← The Fellow on Call: The Heme/Onc Podcast
The Fellow on Call: The Heme/Onc Podcast
Episode 151: Myeloma Series, Pt. 11 - Role of bispecific T-cell engagers for relapsed/refractory multiple myeloma (2026)
Ronak Mistry, Vivek Patel, Dan Hausrath
Loading summary
Transcript50 lines
- [00:00]
A
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.
- [00:08]
B
Enjoy looking to sharpen your clinical edge in hematologic malignancies? Join the Lymphoma, Leukemia and Myeloma Congress October 13th through 16th in New York City, the famous Marriott Marquis. This is real world case based education. You can apply immediately. So head to llmcongress.com podcast or see the link in the description box below to learn more and use the exclusive code TFOC40 for 40% off registration.
- [00:38]
A
Welcome to another episode of the Fellow on Call, the hemonk podcast. We're coming at you from Rouleau University Medical Center. I'm Ronak.
- [00:45]
C
I'm Vivek.
- [00:46]
D
And I'm Sean.
- [00:47]
A
And in today's episode we're picking up where we left off last time, talking about the use of cellular therapy for the management of myeloma. And last time we spoke all about the role of CAR T and we started alluding to the fact that today we'll be discussing bispecific agents.
- [01:02]
C
Yeah, really excited to get into this one and without further ado, let's get to that show.
- [01:10]
A
So just to remind you both and our listeners, I'm just going to briefly summarize the case that we talked about last week. We have a 67 year old female with high risk IGG Kappa myeloma who came to clinic with concerns for progression of disease. Initially she was diagnosed three years ago. She was treated with bortezomib, lenalidomide and dexamethasone. And she underwent consolidation with a transplant and was placed on maintenance lenalidomide. Two years after that she had biochemical progression and she was treated with daratumumab, pomalidomide and dexamethasone. And she did well for about a year. But then more recently she started having evidence of biochemical progression again and that was evidenced by an M Spike going from 0.2 to 1.5. She has great functional status and her imaging and her other workup does not suggest any additional end organ damage. And so what we were discussing was how we approach this patient who has clearly progressed through second line therapy at this point and what the options for her are. And last time we spoke all about the role of CAR therapy. And now let's talk about bispecific agents.
- [02:19]
C
So before we move on, I just want to highlight A couple of really important concepts. Remember, high risk multiple myeloma is defined on cytogenetic abnormalities, not just using lab values. And so please look at the IMWG 2025 update and what is considered high risk multiple myeloma. Always look that up when you see that patient. Those are the patients who certainly need an auto transplant, certainly should be considered for clinical trial if they're interested. And I think that's really, really important. We want to highlight that. And these are the patients who might progress early. In our last episode we talked about using a variety of combination therapies in the relapse refractory setting, using agents that weren't used in the frontline, those second generation proteasome inhibitors, new generation immunomodulatory agents like pomalidomide and carfilzomib, and combining these things together in order to treat our patients, knowing that now we have bispecific antibody agents approved in the second line and CAR T cell therapy approved in the second line, which should be the de facto standard of care for all of our patients. They should be getting some form of cellular therapy in the second line if they have any access to it. And what I'll mention is for this patient, we talked to her about CAR T cell therapy. She had high risk disease. She early after auto, only three years. That's a short relapse after auto transplant and progressed quickly through a daratumumab based salvage regimen. So we think about this patient. We had offered her Cilta cell therapy. We Talked about the Cartitude 4 results, how Cilta cel often in the myeloma community. We think that it's a more effective product knowing that it has more side effects. But she lives in a rural area and she didn't want to travel far to an academic medical center and relocate. But she has an oncologist there who's willing to give her a bispecific T cell agent. So let's talk about that. Sean, can you tell us what are these bispecific T cell engagers? These bispecific antibodies?
- [04:09]
B
Yeah.
- [04:10]
E
So these bispecific T cell engagers, also known as bytes, are special antibodies that have two arms. So one arm is able to bind to CD3 receptors on cytotoxic T cells while the other arm binds to targets that can be found on myeloma cells. And so by grabbing onto both, it can bring the T cells into direct contact with the myeloma cells which, which enhances the immune response.
- [04:32]
D
Bispecific antibodies are available directly off the shelf like most medications. And this is a key advantage compared to CAR T, which as we talked about in our last episode, can take anywhere from four to six weeks or even longer to be ready to be infused into a patient. There are four bispecific antibodies that are currently approved for treating myeloma as of the start of 2026. Three of these, so this is teclistamab, L ranatimab and lemboceltamab target BCMA just
- [04:59]
E
like CAR T cells.
- [05:00]
D
While the fourth agent, which is called talquetamab, this targets a different protein called GPRC5D. There have been a lot of trials evaluating each of these medications and once again we'll include a link in our show notes that summarizes these trials. Now, up until recently, each of these medications had been studied and approved for patients who had progressed through at least four lines of prior therapy. However, as Vivek mentioned, there was a pivotal trial called Majestic 3 that was presented at the 2025 ASH annual meeting looking at the use of one of these bispecifics, teclistamab, in an earlier line of therapy.
- [05:36]
C
So Ronak, since our patient here, she says, look, I understand that this CAR T cell therapy sounds nice, it's one and done, but you told me that I might get Parkinson's. I don't want to do that. And this thing that you're telling me that there's a bispecific antibody agent, I want to do that one. I want to try that one. So for analogy's sake, let's hypothetically imagine that she hadn't just progressed to Daratumumab. Obviously we don't want to give Dara after Dara. That's not something that we want to do. But still, let's say we have a patient, they had progressed through a couple lines of therapy or maybe even progressed through just frontline therapy with Quad. Now we have this Majestech 3 data phase 3 randomized control trial published in December of 2025 and presented at ASH. Can you tell us about that?
- [06:16]
A
Yeah. Patients who had previously received BCMA directed therapy including CAR T therapy were excluded, understandably. Patients allowed to have been treated with anti CD38 agents like daratumumab, as Vivek mentioned, but they couldn't be refractory, meaning at some point in the past they could have been exposed to the drug. But as he was alluding to, it probably isn't a good idea to give them more daratumumab if they just progressed while on daratumumab. And for reference, in this study, only 5% of patients in the trial had prior exposure to anti CD8 anti CD38 treatments overall. So patients in the study were randomized to treatment with teclistamab plus daratumumab which they call tecdara versus standard of care with typical combination regimens for relapse disease. At 36 months, the progression free survival for Tehra was 83% compared to 30% in the standard of care arm. And that's a hazard ratio of 0.17. The 36 month overall survival for Tecterra was 83% versus 65% from the standard of care arm. So these are astounding numbers in this myeloma space. And so clearly this has been generating a lot of attention.
- [07:28]
C
I think this is a really pivotal study. So what this said is teclistamab plus daratumumab. So that combination of these two agents has this astounding benefit for patients. I mean this is mirroring what we saw in CAR T cell therapy. I mean it's very, very impressive. And we know, like we mentioned in our last episode, there are many patients in the United States who got VRD triplet induction years ago in auto transplant revlimid maintenance who are going to progress eventually. That might be at the 10 year mark, that might be at the 8 year mark. They haven't seen DARA before. And instead of reaching for daratumumab, kyprolis, dexamethasone or daratumumab, pomalidomide, dexamethasone, some of these combinations that you can do in the relapse refractory setting. These patients should be getting teclistamab plus daratumumab based on these results. They're very, very impressive or they should be considered for CAR T cell therapy. Both of those are reasonable options for these patients. And we'll talk about who we might choose for what later on in. But Sean, okay, these outcomes look great, right? All these patients are seeming to be doing very well. You know that 3 year OS, 83% in Takdara compared to only 65%. That's a massive difference in overall survival at 3 years. But what are the side effects for TCDhera?
- [08:41]
D
So as with the other bispecifics, we can see CRS and ICANS. However, this tends to happen at a lower severity. So for example, grade one and somewhat less frequently than with CAR T treatments, Cytopenias, particularly neutropenia, are quite common, as is hypogammaglobulinemia. And the most important side effect is the risk for infection. And so this risk for infection is even higher with the BCMA bispecifics compared to CAR T therapy. In this trial, grade three or higher infections occurred in over 96% of patients getting Tehra compared to 84% in the standard of care arm in fatal infections, and occurred in 4.6% of patients getting TDIRA compared to 1.4% on the standard of care arm. And almost all of these occurred within the first six months of treatment. One of the biggest reasons for these infections is the hypogamma globulinemia, an overall impaired humoral immunity that happens with patients on bispecifics. And so as a result of this, recommendations have since been updated. Nowadays, most myeloma physicians will Recommend monthly prophylactic IVIG infusions regardless of the total IGG level for at least the first 6 months while receiving a BCMA bispecific.
- [09:55]
A
That's a fantastic summary, guys, of the Majestic 3 study. And so timely as Tctera was officially approved by the FDA at the start of March 2026 for patients who have progressed through at least one line of therapy based on the results of this trial. So here at the fellow on call, we're on the cutting edge of myeloma therapy. And now you guys are in the know about that discussion. As an aside, we focus primarily on the BCMA targeting bispecific antibodies in our discussion here. But you mentioned that there was this talquetamab that targets a different antigen, the GPRC 5D antigen. And so are there important considerations with talquetamab compared to the other bispecific agents that our listeners should be aware of?
- [10:36]
C
Yeah, absolutely. And one thing I want to highlight before we move on is the importance of IVIG for these patients. It should be tec, dara, ivig. It's a triplet therapy because that immunoglobulin replacement is essential. And what Sean had mentioned, we have those fatal infections. The protocol is updated and mandated to start giving patients prophylactic immunoglobulins because the infection risk was so severe in that Tecdera arm. And this is really, really important for everybody to remember. We said these are transformative therapies. They have really, really good outcomes if given appropriately. So tecdara, ivig. I think that's really, really important. Many advocate for monthly IVIG regardless of the IgG level throughout treatment. Remember that when we're talking about antibodies in multiple myeloma. Sometimes we'll see these M proteins and these immunoglobulins stick around in the body for a while because the half life is longer than something like a light chain. The light chain half life's just a couple of days, so we'll see that tank down quickly. But we might see this residual M protein, some of these residual non functional immunoglobulins hanging out. So we can't trust that Those are functional IgGs in a patient with IgG Kappa multiple myeloma, for example. And this is why you don't just go on the number of IgG that you preemptively give these patients IVIg prophylaxis because they're at very, very high risk for infections. So now moving back to this GPRC5D bispecific ant quetimab. GPRC5D is a protein that's widely found on plasma cells, but can also be found on epithelial cells such as the skin, fingernails and oral mucosa. The risk of infection is not quite as pronounced as the BCMA bispecific agents. However, the main issue are things like rash. The skin toxicity is real fingernail abnormalities. There's very severe symptoms that can be associated with these fingernail abnormalities and most importantly dysgeusia. So just loss of taste and anore. Some of these patients who I've treated with this agent have lost significant amounts of their body weight. They can't eat, they have no desire to eat and they lose a significant amount of body weight. And I think that this weight loss is an on target off tumor toxicity. And so it's important when thinking about the right patient to give talquetamab to and knowing what these toxicity profiles are and knowing that we need to really, really importantly counsel these patients on nutrition and nutrition supplementation. These things are very critical for our patients. Supportive care for their skin and for their nails. All of these things are very, very critical.
- [13:07]
B
Let's take a moment to hear more about the sponsor for today's episode.
- [13:10]
C
If you're serious about advancing how you treat lymphoma, leukemia and myeloma, we've got some exciting news for you. The Lymphoma, Leukemia and MYELOMA Congress returns October 13th through 16th, this time taking place at the world famous Marriott Marquis in Times Square, New York City. Bringing together hematology oncology professionals for focused, practical, single track learning.
- [13:33]
A
We're talking real cases, real decisions, sequencing therapies, managing toxicities, and applying the latest data directly to patient care. No competing sessions, just high yield content from clinicians who are in it every day. And better yet, we have an exclusive offer for TFOC listeners. To learn more, head to llmcongress.com podcasts and use code TFOC40 to get 40% off your registration. That's LLM code TFOC40. This is a meeting you don't want to miss.
- [14:06]
C
Guys. I think it's time to hit us
- [14:07]
A
all with the million dollar question. With all of this though, we are super lucky that at the time of this recording we have so many good options for our patients now between CAR T therapy and bispecifics. So now I'm curious and I know our listeners are too. How do we pick between all these options and how would you go about choosing a treatment for our patient in our case that we started with?
- [14:30]
D
This is one of the most interesting and complex areas in relapsedrefractory myeloma right now. And honestly, the answer is likely going to be constantly evolving as new data comes out. There are so many nuances, but we'll stick with the highlights here to give a good idea conceptually of how to approach it. We'll also include a link to the International Myeloma Working Group Consensus guidelines on sequencing immunotherapy treatments in our show notes because this is probably the best guidance that we have available at the moment. So in general, the sequence that you give these advanced therapies does appear to potentially matter. So if you use CAR T and bispecifics in a patient, especially if both are targeting bcma, there seems to be less efficacy with whichever treatment you use second, and this may be due to a combination of factors. So we can see mutations in the BCMA receptor. We can also see something called T cell exhaustion, particularly with prolonged stimulation of T cells, such as when we're using these bispecific antibodies. The data we have currently favors using CAR T first and then using a bispecific later for maximal efficacy across multiple lines of therapy. Bispecifics tend to still have a decent response rate when they're given second. However, they do tend to have a shorter progression free survival in this setting compared to patients who were BCMA naive. Remember though, that talquetamab doesn't target BCMA, it's targeting that other protein, GPRC5D, and as a result it's a little bit different. And in the limited data that we have currently, talquetamab does not appear to have as much of a decreased efficacy on Future CAR T therapy if it's given first. And similarly, there appears to be higher response rates in patients who have already received CAR T and then go on to receive talquetamab.
- [16:09]
C
Yeah, I think that's really interesting because we're targeting a different antigen. Right. And this is where you might be thinking about using some of these bispecific agents as bridging therapies. As you get to CAR T, you have this patient with rapidly progressive disease. Standard. They've blown through standard treatments. That's possible. Or maybe they're just not responding to something like kyprolis based regimen. Patients with high amounts of extramedullary disease, disease outside the bones, disease outside just these circulating plasma cells that are inducing these paraproteins. But they've got tumor masses in the patient. This extramedullary disease. We know that those patients tend to have a very, very poor prognosis. And we need to do something to help that patient right now. And this is where a bispecific antibody can potentially bridge you to a chronic CAR T cell therapy. When we think about this, like Sean said, we worry about maybe T cell exhaustion and things like that. But we don't have to worry as much about T cell exhaustion if we're just using bispecific for just a couple cycles. Or maybe we just use it for a cycle, calmed the disease down, got out those T cells, and then gave another round of the bispecific therapy just in time to give the patient CAR T cell therapy. So you can see how we might be able to use these as bridging therapy. So where possible, we generally try to go to CAR T first, at least as of early 2026, based on what Shawn had described. But there are certain considerations that might be the deciding factor. One is the patient preference. Right? You ask the patient, you go through the side effects, you ask them what they want to do. So I think that's the number one most important thing. Also, depending on the patient's prior lines of therapy, they may only qualify for certain treatments based on current approvals. Nowadays, we can likely still get teclistamab approved in the second line setting, even if they've had a quadruplet induction. However, we might be favoring giving that patient a car T cell therapy based on the Cartitude 4 results. Some patients may not be ideal candidates for CAR T due to comorbidities. These are older patients, maybe patients who are in their early 80s. Those patients could tolerate a bispecific agent and they can achieve durable remissions with those bispecific therapies. The trajectory of the patient's myeloma is truly one of the most important factors. If the patient has rapidly progressive disease, they may not be able to wait the six weeks, seven weeks, maybe even months to get CAR T cell therapy for insurance approval, collection and manufacturing. In this case, bispecifics have a clear advantage. They're available off the shelf like most medications and can be given as soon as you obtain insurance approval, which is in a matter of days in many cases. So, going back to our case, Shawn, we have this patient. She told us that she didn't want CAR T cell therapy, which is kind of set up the introduction for the discussion today. But let's back up and say that she's undifferentiated, she doesn't know what she wants. How do you counsel that patient? What do you think she should get
- [18:56]
E
in this patient who's progressed through two lines of therapy and appears to be a reasonably good candidate from a functional standpoint, From a disease standpoint, I would probably lean towards offering Cilta Cel first, again, based off of the long term efficacy and kind of this idea of a potentially one and done treatment that can keep patients in remission for quite a long. However, if this patient had rapidly progressive disease or they were uncomfortable with the risks associated with CAR T, then Tecdara might be my next option that I would pick. Especially when you look at how much better it was compared to the sort of standard combination chemotherapy regimens that we had talked about as seen in Majestic 3. If this patient was getting CAR T therapy, remember that the bridging treatments that we discussed are very important to think about. So those conventional regimens that were used previously, so things like, like carfilzomib plus cyclophosphamide, those might be a reasonable strategy to help bridge this patient.
- [19:47]
D
If you think you can get them
- [19:48]
E
to CAR T, but you want to make sure that they're disease controlled in the several weeks that it takes to manufacture these cells. And of course, conventional combination regimens with medications such as carfilzomib could also be considered in this patient as bridging options. So again, what treatments a patient has received previously is important to think about when you're deciding, does this patient have good options to help control their disease while they're waiting for CAR T to be manufactured. Again, all this is kind of a moving target. So this field is rapidly evolving. There are certain scenarios, for example, things like extramedullary disease Plasma cell leukemia. These are certain scenarios where the data for certain agents, particularly these BCMA bispecifics, may not be as strong. And so these again, might be another reason why you might favor something like CAR T or potentially using something like talquetamab in this scenario too.
- [20:38]
C
Sean, I'm glad you mentioned that those patients with extramedullary disease have worse outcomes. We often think about CAR T cell therapy in that patient in particular. And I do want to point out that at ASH of this year and ASH of 2025, we had data from the REDIRECT1 study which looked at the combination of teclistamab and talquetamab for patients with multiple myeloma. And many of those patients who had extramedullary disease achieved outstanding outcomes. And so that's another promising approach. What if you do two bispec targeting two different antigens and in this very, very hard to treat extramedullary population, the patients did really well and it's off the shelf therapies. And so that's what makes it challenging. Right? You know, do you do the bispecifics that are off the shelf? Do you do the CAR T cell therapy? All in all, we love our CAR T cell therapy based on the long term results that we've seen in lymphomas and acute lymphoblastic leukemia. However, in multiple myeloma, time will tell which is going to be better. Is it going to be the bispecific agents? Is it going to be the CAR T cell therapies? And I think it's not going to be one size fits all. These therapies are going to move into frontline settings. Consolidation with CAR T cell therapy is going to be a thing at some point. It's only a matter of time. There's the Determination two trial we talked about. Determination one, looking at the role of consolidative auto. Eventually we're going to look at the role of consolidated CAR T cell therapy or bispecific therapy on MRD adapted approaches. So all of this is truly an evolving space.
- [22:04]
A
Before we close out today, guys, I'm curious. You know, you guys have presented some awesome options for patients. How do you know that it's working? What are your response criteria? When do you check and how do you know before you may need to reach for something else?
- [22:17]
D
Yeah, so particularly with CAR T therapies, oftentimes we need to wait a little bit longer.
- [22:22]
E
So we may need to wait until
- [22:23]
D
around three months to really get the
- [22:24]
E
fullest sense of how well a patient has responded to therapy. We can sometimes see early responses and early and deep responses.
- [22:31]
D
But the three month mark is really
- [22:32]
E
going to be sort of your most accurate time to assess these patients.
- [22:36]
C
And the key thing with that, remember, you might see melting away of the light chains. You'll see in some of these studies, there's MRD negativity from 10 to the minus 5, but they still have an M spike. And you're like, what? And that's because that M protein has a longer half life. That's the optimal time to look at treatment response to CAR T cell therapy is that three month mark. And that's a similar concept. When we think about these bispecific agents, it's not like the M spike's immediately gonna go to zero. However, those patients plasma cells may be blasted down after two to three months of these bispecific agents. So it's important to not give up early and to not assume, Wait, why is that M spike not just disappearing immediately? The light chains, though, we see melt away much more quickly.
- [23:15]
A
And just briefly, just to be explicit, can you just remind us again what markers we should be looking at to assess for a response?
- [23:21]
C
You're going to still be looking at your SPEP and looking at that M spike. And what we're trying to see is ideally a disappearance of that M spike or at least a 90% reduction would be a VGPR. And when we're thinking about the free light chains, a normalization of that free light chain ratio or, or a near normalization of that free light chain ratio. We do bone marrow biopsies to sometimes send this MRD testing to give us a sense of how deep is this remission in this patient. I would say in 2026 it does not change your management. So it's not mandatory. So if you're in the community and you're worried about giving tactera because you're like, when do I do clonaseq testing, when do I do MRD testing? How do I interpret this? It's not gonna change your management necessarily. In 2026, give that patient the best standard of care. Knowing that you're gonna be tracking your conventional metrics, you're gonna be looking at looking at that light chain ratio. Doing another bone marrow biopsy in a patient who's had 100 bone marrow biopsies maybe isn't necessary. If their serum markers look really good, we don't necessarily need to know exactly how deep that remission is for that patient. That patient might be just better off by just continuing on treatment like you would. If you were to give them any carfilzomib based regimen. If you were to give them daratumumab, carfilzomib, dexamethasone, what do you do? You look at their serum markers. If you give them daratumumab, pomalidomide, dexamethasone, what do you do? You look at their serum markers? Any of these combination therapies, that's what you're going to do.
- [24:43]
A
All right, guys, I think this wraps up another fantastic episode of the fellow on call and really does round out the highlights of our discussions about multiple myeloma on our reboot and our refresh of our initial data from three years ago. You know, in the near future, we're also going to release an episode where we talk about this data in more detail with some experts in the field and just really try to understand how people are utilizing all this information that appears to be AI being collected at a light speed. So it's really, this space is just ever evolving as we're alluding to here, an exciting time. But it's important that we also understand how to put all this information into clinical context.
- [25:21]
C
The last thing I'll say, Tecdara IVIG Tech ivig talquetamab ivig give everybody monthly ivig. Couldn't stress it more. Don't forget about PJP prophylaxis and viral prophylaxis.
- [25:35]
E
And I just want to say, you know, it's incredible thinking about how much has changed since we did the original series three years ago. And at the rate that things are going, you know, we may need to do another update in three years. And it may be completely different data that we're talking about, but that's what makes myeloma care so exciting, is that we have so many advances in how we're treating our patients and a lot to look forward to.
- [25:54]
A
And before we sign off, I do just want to say a big thank you to Sean, another voice that you guys have heard throughout the series as well. In case you didn't hear our first episode when we started this series, this time, Sean has been a part of our show for a very, very long time. And we were very excited that Sean treats multiple myeloma every single day in his current role as an attending physician at Rouleau University Medical Center. And so we thought, why not bring the expert into the discussion? So, Sean, thank you so much for your time and all of your energy and all of your insights. About how you take care of these patients. I think it really has enhance the quality of our conversation this time around.
- [26:30]
D
Yeah, it's been such a great experience. And again, this original series is one of the reasons why I got interested in myeloma care back when I first listened to it. So I'm hoping that with the updates that we've had, that maybe it might help to inspire more people to go
- [26:44]
E
into myeloma as well.
- [26:46]
A
So on that note, guys, I think that wraps up another fantastic episode of the fellow on call. Until next time. We'll see you all later.
- [26:53]
C
See you later.
- [26:54]
D
See you later.