CEL. I mean it's the first time we're seeing that. Again, I think it's potentially a class effect. If you have similar efficacy, but without that toxicity, that's really important. And to have 1/3 of patients the argument that my patients and some of my other colleagues have is that if you have a late line therapy that can put 1/3 of patients into this great remission, and that's where the risk benefit ratio for these toxicities are okay versus you do it in second line and then these patients that end up at a younger age, getting some of these toxicities that can cause problems. I mean this is what we talk about. Do we have other options? Do we use those right now and then hope that we can get you to the CAR-T down the road, you'll still do well. And maybe if you get the toxicity, then it's okay, that -- at least we tried everything else before because if they get the toxicity in second line, that's devastating because I have all these other options that I can't now give and it's the opposite of what I was trying to do it.

To that end, there's been a lot of discussion over the last months or so around risk mitigation strategies for some of these adverse events. Have you found -- or have you used any of those? Have you found any of them to change your thinking on how you cancel patients? Or influence your willingness to then move therapy to earlier lines as a result of thinking there is a mitigation? Or are you not quite comfortable that, that's reality yet?

Yes, those are great questions. I think I still bring -- I am a CAR-T enthusiast. So I still bring up CAR-T the second year eligible for it because if I need to know if my patient wants it or not, number one. So that if we're not going to go now, at least I know what to do it and make sure I can do CAR-T later. But the second thing is everybody has different philosophies in life. So there might be a patient that says, I really just don't want therapy, give me the CAR-T. And then if I go over everything they still want it, we do it. I think the mitigation strategies are -- I think it's important that we think about these things and try, but I think we don't really know it right now. It's -- I hope giving steroids or something if the ALC gets too high, which is what's happening, maybe the ALC is a biomarker, I will say it's also a biomarker for response and efficacy though. So which are the patients that still get the toxicity versus those who are just going to do well and get great efficacy. And if I do a modification strategy, am I going to affect the PFS. We don't have that data. And so for us, we don't do the mitigation strategies as of right now. I wait until they have a symptom and then throw everything at it. Again, we had a patient recently had ICANS, got 400 milligrams of dex, and they still have CAR-T around, thankfully, you've got the treated but I'm not going to treat everybody with 400 milligrams of dex. So I think there's -- these are biologics and T cells are not drugs. So everybody is a little bit different.

So I think the most important risk mitigation strategy is I try to cytoreduce the patient as much as possible before I take them to CAR-T. I think that pans out in term -- that should be even classified not just as a response to CILTA-CEL or Abecma even possibly f anito-cel. We just know the cyto reduction and taking the patient to CAR-T cell therapy in that setting where the disease is controlled is good on all fronts. And I think the myeloma community has gotten a signal on that. Similarly, I think the predict is still out. I do not know if this dexamethasone mitigation strategy is the solution. I know many people are doing it. But I think it's -- I haven't adopted it fully. For the right patient, if there is no -- like you said, if everything is going back, you're going to try everything that comes your way. But at this point, I have not implemented it that my colleagues have.

And either have you tried systemic or intrathecal cyclophosphamide for any of these cases?

So for colitis. So again, I haven't had Parkinsonism, we have been lucky, I think but colitis we gave the last 2 patients. And my very first patient with colitis unfortunately passed away from horrible sepsis because everything we tried just made the immune system worse. But my last 2 patients, we ended up giving 2 grams per meter square or 1 gram per meter square of cytoxan just to try to kill the CAR-Ts and see if that helped after trying other local therapies, GI therapies, et cetera. And so far, they're out of the -- 1 is out of the hospital without diarrhea but there's still some T cells left. So we're watching very closely and kind of seeing as these numbers go up. And the other patients still in the hospital already now.

Yes. I think enterocolitis is now giving us a lot of pause. I have myself not treated a patient, I have not seen someone with enterocolitis but my colleague have. And it's been a horrible case, somebody who has been -- who is in the hospital for almost 9 months, couldn't manage the enterocolitis and then that led to 1 episodic sepsis, to the second episode sepsis, to the third episodic sepsis to the patient, getting their leg amputated eventually and now is mental -- they are in a remission but they're mentally devastated and are almost becoming narcotic dependent. So you've seen this young person who would have maybe CAR-T was really indicated in their setting because they were young and they had myeloma, which itself is a high-risk marker but it makes you rethink a lot of things. I have not tried cyclophosphamide yet.

Okay. Maybe we can move away from that just a little bit and also talk about other therapeutic options. And Krina, you mentioned this plateau that we're starting to see with CAR T. I think you've -- I think I've heard you say that it maybe puts myeloma into the category of lymphoma, which is really exciting. I guess first question, you've both used on anito-cel. You've seen the data. Do you have any reason to believe that the sort of plateauing effect that we've seen with Carvykti couldn't be seen with a CAR-T with a similar efficacy profile in terms of CRA, MRD negativity, et cetera? Or do you think that, that might just be unique to Carvykti?

No, I am excited to see the long-term data. If I could fast forward to 5 years from now, I am really happy. So no, again, I'm hoping this is a class effect. I think it can be a class effect. We didn't see it with Abecma but that's a different CAR-T completely. And I think the manufacturing and just the ability to get these patient cells, we just we're better and better at it. And I think it's going to actually improve outcomes because, again, when I know when I'm getting the cells, I can give the bridging that I need and even on study, it's actually even easier to do it now, partly because we're smarter but partly because it's just been a lot easier to get the cells and know when they're coming in and moving forward with the logistics matter in T cell therapy, right? And they matter a lot actually to our teams for us to be successful.

Yes. I think likewise, I don't have any doubts that the efficacy will not hold. I think it's exciting -- it will be exciting to see how this data plays out and the safety profile to me, is actually the most exciting part. And I think the 17-day turnaround time that was highlighted on 1 of the slides as clinicians, when patients are getting through CAR-T. CAR-T is like a very -- it's a high maintenance therapy. It requires an army of people to actually execute. There are a lot of folks on the nursing end, on the patient end that are constantly talking and coordinating. So to know when the product is going to come, and you be the decider when you're going to give that therapy and you can plan that at least a week or 2 in advance. I think that that's an accomplishment. And that's a goal that we strive for. We have been striving for the last 4 years, actually. So I think that's an advantage that's going to be leveraged when we may have to pick 1 product versus another, right?

Yes. And I was going to say the studies that we have right now, the iMMagine-3, I could give all those patients CILTA-CEL but I talked to them about the both profiles for both products, the efficacy that we have so far. And the majority of my patients who are willing to do a randomized study, pick that study, right? Because they say, "Oh, if it could be safer, and it's still really good. I want a chance of getting that CAR T." So that's how I'm able to get patients on a randomized study even.

Okay. Yes, those points, I think, are really interesting maybe want to highlight Gurbakhash, what you were talking about with planning because what we hear a lot is from various institutions is that there are probably enough beds and there are probably enough staff to treat many more patients if the planning could be more cohesive. But the moving parts actually make it so that you kind of have to be overstaffed at all times to account for the variability. Is that your experience as well? Do you have this sort of crunch that can happen as a result of moving time lines for when the cell therapy arrives and needing to change bridging therapy, et cetera.

I mean that happens all the time. We're constantly having to, hey, the patient is going to come in 1 week on this date, plan for this and this and then 2 days of 4, okay, we either don't have the cells or some things happen and we have to move that. And there might be a time when we have 5 or 7 patients with the same products going in. We don't necessarily want that, right? We want like a sort of a continuous flow of patients that because more volume means less being able to pay less attention to those patients actually naturally. So yes, I do -- we do see that.

Yes. No, I think my team, if my team is happy, I'm happy. If my team is not happy, I threaten the quit as well. So we do actually hire a lot more people because the logistics just take a lot. And I think the Kite Konnect that you were talking about, I can't tell you, since the day myeloma got CAR-Ts, my coordinating team that deals with all that, they hate every other one. They're like, why is this like this because this one is so easy and makes so much sense, why do I have to deal with all of this. And that's where all the communication happens. So my team can't do it or they put it to the side because this one is easier than that affects our patients and being able to bring them in on time. And I think that out of spec rate too. That's where I guess, most of the time I get my sells in 4 to 6 weeks but when there is a patient out of spec, we don't figure that out until later. And then you have to actually talk to the team again to say please do more bridging, figure out if they're responding or not, and it just -- it makes it a little bit harder to get those patients back in pristine condition that we want them in to give them the cells. And with out of spec, actually, it creates a lot more work. We -- each institution sort of does it differently. We have like protocols. So the patients essentially ended up into a study protocol, which itself it's requires maintenance and resources on the academic sites, right? So -- not something that we -- what we want. We want to deal with the time.

Do you compare notes with your lymphoma colleagues and say, well, that sounds so much easier? Or what is that experience like comparing and contrasting the myeloma department versus lymphoma department. Have they seen because of the availability of multiple products that are delivered with a lot of consistency. Obviously, Kite having been the leader in all of that for a long time now. Is that a different experience within the institution?

In my experience, I feel like when because maybe the lymphoma had been there before myeloma got CAR-T, they had kind of teased up the kinks of it. So it always seems like it was a more seamless transition to get someone getting CAR-T, we're going to plan the cells. And whereas in myloma feel like we have always been trying to deal with this. So I think up until now, actually, that has been the story that it's always like, oh, we could do this, we could do that, we could, the planning is sort of like very haphazard. It's not as smooth as I've seen it in my lymphoma actually.

No, my teams will say. Again, like, why can't everyone be like Kite? Again, this is before I even started working with any of you and that you guys even joined Kite. That was the gold standard for my entire team that why can't everybody else be like them.

Yes. I think departmentally, you fall within the same group of lymphoma...

Care resources. So it's the same people that work and they rank [indiscernible] rankings that myeloma is mostly at the bottom.

Yes. Great. So also on the topic of comparing how you're thinking about what you're going to use for treatment for patients, obviously, we've seen a real improvement in the T cell engager therapeutics over the years. I mean it's I'll admit better than when I first saw a T cell engager therapy, and I think 2012 at ASCO, I thought, wow, that's -- that might be the best it will ever be. And things have improved really significantly. The observation, though, of the plateau effect in CARTITUDE-1 seems to have brought up for a lot of people, this question of, well, if I give a T-cell engager before a CAR-T, am I giving up a possibility of long-term durable benefit with high quality of life in exchange for something that, I guess, is a little easier in some cases to deliver. Do you -- I mean, can you just comment on the conversations maybe you've had with your colleagues on that topic over -- I know it's recent, but over the last month or so?

So if you ask the folks who are at the IMWG conference and who treat myeloma, CAR-T is always preferable if it can be delivered to the patient and the patient and the candidates. That's usually a #1 go-to. And I think that's across the board. Certain patients are truly not CAR-T eligible, whether they're frail or that. So I think you exclude that patient population. I think myeloma keeps on surprising to you actually. Just when we were having conversations so T cell engagers are going to move up. But with them comes repeated toxicity of infections, oral and skin toxicity that has not been well mastered yet. And then you have this treatment-free interval, that this phase and patients want freedom from the clinic, and they want time toxicity that adds on. So I think, yes, the T-cell engagers have come a long way, and they are very effective. And they will still be given in the myeloma space. I think the preference amongst us is still to go for CAR-T because it leads to improved quality of life for patients. So that's how I've sort of seen this.

And there's no randomized trials, of course but median PFS for the current CAR-Ts is still much better. CILTA-CEL is still way better than any of the bispecifics single agent. I think the question of CAR-T before -- or bispecifics getting it and then going to CAR-T, we know that not just the response rate, but the PFS drops so low that it's not worth it. It's not worth to get 6 months PFS if you're going to get a CAR-T. So in the end, for my patients, I tell them, I think bispecifics after CAR-T makes total sense that if you're not in that 33% or hopefully higher for earlier line to stay in remission and we need to treat again, bispecifics at that point make much better sense because your T cells are back to normal, you're doing great, you're in better shape because not on continuous therapy with these side effects or serious infections, that PFS 1 and 2, if we need that PFS2 is going to be much better. But yes, I've had multiple conversations with local doctors recently because there's a few that are trying to bispecifics. So a lot of my colleagues can't because it still causes CRS and it still causes weird infections and they need a hospital. But it's easy to get it off the shelf. But then when you're done with it and they're relapsing, now you've run out of things. Because other way around, you actually have -- if you get 5 years or even 4 years, let's say, you have all these other therapies we've gotten in myeloma then, right, that they live longer because they have access to other drugs again.

And I think some folks actually go to bispecifics because the CRS and ICANS seen with bispecifics is much lower. But then if you can offer them a CAR-T that's 15% experiencing no CRS and the remaining that do is usually grade 1 or 2, which is what we actually see with bispecifics. It makes the CAR-T even more appealing actually that the immediate toxicity that patients dread or even our community oncologists who may be referring to us dread with only 8% ICANS. I think if you -- when there is an improvement in that safety profile and it's comparable to the bispecifics, you're going to have more of an appeal for CAR-T.

All right. So now we can play predict the future a little bit. So you both touched on a few really key points that I think -- I know you both think everyone knows but I don't know that everyone does know. So the data that were presented at ASCO looking at the subgroup of patients in CARTITUDE-1 who had a greater than 25% reduction in their disease burden with bridging had significantly improved outcomes compared to the rest of the population. That seems consistent with what we've learned in lymphoma. It seems consistent with other clinical trial data and real-world data. But I'd love for you to just talk about how you think about that in the real world, different even than what we're allowed to do in clinical trials and where you think that is going?

Sure. Yes, I think I was at a meeting earlier today. We think about CAR-Ts consolidation more than as a therapy of its own, right? So I have a patient coming to me, let's say, third, fourth line, wherever they are, they're relapsing. The second, I see that biochemical progression, I start talking about CAR-T therapy, and we start getting financial clearance, even if they're not eligible yet, we start working on everything because the second they are eligible, I get their slot, I then start bridging. And our plan is that in 4 weeks, 5 weeks, we'll go to the CAR-T. But if they're not responding, usually within 2 or 3 weeks, I check their myeloma labs. And if it looks like they're not responding, I actually switch their bridging. And we changed that to something else until they have a response, and then we go to CAR-T. So we might delay actually giving LDC or -- and the CAR-Ts until we know they're coming down because it is such a big biomarker for toxicity reduction but also efficacy. And I think the other thing is when people are coming in with horrible relapse. So my high-risk patients, they might not just biochemically progress. If they're fine 1 month, the next month, all of a sudden, they have all this disease, I can actually start treatment. So I can start [indiscernible] and then as soon as I know that they're responding, then go to CAR-T. So again, these are therapies that don't affect the T cells. So I'm okay doing it before apheresis, and then I go to the bridging to even get further reduction and then to CAR-T. So remember, in CARTITUDE-4 there's all these patients that never got cells. That's because we have to have a 2-week washout. You can't have any therapy that gives you a response before you go on to the study. And in the real world, that's not the issue. We don't have to do any of that. So we can get -- most of my patients get their cells now because of that.

I agree.

Same.

Yes.

Well, let's maybe add on to that then because most of the CAR-T trials to date have not incorporated every therapeutic option for bridging because it either wasn't approved yet or because it seems maybe too risky at the time? Or are there any of those therapies, for reference, bispecifics that you might use in bridging at this point?

Yes. I actually just used it last week. I had a patient who was getting -- who had gotten apheresis at a clinical -- very clinical relapse with extramedullary disease and was not responding. So I actually ended up giving talquetamab as the bridging therapy, markers went down, cells are ready. I'm ready to infuse. And I like that profile going into CAR-T because I just know that I'm not going to deal with the crazy CRS and ICANS and them toxicity. I don't know what that means long term. I know there's been a whole discussion about disease control and whether that really truly has an effect on those delayed toxicities. But yes, we are using bispecifics. You see we choose a different target. So the preference is to use talquetamab, not necessarily teclistamab or elra because they're both BCMA. And we have that as an option now, which wasn't available 4 years ago.

Same thing. We know that -- before we did this, the question was if you have bispecifics around, will it make the CAR-T worse, [indiscernible] and ICANS worse. And we have a huge series retrospectively but that shows that it's actually really safe. And it's late line, it's been amazing.

Yes. And one of our -- sometimes our hesitation in actually even going to bispecifics is the T cell hit. And who knows, maybe another ADC will come around. And if someone just needs a little bit of that, which doesn't really exhaust the immune system, maybe that's going to be an option. I don't know. It's time to be seen. But yes, we have more engaging options than before.

Well, you used a word -- to kind of close out our panel, you used a word that I think is associated with first-line therapy, consolidation. So that leads me to wonder then, are you in the camp that is thinking, ultimately, there's no better use case than use my best consolidation therapy when I have my best therapy to cytoreduce. Is that -- are you in that camp that you're hoping to see CAR-T get to that place because you think it's an ideal fit for that setting? Or are you still on the fence?

Yes. No, I think it's about toxicity. I think efficacy-wise, for sure, I mean, we see better MRD negativity than we did in transplant, definitely in earlier and later lines. But I do think that CAR-T 6 is going to win for efficacy. It's the toxicity we're all looking for, right? That melphalan, high-dose melphalan has been around a lot. We don't have mortality. It's less than 1%, 0% CIBMTR. So it really comes down to the tox. So if you have another product that's going to do something similar and not have toxicity, I would put, I would bet my money on it. And I think it's different than high-dose chemo, right? Again, transplant is chemo. It's not cells, even though we talk about is consolidation. This is just a very different ball game. I'm hoping that we're giving, let's say, [ telc, tara, mezzi ] as an induction followed by CAR-T and then you do maintenance for a little while and you're done. In high-risk patients, maybe you keep maintenance going standard risk, you could stop everything.

That is, I think, a future that we all hope for, right? I mean I think you said to me earlier today that we really -- even up until this year, no one's talked very seriously about cures in myeloma. But in other diseases, other cancers, cure has always required a multimodality approach. especially with if you'll consider it systemic or metastatic disease. In the rare cases of solid tumors that can be cured, those require multiple different drugs, multiple different mechanisms of action. And I am encouraged by the excitement I hear from physicians like you about the patients you're taking care of and that there may be ways to optimize further with the right product at the right moment. So I think we are proud to have worked with you all on this study but also that this could lead to patients just not needing to be treated forever, which is a really exciting potential. So on that optimistic note, we will switch over to our Q&A, and I'll invite Rami and Michelle up to the stage. If you all don't mind sticking around with us because some of the questions may be addressed to you.

Well, thank you, guys, for a great panel discussion and for being here this evening. We will maybe start in the room. Like I said, we are extra credit for those who made in Milan, and it looks like John has microphone.

Great. John Newman from Canaccord. Thank you to the physicians as well as. So I think Dr. Kaur, you mentioned something that I actually heard from another group at ASCO about pulling talquetamab forward and using it as bridging. My question is, when you have some of the CAR-Ts that require a very long manufacturing time, -- does that require you to pull therapies forward into bridging and ultimately use them longer than you normally would such that maybe later on, there may be not quite as attractive. I'm just curious about how you think about that.

So I think you're asking more about whether the usage of talquetamab is bridging, right? And I think even if -- and how does that play into manufacturing? Did I get the gist of the question right? As of right now, we want to bridge people and go into CAR-T with least amount of disease. And sometimes with our conventional therapies that we have, that's not achievable. So then we do move forward with talquetamab. Usually, it's always good to -- it's always good to have a product ready before you're done with bridging, so you can plan. So even if that cycle of bridging is going to go, let's say, your cells are ready, but then your bridging is going to finish 2 weeks later, that's okay because the cells being ready and you being able to plan around that, I think, is the most important option. And I don't think if you use talquetamab as bridging, that means you cannot use talquetamab later on. I don't know if that was part of your question. Yes. I would say talq exposure does not necessarily mean talc resistance. And it just depends on how long you use it for, right? Most of us are using it for a cycle or 2. Sometimes a cycle is more than sufficient. You make -- and cycle just equals about 28 days, 28, 30 days. We may go into cycle 2. Let's say, the patients kind of worn and torn out from all the hospitalization, you may want to just allow for them to recover, get stronger, you're able to bring them in. So actually just allows for them to get stronger and better planning. But we would like to do the minimal amount of bridging if needed. If they're already responding, I only do the step-up dosing for talq because, again, we don't see the toxicity, but the longer they're on it, the dyskinesia, the other issues going into CAR-T and it lasts for a little while. So it's not just 1 month and it's gone. So you don't want those quality of life issues. So if we can minimize it and we have the cells ready, but they've already had a response, I'll stop in the middle of the cycle and go.

Daina Graybosch from Leerink Partners. I thought the survey you put at the beginning, the one number that really jumped out was the difference in the community's response from '24 to '25 in their willingness to give CAR-T share in second line. And I wonder if the doctors, I think it went from 26% to 11%. I wonder if the doctors could talk about what you think is specifically driving that actually big increase in pessimism or more pessimistic there it is, whereas the academic, the treaters got a little more optimistic on their use.

So I think for us, we know what CAR-T means in the grand scheme of things. And so it's like, okay, we have something that -- especially our high-risk patients. So on the academic side, I will see a lot more younger patients with high-risk disease. I think in the community, again, a lot of other therapies are out there, bispecifics. They have dara combinations or ESA combinations that they can use. It's hard. Getting community doctors to send us patients, especially if they think that a treatment is too high maintenance or the toxicity is bad, they'll say, well, we don't want to give it second line. We think it should be third or fourth line. And what we've always told everybody is that once the CAR-T, if you're one line of -- we want to see them one line prior to CAR-T because, again, community versus academics, they think we're going to steal their patients, all these things. So we try to make it that we're not trying to steal your patients. We're here to help you when you need us. And then when it went to second line, that means they would have to send us at first line. And then again, I've done a lot of talks to community doctors to do education. And what I hear all the time is, well, the toxicity sounds pretty bad. I don't want secondary malignancies, this weird neurotox, my patients are older. I don't really think that they want to get this done. So we'll just sort of do these other things here at the local hospital. I don't know if that's.

No, I think that's exactly that. There was definitely a lot of enthusiasm. And I think the toxicity is probably what's preventing that -- it's probably driving that number going down actually. And I agree with Dr. Patel that we like to see the patients one line prior before we actually have to give them CAR-T, so we can start the logistics and planning.

And maybe it's important to point out that the nuance in this slide, though, Daina, where the difference that you're talking about is specifically focused on the currently available CAR-T therapies, not assuming the availability of a anito-cel where that actually looks quite strong again. So I think that does support the idea that this is mainly driven by toxicity or challenges that exist with the current therapeutic options.

Yes. I said that earlier. I think it is important, as Chris mentioned, that the end market experience seems to us to be impacting this variability with the current CAR-Ts, whereas the future state seems to be fairly consistent. Again, these are very large quantitative kind of statistically powered studies, and I found them to be very reliable in the past. So we do trust this when we see it.

One more. Sure. You talked -- it was really nice to hear the cases about how you're bridging today in the real world. And I wonder if you could talk about the real world versus the protocol on iMMagine-3.

Let me just lay the groundwork for iMMagine-3, just because that's -- it's public information, but I want to make sure we -- everyone knows where we started from. So iMMagine-3, randomized trial, obviously, and patients have to have a selection at the time of enrollment for what their standard of care would be if they're assigned to the standard of care arm. And if they are assigned to the anito-cel arm, that's therapeutic option they have to use for bridging. So that is just the groundwork for ImMagine-3 and then please take it from there.

Yes. So I think having it earlier line makes it a little bit easier that we have these washouts. I will say the washouts of the vein of my existence for all CAR-T protocols, but I have a lot of late line, even post-BCMA CAR-T protocols where that is a lot harder to deal with than earlier line, but it does make it more difficult compared to standard of care where I can do what I need to do to get that patient through. So right now, yes, we pick the standard of care based on -- I pretend my patients getting anito-cel, and I want them to get the best bridging. So I pick the standard of care based on that, right? And so then hopefully, that's the therapy that's going to actually work for bridging. But if they get it a standard of care, that's the best potential option for them, too. But yes, the washouts will for any of the -- any trial, just make it a little bit harder.

And maybe just to drive home that point, if you just look at the data with KDd, for instance, in the clinical trial that led to the approval of KDd, the response rate isn't 100%. So even though you're going to pick the best regimen for the patient, there is still a chance they're not going to respond to whether it's the control arm or whether it's the bridging in ImMagine-3. That's still a distinct possibility. The challenge that I think Dr. Patel is highlighted here is that you don't have another opt-in in a trial like that. That's just not allowed. And so that isn't a limitation you'll necessarily or definitively will not see when it's an approved product, whatever the product might be, the clinical trial design doesn't influence what you can do for bridging.

Yes. That's it. In the real world, when you're doing it, is your own discussion and what you think is going to work, what's available to the patient and how quickly you can get it?

Yes. For instance, we just heard cases of using talquetamab as bridging, which obviously didn't happen in any of the Cartitude studies.

Karina for Asthika I had a question on the long-term follow-up for Cartitude-1, which was presented at ASCO & EHA, which showed that patients with lower tumor burden ended up being long-term responders. But anito-cel probably it's going to have 17-day turnaround time. How are you thinking about debulking the tumor with bispecifics potentially?

Yes. So less tumor burden. I mean I mean, honestly, I know we encourage bridging therapy, but if somebody -- the goal is you get the patient earlier where the disease is not as aggressive. You're not dealing with M spike myeloma protein that's a disease burden of 5 grams. You're dealing with a 1 gram or 2 grams. So you actually don't need bridging therapy. That would be ideal for me. Do I get that in real life? That does not happen. I usually -- I think I lost track of your question. I sorry.

I was going to say, if I have 17 days and a patient needs bridging, I can just do the step-up dosing, which takes 1 week and you actually see a response. So I've had a few patients that had allo transplants before or renal failure. I don't want to give them too much because I was worried that it would put them into toxicity from the talquetamab itself. So I just did the step-up dosing and then a week later, they're ready to go. So if I had cells ready, I can do that, especially with bispecifics. I think it's harder with other therapies that are actually available on the study, for instance, that we can't do that. So then at least having the cells ready, I know that I can go as soon as I need it. But I think I'm excited for the real world part of this.

So let me just highlight because Daina was asking the same question. So I just want to make sure we're clear on this. If you give bridging therapy, for instance, iMMagine-3, there's a washout window from whenever the last dose of that therapy is to when you're allowed to give the cells. In the real world, you don't have to wait. So what it means is that, for instance, you could bridge a patient, have the cell sitting and waiting in the freezer for a week or more because they already arrived because they turned around in 17 days. That is pretty unheard of at this point in myeloma, and it's a good problem to have because it gives the physician the flexibility to make the right decision for the patient.

We actually want that problem. We want the cells to be ready, so then it's at our discretion on when we want to give it. Unlike the other way around, where we keep on giving radiotherapy, but we don't know when the product is going to arrive. So we are actually more predicting and not necessarily planning.

Yes. And our experience in iMMagine-3, which we've shared before, thanks to how incredible Kite is at manufacturing is that cells are generally arriving before the patients are done with bridging. And so it's almost like in effect, an off-the-shelf therapy. And I think both physicians have spoken about the predictability and the scale with which I think one of the things that's really underappreciated here is to really truly address second line you have to be largely scalable and predictable. Otherwise, it's all theoretical. Like to really truly address the number of patients that are needed here, you have to be able to do it the way Kite is able to deliver. Other than that, without getting this to that less than 17 days, without getting the inspect rate, without having the Kite connect and the logistics and then the reliability, kind of the wheels fall off the bus. And I think that's something that isn't really fully appreciated. And I don't know if either of you want to add to that.

Yes. I'm just going to add in reference to your question, the real-life case, my patient got bridging, got talquetamab, has a response, finished up of dosing. And my nurse is asking, when do you want to give for the dose again? And I said, hey, she'll be due for the next dose in 2 weeks, let's plan for that. But I don't know when the cells are going to be ready. So I can't make a decision today on when that patient will get their cells. And what I'm doing is I'm on the edge, keeping a check on their markers and the cells were supposed to be ready this week. I have not gotten a word that the cells are ready, and I'm going to have to end up dosing for the start of the next week -- the dose next week. So that's a situation we do not want to have. We want to be in the other situation.

Maybe while we're transitioning, I can just point out though that, that -- this debulking idea consolidation idea also may allow for more predictable outpatient dosing if you know which patients are now debulked, is that a fair assessment? Or have you had a different experience?

Yes, the less tumor you have, the less CRS and ICANs and the more I can keep people outpatient. We know that bridging helps with decreasing toxicity, short term and long term.

All right. And now we'll -- we have some online questions that I'll read out loud. This one is from Jason Gerberry at Bank of America. What line of therapy are you mainly prescribing Carvykti and I'll add in Abecma too. How do you see the supply of CAR-T naive patients in fourth line and fifth line when anito-cel is commercially available?

Currently, I have a very small subset of patients who are getting second-line CAR-T. Those are my high-risk patients with functional high risk who relapse earlier within a year or 2 of stem cell transplant. Majority of the time, it's being given in the third and the fourth line setting in my practice.

Yes, same. I think there are quite a few patients out there that are third line already for other things. And I still get those patients. We talk about CAR-T, and I give it to them then. I try to go at third line for most of my patients, again, because of the fact that I need better bridging, I need predictability, and that's going to happen in an earlier line for the current products. But again, I will take every patient that comes to me for CAR-T to CAR-T.

There was a second part to that question, right? How do you expect the supply to be if you've given patients CAR-T in third line, what's going to look like for fourth line? I actually think the conversation is changing as patients are more informed, and that's going to be part of our counseling, right? If there's a product that has similar efficacy and less of that toxicity than endocolitis and less risk of the toxicity enterocolitis and Parkinsonism, that patient is going to be willing to wait to get the CAR-T in the fourth-line space. versus before. And I've actually -- one of my patients said, Dr. Kaur, I'm not the one who wants to try out the first model of anything. I want to wait it out. I want to see when others have done the test driving and then I can go on in the second one. And there are patients like that. So I think that highlights that there will be -- there will definitely be a supply of those patients.

All right. And this question is from Tyler Van Buren from Cowen. As the patient preference to enroll in the ongoing second line plus iMMagine-3 trial as opposed to the commercial Carvykti as opposed to commercial Carvykti, given the lack of delayed neurotox and Parkinsonism was mentioned, what do you expect peak penetration of Carvykti to be in second line? And how much could that increase with a lack of delayed neurotoxicity as has been observed with anito-cel.

So I think this 5-year update, right, for anito-cel, I do think people are like, oh my gosh, CAR-T, again, it's changing the way we think about myeloma, which is huge because no one has ever thought that we would have a therapy you give once and then you don't get any treatment for 5 years, especially in relapsed/refractory. So I do think I have a few more patients that are asking about CAR-T that might not have before. So it's brought great attention to CAR-T. But again, coming back to the toxicity, if I have a standard risk patients, so my high-risk patients, I'm going to take them as soon as I can. That is something that I need to do. These are patients that don't get to third, fourth line, and I can get them to CAR-T. They're the ones that fall off. But for standard risk patients, again, you talk about all the potential options. I think about will I have bridging available, and I think I will because we have all these new therapies now. It's up to the patient and us to say what's the right move. And again, a lot of my patients in the past have picked Abecma because they thought it was safer. And again, if you give better bridging and you can give a CAR-T and get better outcomes and maybe I have less toxicity. So I think, again, there's going to be some patients that go in second line and third line, even if they're standard risk, but a lot of patients will say, wait or a lot of physicians will say, I'm going to give my things first and then we'll do CAR-T after.

If a patient goes on trial for iMMagine-3, they still get standard of care therapy. And I think iMMagine-3 has some of the best standard of care therapy options that are available to patients. And then if they progress on that, they can always move forward to Carvykti. So Carvykti will always remain an option for them. Two years ago, when I thought about any trial that was evaluating patients in the 1 to 3 lines of therapy, and we knew Carvykti was going to be approved, there was a little bit of nervousness, like, oh, my God, CAR-T is going to be available. How am I going to get a patient onto this study? And I actually think that, that's no longer true. That was -- and that was a fear that really had no basis because there are plenty of patients who do not want to take on that risk and we'll wait.

And this is another one from Tyler. At this point, what is the probability of a delayed neurotoxicity event or Parkinsonism case showing up with the anito-cel treatment? And have you monitored for ALC in the anito-cel trials to inform treatment? And have you excluded patients with peripheral neuropathy with Velcade?

Well, there's a lot in there. So the -- you want to take the second.

Take all of it. Yes. We didn't exclude patients with peripheral neuropathy because you couldn't enroll a trial if you did that. We didn't monitor ALC for how to intervene on anything. We obviously monitored CRS symptoms and intervened if patients had CRS, particularly CRS that needed ongoing intervention. So for instance, the patient had recurrent fever, rising inflammatory markers, et cetera. And I think as we've shared before, of the patients who got any dexamethasone, 60% of them only got a single dose of dexamethasone. So there was no prophylactic dosing of dexamethasone. This is really just a difference between products. And I think any other comparison between them is really fall short because these aren't the types of interventions that would preclude, as we just heard, ALCs continue to rise even when you give 400 milligrams of dexamethasone. So I think that's pretty well documented at this point. We've seen it in the ZUMA-1 trial, for instance, that you could give steroids at different times and doses that doesn't affect peak CAR-T expansion or area under the curve.

Yes. I'd just add that build a little bit on what Chris said. These are fundamentally different therapies. I feel like a little bit of this dialogue is pretending like we're using the same binders and one therapy has this issue, and it's like a mystery why the other one doesn't. It is very clear. The only difference between the 2 CAR-Ts is that one has one binder and the other one has another. So fundamentally, they are different. As to the question of probability, I have to channel my professor in probability and stochastic processes, Dr. Yates was very memorable, one of the better professors I've had. I think if you plug the difference of these observed rates between cilta-cel and anito-cel, you're going to get a p-value with a lot of zeros in it. Like statistically, they're very, very different. We cannot sit here and tell you that we can never have a case. But the more interesting question is, does it matter? I'll ask the physicians, do you think about Parkinsonism when utilizing Abecma? Investors don't think about Parkinsonism when it comes or delayed neurotoxicities when it comes to Abecma. Abecma has had more than one case. They've had multiple cases. The reality is that at some low level of cases inevitably happens, it seems for attribution or other reasons. But we have had sufficient follow-up with a sufficient number of patients to know that this therapy is fundamentally different from any other therapy out there in the myeloma space. We're very confident in that profile. And as I shared before in closing on this particular point, when you go back to the Cartitude-1 data from 5 years ago in ASH 2020 with similar median follow-up as we have now, the profile of Carvykti has not really changed from an efficacy, safety, manufacturability. So we believe that we have a similar degree -- well, we do, in fact, have a similar degree of follow-up with this therapy. And as a result, we're quite confident that on a go-forward basis, this is the profile of an anito-cel. And I think for some people, like there's this hypothetical of like what happens if you get a case. And I can kind of understand a little bit more if Abecma didn't exist, but it does exist. And we know what happens when they've had a low level number of cases. And the answer is absolutely nothing. Like we're talking about a materially different rate here that Chris went through earlier and materially different expenses as both Dr. Patel and Dr. Kaur shared earlier, and that is a different world than the world of anito-cel.

There was a question about peripheral neuropathy. Almost all patients with myeloma have peripheral neuropathy. We end up not excluding them from clinical trials, but we almost end up never excluding them from getting Carvykti even. That's just the reality of the patients we deal with. So I don't think that is a barrier to us being able to give them any CAR-T cell therapy.

Can you imagine a clinical trial in myeloma that excluded peripheral neuropathy? Honestly, would it enroll?

No, no, I would not. And even if we renew it with grade 1, that would not be written in the chart. If that was exclusionary criteria, and therapy was really effective.

All right. And -- are you able to provide -- sorry, this 1 is from Judah Frommer from Morgan Stanley. Are you able to provide insight into prescriber affinity for anito-cel as broken down by the product's clinical data profile versus supply and manufacturing benefits that are born out of the Kite collaboration. More curious as to whether the Kite relationship and related to superior manufacturing is a driving factor for certain dogs.

I think both, right? The efficacy and lack of toxicity, efficacy is always going to be #1. I will go through painful things if I have to for my patients, if something is superiorly better. But if they're similar and one has better toxicity, well, that's the next reason. But then the icing on the cake is the fact that I know when I'm going to get the cells, my team is happy, I'm happy. I'm not burning out just trying to get CAR-Ts to my patients. That's sort of the secondary, again, really important, but it is still secondary compared to the efficacy, but exciting. And again, my team is excited that Kite might be the people we use for everything rather than lymphoma right now.

All right. And -- for the management team, can you talk about your commercial -- sorry, this one is from Qize Ding from Redburn Atlantic. One question for the management team. Can you talk about your commercial launch plan for anito-cel in community hospitals and the major hurdles?

Yes, sure. Look, we're obviously, as we talked about, really excited to cover the entirety of this market, again, jointly with our partners at Kite, and we do believe that the community element here is going to be really important. It's a big part of why we shared this level of detail on the research because we are really encouraged by the reaction of the community physicians to the anito-cel profile. So getting into a little bit more detail, which I covered at a high level, we will be co-commercializing with Kite, meaning that we will also have a sales force and between the 2 of us, we will very much cover the entirety of the market, including the community. We have very detailed plans on how we will do that because we do believe it is critical. Again, our goal is we really truly believe, and you heard that today that we have the best therapy for these patients that God forbid if we knew anyone personally that needed a myeloma CAR-T, we would want them to have this one. So we are going after this market with that vigor to make sure that every single patient who can benefit can get there and a huge part of that is the community. I don't know that I can give you a lot more detail without showing a lot more detailed plans, but I think this is one of those where you have to trust us that is a huge focus of the launch from almost day 1. And because we have this dual sales force, we feel like we'll have the coverage to do it, and we will do it.

And if I could add one other thing on the -- the other element of this, of course, is education. With community doctors, they are usually covering many, many diseases and many different kinds of patients. And so part of our role and responsibility as a company involved in this space is actually to help share the knowledge that you heard from these physicians with physicians who are taking care of lots of other diseases. That's not always easy. And so part of what our job is, is to create data packages that will allow us to be able to go and share that with community doctors and demonstrate to them that this is a therapy that you cannot forgo because you're giving up too much. We believe that, obviously, but it is part of what we will do in the launch of anito-cel is help to share that message more broadly, not just with the doctors who give the therapy. They're already fairly convinced, but with the doctors who have to refer the patients for this therapy.

All right. And the last questions are from Gil Blum from Needham. Do you -- do you consider anito-cel as potentially expanding the market with difficult or frail patients? And for delayed neurotoxicity, what, in your view, is sufficient follow-up to exclude as treatment associated?

I guess it depends on your definition of frail. But yes, I think there is -- when we think of Carvykti, we give it to the younger fit patients, that's our #1 age group. But I would say mid-70s, we get worried a little bit about giving Carvykti and we start thinking about Abecma as we go into the 80s. I definitely think that, that population that's not going to be as physically fit will be actually opened up to anito-cel more so than even Abecma and it will take a share of the piece from even the Carvykti patient population. So yes, they will, I believe.

Yes, I don't have anybody above the age of 78 with anito-cel. The majority are 65 or younger. We have multiple patients in their 80s and even a 90-year-old with Abecma. But again, with the safety profile here, I'm not worried about the neurotox. That's really the main issue is the delayed neurotoxin these patients don't have the reserve to actually go through all that steroids and cytoxan and other treatments when they're already going through CAR-T. So that's -- again, that's the reason I don't do anito-cel. And if I don't have that, then I wouldn't be afraid to try an anito-cel for those frail patients. Even though I know on trials, none of our -- none of those patients are ever on any of our studies. So it takes the real world to figure it out, but I wouldn't be afraid to use it as we are as a group, I think, with anito-cel right now for patients going into 75.

It sounds like particularly if you could debulk the patient in your optimal way.

Yes. Look, I think I would add from on Arcellx perspective that we clearly believe and supported by this research that anito-cel is going to expand the market broadly. And it's going to expand in a lot of different ways. It may expand it by allowing use in some older failure patients. I think one of the biggest takeaways, hopefully here, it's going to expand it a lot in earlier lines. In second line, you're hearing a continued hesitation of utilizing CAR-T due to toxicities in earlier lines. It's going to expand it by driving into the community. The profile is clearly much more favorable in the community setting. So to be able to even access these patients, and needle cell is going to play a significant role. So from our view, again, based on our experience, what we've heard from physicians more broadly and then specifically from this research that it's going to be significantly expansive. As to the other part of the question, what is the sufficient follow-up needed to assess whether or not this is related. I think I can say from what we know, Carvykti, I'd love to hear from you in closing that it seems like these events tend to happen in the first 1 to 2 months. So we had a minimum follow-up of 4 months with iMMagine-1, 117 patients plus the Phase I, which obviously had significantly longer follow-up. So we're quite confident in the profile again. But maybe in closing, I love to hear from the 2 of you.

Yes. I think it's -- the delayed neurotoxicities are they're delayed, but they're after day 30. So even our cranial nerve palsies happen in that third to fourth week for the most part. We have seen it up to the second or third month. But after that, I don't expect -- if you don't have any neurotox after that third month, I don't expect any of my patients to have issues after.

Yes. I think when you have -- even though the number in your Phase I, what is reassuring to me is the N is small, but you have almost a 38.1 median follow-up, right? If there was a signal, let's say, not Parkinsonism, we should have seen it by now. And the patient population probably early on in your trials was sicker than later on, and we often tend to associate those 2. So I think there are less chances of seeing these types of neurotox with anito-cel. I firmly believe that not because [indiscernible] actually.

Well, thank you both for joining us and for sharing your wisdom and insights. Hopefully, I made Dr. Yates proud today, some of that recall of statistics. Thank you all for joining us here and via the webcast. We continue to really appreciate your time and your interest in Arcellx and so we meet again at the next meeting. Thank you.