← The Fellow on Call: The Heme/Onc Podcast
The Fellow on Call: The Heme/Onc Podcast
Episode 150: Myeloma Series, Pt. 10 - Role of CAR T for relapsed/refractory multiple myeloma (2026)
Ronak Mistry, Vivek Patel, Dan Hausrath
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Hey, friends. This episode of the Fellow on Call is not meant to be used for medical advice and is intended for educational purposes only. Patient information has been modified to ensure privacy. The views expressed in this episode do not necessarily reflect the views of our employers.
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Enjoy looking to sharpen your clinical edge in hematologic malignancies?
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Join the Lymphoma, Leukemia and Myeloma Congress October 13th through 16th in New York City, the famous Marriott Marquis.
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This is real world case based education.
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You can apply immediately.
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So head to llmcongress.com podcast or see the link in the description box below
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to learn more and use the exclusive
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code TFOC40 for 40% off registration.
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Foreign. Welcome to another episode of the Fellow on Call, the hemog Podcast. We're coming at you from Merlot University Medical Center. I'm Ronak.
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I'm Vivek.
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And I'm Sean.
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And in today's episode we are continuing on our myeloma journey and this time talking about part one of our cellular therapy options for patients with multiple myeloma.
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C
Yeah, really excited to get into this one. You know, we split this episode into two so it's easier to digest. This episode we're really going to focus on car T cell therapy for a big chunk of it, but we're also going to talk about just relapse refractory regimens in general as an overview. So really excited to get into this one. The data is so complicated and so we're really trying to distill it into high yield points.
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Sounds good. So without further ado, let's roll that show. I don't want to give too much away, but I know throughout this series not only have we been talking about myeloma, we've also been alluding to Love is Blind in Bridgerton at the time that we're recording this. Now both of those series have completed and Vivek, just if you had to describe it in one word each show, what would you pick?
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I never want my children to be on Love is Blind. That's a failure. As a parent, I can say that it was a great season, but so ridiculous. It's like that you've really hit rock bottom if you're entering Love is Blind. I, I will say that I haven't finished Bridgerton yet, so I can't really comment on the second half. It was kind of slow. The second half of the season. First half of the season was great. Second half, I'm like, come on, you guys are dragging this out, but I think I've got one more episode left or two more episodes left. So still recommend but second half is slow.
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Sean, I can't remember, do you watch either of these?
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No, I was really going to base which one I watch first off of Vivek's Pick, so I'll have to decide. I think the main show that I'm into right now is Food Network's Tournament of Champions, so. So shout out to that.
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That sounds great. I will say I finished both Love is Blind and Bridgerton. Both of them are fantastic. Love is Blind. But I agree, I would never want to see anybody that I know on that show because that is just horrifying. Although I am excited the next one is in Philadelphia is what I'm told. So I'm very hopeful I will recognize a face or two when that one comes out. But guys, on to, you know, we are rounding out our myeloma series and we only got a few episodes left. This time we're focusing on the first part of our discussion about cellular therapy options in myeloma, which is a hot topic certainly in hemolignancies as a whole, but most certainly in myeloma. And then, you know, just as a sort of teaser for our audience, we will be having another sort of roundtable discussion with an expert that you guys may recognize in a future recording as well. And this is a great way for us to just showcase just how complicated myeloma therapy is. So I'm really, really excited for what's to come in the remainder of this series. But maybe I'll start us off with a case for our discussion for today. You guys game?
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Yep. Let's do it.
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So we have a 67 year old female with high risk IGG Kappa multiple myeloma who presents to clinic with concerns for progression. She was originally diagnosed three years ago and received induction with bortezomib, lenalidomide and dexamethasone or vrd, followed by consolidation with an autologous stem cell transplant and was maintenance lenolidomide. Two years after her induction she was noted to have biochemical progression with a rapidly rising M spike and as a result was started on daratumumab, pomalidomide and dexamethasone or dpd. She has been on DPD for one year, but for the last two months her M spike is continuing to uptrend with a nadir of 0.2 grams per deciliter to 1.5 grams per deciliter, which confirms that she has biochemical progression. Her medical history is only significant for well controlled hypertension and hyperlipidemia and she has a good functional status. She does not have any evidence of end organ damage from her myeloma. And re staging scans do not show any signs of overt disease. So clearly in this case we have progression of disease. And so based on this information, guys, what treatment options should we even be considering in this patient?
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Before I let Sean really talk to us today about cellular therapies, I do want to go over just an overview of relapsed refractory myeloma. And it's Alphabet soup, word salad. Choose your own adventure, truly. And the way to think about this in broad strokes is choose drugs that you didn't use in the frontline setting. I will say historically, it's always important to have historical context. Historically, dexamethasone single agent was used for these patients and had activity. This is why dexamethasone is in the backbone for every single one of these multiple myeloma regimens. When we think about the relapse refractory setting, we think about using a different proteasome inhibitor. So often we're using velcade in the front line. That's when you can use the drug called carfilzomib that has a unique toxicity of cardiac and potentially renal. So you have to have a good creatinine and appropriate cardiac function to get that drug. But we really believe that is one of the most effective agents in the relapse refractory setting. So if the patient can tolerate it, do a carfilzomib based regimen. If you're not doing cellular therapies, and I think that's important, then we add on another immunomodulatory agents. Really all of our patients are on lenolidomide. So the immunomodulatory agent we're talking about is pomalidomide, like what this patient got. And if they haven't seen an anti CD38, you're to add that on like a daratumumab or an isatuximab, which we've talked about before. The patient we're talking to you about today is going to be in your clinic. We have many patients who got triplet inductions before the era of quads followed by auto, who will relapse maybe 10 years later, maybe eight years later, maybe seven years later. This case, it was an earlier relapse, but not all of your patients would have had that quad induction. So in the second line setting, as we think about, what do we give them? Remember that carfilzomib based regimens are the most effective. And there's a study called the Candor trial and that looked at a carfilzomib based regimen with daratumumab with really, really good outcomes. Better PFS than something like a DARA Velcade Dex regimen where you're repeating the Velcade usage. So again, these are kind of accommodations that you can use, but it's really a choose your own adventure. We'll really link, there's some Mayo Clinic guidelines on the relapse refractory setting and a couple papers in there. We'll link you a table to see. You can kind of see what the options are, but it's really choose your own adventure. And nowadays what really thinking about for patients, particularly if they progress early, we're really reaching for these cellular therapies. They're really, really important. And in general, because of the great outcomes that we've seen that we're gonna talk about, pretty much all patients should be getting some form of cellular therapy in the second line setting for the most part. And so that's why I really wanna transition and talk about those right now. So Sean, can you tell us a little bit about these cellular therapies? And the last thing I'll say before I kick it to you, just to give our listeners one full recap of all of this, the regimens I talked about, the things that'll be linked into our show notes, those Carfilzomib based regimens, those potential bridging if you're going to something like CAR T cell therapy. So Sean, can you tell us about these cellular therapies?
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Yeah, absolutely. So this case is really a great introduction to the types of patients that you might see when you start to consider the two types of advanced treatment that we'll be covering in this episode and the next episode. So these are CAR T cells and bispecific T cell engagers. And so these therapies both use cytotoxic T cells to kill myeloma cells, but in different ways. And they really drastically changed how we approach multiple myeloma in the relapse setting. And particularly, as Vivek mentioned, in patients with aggressive or multiple relapsed disease. And this is a population that has historically been associated with poor outcomes. Let's start with a quick overview of CAR T therapy. And so if you remember from our lymphoma series, CAR T therapy is a form of cellular therapy that leverages the function of our immune cells in order to target cancer cells. And CAR stands for chimeric Antigen receptor. And what this means is that we're essentially reprogramming a patient's own T cells, tuning the T cell receptor to directly recognize an antigen present on the surface of myeloma cells without needing the help of an antigen presenting cell. And in myeloma, these CAR T cells specifically target B cell maturation antigen, or bcma, a protein that's found primarily on plasma cells as well as some other B lineage cells. The other type of treatment that we'll be discussing in our next episode are Bispecific T cell engagers, also known as bites. So stay tuned for that.
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Sean, that was a fantastic overview. And Vivek, thanks also for giving us that background because I think these terms like bridging therapy and stuff is going to be really, really helpful as we talk about our patient today. So we sort of talked about CAR T as a whole, but specifically what CAR T therapies are actually available in myeloma. And can one of you or both of you kind of give us some of the supporting data from for these treatment options?
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As of the time of the recording for this episode in 2026, there are two FDA approved Car T products for the treatment of myeloma. Idacaptogene Viclusil, also known as IDE CEL or ABECMA by its brand name, and Ciltacaptogene Autoleucel, also known as Cilta CEL or Curvicti by its brand name. There have been multiple trials for both of these CAR T products, and these were patients really looking at fifth line setting patients. They had received all conventional therapies, nothing left over, and they had durable remissions to some of these therapies. So they seem to be pretty transformative for this heavily pretreated patient population who also had impaired T cell fitness. So we're not going to go through the data for all those trials. The IDE cell trials are called the Karma trials. So if you look at Karma, that's for IDE CEL and Cartitude is for the CILTA cell trials. So again, I think it's very, very important to go through just the data that we have most updated, which is really in the second line setting for these products. So let's start with IDE CEL. So, Sean, can you talk to us about the CARMMA 3 study that really got IDE CEL approved for an earlier indication?
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Yeah. So the Karma 3 study was a phase 3 randomized controlled trial that was published in 2021. And in this study, all patients were required to have progressed through at least two to four prior lines of therapy. And all these patients were also required to have previously received daratumumab as part of their earlier treatments. Patients in this trial were randomized to receive IDE cel versus standard of care with one of five typical combination regimens similar to what Vivek mentioned at the start of the episode. And investigators could choose which of those five options they picked for a patient if they were randomized to the standard of care arm. Now, in this trial, the median progression free survival with ide cell was 13.3 months, and this was compared to 4.4 months in the standard of care arm. The median overall survival with IDACEL was 41.4 months, and that was compared to about 38 months in the standard of care arm. And so this was not statistically different. However, it's really important to keep in mind that crossover was allowed in this trial. And actually 56% of the patients who were initially assigned a standard of care eventually crossed over and then later received IDE cel when they progressed.
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And Sean, I think that's really, really important because what we're seeing here is that they got appropriate crossover. Crossover doesn't dilute the results. It's appropriate. It's sequencing of therapy. CAR T cell therapy is very expensive. It can cause some late toxicities, things like that. So when it comes down to it, the question is, do I give it now or do I give it later? And so it's important that the control arm, many of them did get CAR T cell therapy later. You might be asking why isn't it 100%? That's because logistically getting commercial CAR T product is quite challenging. And so that might be the argument to give it earlier because maybe patients can't wait to get the CAR T cell product. The manufacturing time, some of the logistical issues behind CAR T that we'll talk about shortly. So that's very important to consider.
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Let's take a moment to hear more
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about the sponsor for today's episode.
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Now let's talk about the other product, Cilta cel, also known as Carvicti. We often think that Cilta CEL is the stronger product, quote unquote, although they've never been compared head to head. So Rona, can you tell us about the Carvycti data or the Cilta CEL data?
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Yeah. So the Cilta CEL was initially studied in the single arm Caritude 1 trial and then later in that Carititude 4 trial that we'll focus on here. So Cartitude 4 was a phase three randomized control trial published in 2023 and all patients had progressed through one to three prior lines of therapy. And for this trial prior daratumumab exposure was not required and only a quarter of patients had seen DARA before. Patients were randomized to either CILTA cell versus standard of care with combination regimens used in the relapse setting. And we' our show notes at the time of the initial publication, the median progression free survival and overall survival had not been reached with Cilta CEL. However, in February of 2026 there was an updated analysis of Cartitude 4 that was published. The progression free survival at 30 months was reported as 59% with Cilta CEL versus 26% with the standard of care. The overall survival at 30 months was 76% with Cilta CEL vs 64% with the standard of care. Keep in mind that unlike with the Karmma trial, patients in Cartitude 4 who progressed on the standard of care arm were not allowed to cross over to receive Cilta cel. So that is one big difference between these agents.
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And I think the key thing there is that in this Cartitude 4 trial, not allowing crossover, the overall survival isn't going to be accurate to the real world what we're seeing for patients. That being said though, progression free survival is an important endpoint. And why is that? We're hopeful that maybe there's a plateau in progression free survival for a subset of patients. So patients that might be able to experience very prolonged remissions after something like a car T cell therapy. And what I want to highlight here too is that when you think about high risk patients here, they did very well with the Cilta CEL arm. So Cilta CEL seems to have maybe normalized some of those high risk features. Not completely normalized it, but definitely improved the outcomes for those patients significantly, which I think is really important. And then the other thing I want to mention, so we had the IDE CEL product approved in a third line. From what Shawn said, they had to have two prior lines of therapy. In this case, one prior line, and one line of therapy is induction, transplant and maintenance. That's all one line. And so now we have this open to our patients. So which patient are we going to think about? CAR T cell for that younger patient and maybe that patient who progresses very quickly, rapid relapse, you know, like this patient, within two to three years, we know they have poor outcomes. And now we have this product, Carvycti, that really has had outstanding results. Those three year PFS around 60 is very, very impressive compared to only 26% before, is what Roanoke said. So I think that's huge. So, Sean, all this sounds nice, right? When we're saying Cilta Cel has these ridiculous PFSs better than Ide Cel. And we know that from the earlier phase studies as well that Cilta CEL always had numerically better outcomes. What about the difference in side effects?
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Yeah, so that's a really good question. And honestly, it's one of the most important distinctions besides the efficacy between these two treatments. And so a lot of the side effects are shared between IDE CEL and Cilta cel. And so, for example, for both treatments, there is a risk of CRS and icans. And if you need a reminder of what CRS and ICANS are, check out our previous episodes on CAR T. But just as a quick refresher, CRS is an inflammatory response that can be as little as fever or can include hypoxia or severe hypotension. Meanwhile, ICANS is neurotoxicity, which can range from confusion and word finding difficulty, all the way up to seizures and obtundation. Now, both of these treatments have risks for CRS and icans. They also have risks for things like cytopenias, infections and a delayed HLH like syndrome that we call iechs. However, the key difference is that Cilta CEL was also associated with what we call non ICANS neurotoxicity. And these are delayed neurologic symptoms that can include things like cranial nerve palsies, atypical Guillain Barre syndrome, and most importantly, Parkinsonism and Parkinsonism symptoms occurred in about 6% of patients in that initial Cartitude 1 trial, which is in patients that had progressed through later lines of therapy. And it was down to about 1% in the Cartitude 4 trial. These were the patients that had received one to three lines of prior therapy.
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So, you know, you guys have outlined what the different options are, what the different side effect profiles are. Clearly we're taking all this into account when we pick one product over the other. So when you're tasked with this question in clinic, how do you go about
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deciding, yeah, I think that's really tough when we look at these two trials. They're different trials, they're different study populations. You know, in the Cartitude study we had patients who hadn't had DARA exposure before. And for non DARA exposed patients, when you think about that, they're earlier on in their treatment journey. So maybe they will always have more favorable outcomes than those patients who had already progressed through Daratumumab. So I think that's one thing to consider. Carta 2 didn't allow crossover, so we can't trust that overall survival analysis. If there's no OS difference in the IDE CEL trial in that Karma 3 trial, but there is an OS difference in the Cartitude trial. Is that just because we didn't give patients to CAR t when they should have been getting CAR T in later lines of therapy? With this context though, the prevailing opinion in the myeloma community is that Cilta CEL seems to be more likely to keep patients in remission for a longer period of time. Like I had mentioned earlier, part of this comes from the single arm cartitude 1 data. These patients had all progressed through at least three lines of therapy, but even though they had advanced disease, we saw a median overall survival of 60 months on long term follow up. So that's five years of median overall survival in a heavily pre treated population. And this was higher than the early Karma studies. This is also backed by real world analyses. Obviously these aren't perfect head to head comparisons, but they do show an association with longer pfs and OS and CILTA cell compared to IT cell. Albeit we do have higher rates of infection, severe cytokine release syndrome and more of this delayed neurotoxicity. Sean had mentioned some of those cranial nerve palsies. Those really approached maybe about 9% in that Cartitude 4 trial. So they're not trivial. They can take a long time to get better in some cases. So it's something to consider. So some might say look, the more effective product is Cilta Cel. That's the one that I'm going to give to my patient. Others would argue, well, if I have an older patient, maybe a little bit more frail, they just want a one and done therapy. Unlike Bispecifics, which is more continuous therapy, but they want a one and done therapy. Maybe that's the patient I would give IDE Cel to. Though a vast majority of providers who I think are eligible for CAR T, we think that Cilta Cel is probably the better product to go with just because we see these longer gains in progression free survival which will likely translate into overall survival.
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So essentially in summary, from what we just talked about with IDE Cel and Cilta Cel, both of these CAR T products are approved for treating myeloma. We talked about how Cilta Cel is approved after at least one line of prior therapy and based on the information that we have, it seems like it's the one to more likely achieve longer remission. Ide Cel is approved after at least two prior lines of therapy, but does not appear to have the same level of risk of non icans neurotoxicity such as Parkinsonism that we saw with Cilta Cel and most myeloma physicians seem to generally lean towards using Cilta CEL based on the efficacy. However, if a patient is not comfortable with the risk of Parkinsonism or other delayed neurotoxicities, then maybe something like IDE Cel may be a better choice. Guys, I think that was a really, really nice overview of a super complicated topic like CAR T and myeloma. And we'll also include a nice little review in our show notes for our listeners to take a look at as well if they want more information. So before we move on to talking about our T cell Engager products, we sort of started alluding to this already, but can we just talk a little bit about what the actual process of giving CAR T actually entails? We talked about reprogramming cells, that there was going to be some sort of delay in terms of administration. Can we just sort of more explicitly discuss this?
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Yeah, of course. And be sure to check out our DLBCL series where we discuss this process as well. So practically speaking, the very first step in CAR T therapy is getting insurance approval. And unfortunately in the real world, this isn't always a smooth process. And sometimes depending on the patient's insurance, it can introduce a substantial delay in being able to start the process for CAR T therapy once it is approved by Insurance. However, the first real step is T cell collection, which involves collecting a patient's own T cells via apheresis. And keep in mind that before we do collection, we generally need to hold any myeloma therapies for at least seven to 14 days before in order to ensure that we have a good quantity and quality of the T cells that we collect for CAR T. Once these T cells are collected, they're shipped to the manufacturer where they're re engineered with this recombinant CAR T receptor. And this process of manufacturing can take anywhere from four to six weeks on average. Once manufacturing is complete, those cells are then able to be shipped back to the clinic. During this prolonged four to six week wait period, patients will frequently receive some sort of bridging therapy. So this is what Vivek was alluding to earlier, where we may use something like a kyprolis based regimen that a patient hasn't seen before as a way to help control their disease while we're waiting for the CAR T cells to be ready. Once those cells are ready, the patients will then be brought in to receive what we call lymphodepleting chemotherapy. This lymphodepletion step essentially clears out space for the CAR T cells and allows them to be able to quickly multiply once they're infused into the patient and then once that chemotherapy is given a few days later. That's when patients are able to receive their CAR T cells. So all of this means that the patient's myeloma needs to be stable enough to allow time for this all to happen. If a patient has a very rapidly progressing myeloma, they may not be able to wait long enough to go through all the steps that it takes to get CAR T treatment. And that's where something like bispecific therapy, which we'll be talking about in our next episode, may come in very handy.
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And I think this is the challenge in multiple myeloma. Today we talked about how effective these CAR T cell therapy products can be. That Cilta Cel product, you know, when we're looking at that Cartitude 1 data, median overall survival at 60 months is so good. I mean, that's very, very, very impressive that these patients are living that long with this therapy. So it's a truly transformative cellular therapy. We know that it's highly effective for patients. The problem is not all patients can get there. And that's the argument to give these earlier when you're later in later lines of therapy. And let's say you have a Three month delay to get your CAR T cell product because insurance took a while and then it took a while to eventually get the patient in apheresa slot. Then they got apheriste and then he waited for manufacturing and oh, there's an out of specification product. There's a quality control that comes in and maybe we have to collect again. There's this long lag that can exist and that can last three months is a very common time period before the physician thinks, I need to give CAR T before the patient actually receives CAR T. And I think that's a very challenging thing here. So for that patient population, you're thinking, what can I do to control their myeloma before the myeloma takes their life? And this is where bispecific antibodies are off the shelf. And we're gonna talk about it in our next episode. That's a good use for them. We'll also talk about maybe you can use a bispecific antibody to bridge somebody to CAR T cell therapy. That one. And done therapy to really blast away that aggressive myeloma. Because we really believe that the highest rapidly progressive myelomas need some form of CAR T cell therapy. Remember, when you're trying to hold the disease, if the patient hasn't seen carfilzomib, that kyp use a kyprolis based regimen. It is highly efficacious. Most of our patients are going to have seen daratumumab before for the quad inductions, but that's going to be ten years from now. What we're going to see in our clinics are the patients who got triplet inductions with something like a VRD and an auto transplant. So remember, you can use Daratumumab, kyprolis, dexamethasone. That is a highly effective regimen in the relapse refractory setting. As long as their heart's okay and their kidneys are okay. Remember, that's really good. And that's why you're seeing daratumumab, pomalidomide, dexamethasone as the control arm in that Cartitude 4 study.
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And that bridging therapy is so important because one of the things that we've seen is that the more active myeloma a patient has at the time that they undergo their CAR T treatment, the more likely they may have significant side effects with it too. And so we want to have effective bridging options available. And sometimes that is part of the consideration of why we want to try to give these treatments earlier in their lines of therapy because sometimes if we wait too long, we may not have effective bridging options available for that patient.
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C
And the other thing, the last thing that I'll say is never forget about the efficacy of Cytoxan. We have data that we can give Cytoxan, dex, higher doses of Cytoxan, and this can control patients myeloma when they're rapidly progressing. These are things that we'll talk about in our capstone episode. We'll have a roundtable discussion with multiple experts. And I just wanted to throw that in there, that these are the considerations, the complicated considerations, and why referral to myeloma experts at academic medical centers are essential for these cases.
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A
That was amazing. That was fantastic. And I think this is a really good place for us to pause in this discussion and pick this up next week. We're already alluding to what we'll be talking about, which is the use of bispecific agents for myeloma therapy. So let's give our audience a chance to sort of digest this information. Guys, check out our show notes as we always tell you to do. We'll lay all this out for you. We have some more papers and resources for you to take a look at to further your understanding of these topics as well, to make you all a pro. So, guys, I think that wraps up another fantastic episode of the fellow on call. Until next time, we'll see you all later.
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C
See you later.
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B
See you later.
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C
This podcast was edited by Resonate Recordings.