Podcast: Shifting treatment paradigm in multiple myeloma: a podcast integrating ASH 2025 data with patient and physician perspectives

Abstract

In this plain language podcast, highlights from the 67th American Society of Hematology Annual Meeting and Exposition (ASH 2025) are discussed, with insights from the perspective of an expert patient and physician experienced in the field of multiple myeloma (MM). This podcast aims to enhance the communication and understanding of complex scientific data on MM among a broad audience, including both specialists and non-specialists, and help guide the partnership between patients and clinicians in making informed treatment decisions. Three key topics are covered by the podcast: Emerging evidence supporting a shift to earlier use of T-cell directed therapies facilitating an earlier immune response in MM patients; evidence for proactive strategies to optimize the patient outcomes and experience with T-cell-redirecting therapies; and an overview of novel T-cell-directed regimens entering the field for typically difficult-to-treat relapsed/refractory multiple myeloma (RRMM). We will discuss the growing body of clinical trial data showing that, aside from the proven benefits observed in the RRMM setting, shifting bispecific T-cell engagers and chimeric antigen receptor T-cell (CAR T) therapy into earlier lines of therapy enhances outcomes and may even offer potential for cure. In addition, we will consider how the findings from retrospective and real-world studies inform proactive strategies to optimize the patient experience with T-cell-redirecting therapy use, focusing on mitigation of commonly seen side effects and reducing treatment burden. We will also provide a roundup of novel T-cell-directed regimens that are in development for MM. Finally, we will discuss what these data outputs mean for the immediate future of treatment for MM, and how understanding MM patient experience with bispecifics and CAR T therapies, particularly effects on patient overall wellbeing, can guide therapy selection and ensure that patient-centered care, in partnership with clinicians, is a realistic goal.

Introduction

Rahul Banerjee:

Welcome to this podcast [in] Therapeutic Advances in Hematology. This podcast will highlight data presented at the 67th Annual Meeting and Exposition of the American Society of Hematology, which we will call the ASH meeting for short, which took place in December 2025. ¹ This podcast is aimed at everyone interested in the latest multiple myeloma research presented at ASH.

Listeners do not need to be physicians or experts, as the discussion will be in plain language, with explanations given for any technical terms used. Podcast speakers include Todd Kennedy and Dr. Rahul Banerjee. The views expressed in this podcast are solely those of the authors, and do not necessarily reflect those of their employers, the podcast sponsor, ASH, or any of their affiliates. This podcast was sponsored by Johnson and Johnson. The authors received no honoraria or funding related to the development of this podcast. Medical writing support was provided by Amica Scientific and funded by Johnson and Johnson.

Rahul:

Welcome to this podcast for Therapeutic Advances in Hematology. My name is Dr. Rahul Banerjee, I’m an Assistant Professor of Medicine at the Fred Hutchinson Cancer Center in Seattle, Washington, USA, and I specialize in multiple myeloma, smoldering myeloma, and other plasma cell disorders, and it is my distinct pleasure to be joined here by Mr. Todd Kennedy. Todd, if I may, can I have you introduce yourself?

Todd Kennedy:

My name is Todd, and I am an independent patient and research advocate serving on numerous advisory boards and multiple myeloma research committees affiliated with the National Cancer Institute and the American Society of Hematology. I strive to be a voice for patients based on my own eight years of lived experience with myeloma, as well as by serving as a support group leader and myeloma coach.

In this podcast, we’re going to discuss three key areas of research presented at the ASH meeting including: earlier immune engagement for better outcomes for patients with [multiple] myeloma in both the relapsed refractory setting as well as in the newly diagnosed setting; secondly, we’ll talk about optimizing patient outcomes and experience with T-cell redirecting therapies for [multiple] myeloma, using proactive strategies to mitigate potential side effects and treatment burden. And finally, we’ll wrap-up with some discussion around encouraging early phase data with additional novel therapeutic approaches for [multiple] myeloma, including difficult-to-treat populations.

Segment 1: Shifting the curve: Earlier immune engagement for better outcomes in multiple myeloma

Todd:

So, let’s start first with a discussion on earlier immune engagement for better outcomes in myeloma patients. We know that the standard of care for newly diagnosed patients has evolved over recent years towards quadruplet combinations for most patients, including an anti CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulator, and a steroid with or without transplant. And despite the effectiveness of this approach, relapse remains inevitable for most, and improving quality of life remains a key goal. Research is now focusing on moving highly effective immune therapies and combinations earlier in the treatment pathway to achieve the deepest and most durable responses as early as second line. And there’s now a growing body of evidence suggesting that earlier and deeper immune engagement may improve long-term outcomes for patients and possibly shift multiple myeloma towards functional cure. And I love that concept.

So, before we talk about the latest research from ASH, Dr. Banerjee, can you provide us with a brief discussion on bispecific T-cell engagers as a treatment option for [multiple] myeloma?

Rahul:

Absolutely, so I think that was the highlight of the ASH 2025 meeting, and we’ll have a lot to talk about. In brief, a bispecific T-cell engager is any drug that teaches your T-cells to work better; it’s an antibody or [a] molecule with two arms. With one arm it grabs a tumor cell, and with one arm it grabs a T-cell—a T-cell is a type of immune cell—and it forces the T-cell to recognize that other cell as a threat. We often call them T-cell redirection or T-cell engagers [and] you could say they’re almost either hijacking the T-cell or blindfolding the T-cell.

You take the T-cells, [and look at] what’s called a CD3 receptor [on a T-cell], which is how a T-cell sees the world. That T-cell was designed to recognize some virus or other threat, and you block that and say “hey, forget what you’re doing, attack this other cell instead.” That [or these] other cell[s], in this case, are myeloma cells. They [bispecific antibodies] can use your own immune system to wipe out the myeloma, and they work very well in that regard. There are two major types of bispecific engager approved in the US in 2026, many of them target a protein called BCMA: B-cell maturation antigen. The other targets a protein called GPRC5D.

A bispecific antibody can be started quickly because there’s no need for T-cell manufacturing. You take the T-cells you already have and put this antibody on top into them to redirect them. For as long as the drug is in your system, the redirection is happening [and] the myeloma is being killed. When you stop it [bispecific antibody treatment], the effect may go away, [so] treatment with bispecifics is generally given indefinitely. Most bispecifics right now are approved in later lines, meaning for patients who have had at least four prior relapses or unplanned escalations of therapy one way or another in the US.

We saw data at ASH showing that you can use bispecific antibodies at earlier lines of treatment for relapsed myeloma and importantly, can combine them with other drugs.

Todd:

I think the listeners will really appreciate what you just described and how these drugs work, and how they’re moving into earlier lines of therapy. At ASH, I was in the room when they presented the MajesTEC-3 trial as a late breaking abstract. ²

There were thousands of people in the room, and I had goosebumps when I saw those curves [progression-free and overall survival data], and admittedly, as a patient, it hit me so strongly there were some tears, it was that powerful. To see those results, to hear the fact that it’s simultaneously published in the New England Journal of Medicine, ³ and then shortly thereafter, to hear that we have a national priority review—that this combination may be available for patients quite soon [FDA approved as of 05 March 2026, for adult patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy].

So, can you share with us why MajesTEC-3 was such an important trial and a highlight of the ASH conference?

Rahul:

Thank you for sharing that. You know, Dr. Mateos got a standing ovation. The press has been covering this and this is a big deal; and to your point, the FDA reached out to the company first and said, “let’s get this to patients quicker” and I’m so happy to hear that government, regulators, sponsors, everyone’s working together to make this happen. There’s a lot of really cool things about this.

[The] MajesTEC-3 trial was a study of two drugs combined together; one is a bispecific T-cell engager called teclistamab. ² Teclistamab targets CD3, which is that same protein I mentioned on T-cells, and BCMA on myeloma and other cells. And so, the idea is that anything that expresses BCMA, most of which is myeloma, is instantly destroyed by the T-cells once they’ve been activated by teclistamab. That arm of the study got teclistamab plus daratumumab. Many of you may be familiar with daratumumab, that is an antibody targeting CD38, another myeloma protein. The reason they combine them [teclistamab plus daratumumab] is there may be some synergy.

Daratumumab may also be able to knock the myeloma cells down deeper and may, based on some other studies,^4–7 make T-cells work better, rejuvenate the T-cells, modify the T-cell environment to make the T-cells less likely to suppress responses, and more likely to activate responses. So, the experimental arm of this study, teclistamab and daratumumab, versus a control arm receiving treatments that we would typically give to patients with relapsed myeloma in early lines, 1 to 3 prior lines of therapy.

The most commonly used [treatment in the] control arm was daratumumab plus pomalidomide plus dex [or dexamethasone]. In brief, the response rates were somewhat similar between them in the beginning, but the durations of response and the what we call progression-free survival, how long a patient were [or was] in remission for, were way better in the teclistamab plus daratumumab arm. ²

Three-year progression-free survival, so that is how many patients three years from starting this trial were alive, [and] doing well in remission, 83% of the patients in this arm getting teclistamab and daratumumab, only 30% of the patients in the dara pom dex arm [control arm of daratumumab and pomalidomide and dexamethasone], that are conventional treatments. ² The hazard ratio there was 0.17, ² which is one of the most profound differences I have ever seen for a randomized study like this. So, to your point, the goosebumps, I felt them too.

Overall survival was also better, so at the three-year mark, 83% of patients in the tec dara arm [teclistamab plus daratumumab] were alive, whether the myeloma was there or not. ² Only 65% of the patients were alive in the control arm [daratumumab and pomalidomide and dexamethasone]. ² MRD [measurable residual disease] negativity, so that is the depth of response—if you can’t see any myeloma there—was also better in this group and the time to quality of life staying the same [based on patient-reported outcomes of time to worsening of symptoms], or at least not getting worse was also much longer in the tec dara arm [teclistamab plus daratumumab].^2,3

To summarize this in plain English, patients who got tec dara [teclistamab plus daratumumab] versus a control regimen like dara pom dex [daratumumab and pomalidomide and dexamethasone], they not only were in remission for longer, they not only felt better for longer, but they live longer. And again, this is without dexamethasone, without IMiDs [immunomodulatory drugs], basically all that I could ever ask of in a myeloma regimen.

Most treatments in myeloma have not been shown to make patients live longer, even transplant has never been shown to do that. This did all three. This is huge.

Todd:

It’s huge. Patients appreciate the superior PFS [progression-free survival] and the overall survival, [and] they really appreciate that component around quality of life because the patient experience truly matters. And to be steroid free at Cycle one Day eight, that matters. So not only is this a highly effective therapy, but it also demonstrates quality of life and a reasonable patient experience, so you’re focused more on living your life than actually treating your disease, which is unbelievable.

Rahul:

Very well stated. To clarify, the original studies of bispecifics were all dosed every 1 to 2 weeks, here the tec [teclistamab] and the dara [daratumumab] both go out to once a month after six cycles, much better for patient quality of life. ² Ironically, it actually might work better because your T-cells are less exhausted during that time. It’s not The Boy Who Cried Wolf every single week, it’s once a month.

Todd:

One thing that really struck me was Dr. Mateos’s concluding comment that this plateauing curve after six months suggests the potential for functional cure, and we’re hearing that concept discussed more and more.

A landmark study and thanks for such a great overview of the results. But there was another great study too, that I think builds on the use of that combination, but in a different population, and that’s the IFM2021-01 study. ⁸ It was a phase 2 trial with tec dara [teclistamab plus daratumumab] in older transplant-ineligible patients. ⁸ Tell us why this study is important.

Rahul:

Absolutely, it’s a French study and exactly as you said, this was a doublet of teclistamab plus daratumumab in transplant-ineligible newly diagnosed myeloma, not relapsed myeloma, MajesTEC-3 was relapsed myeloma.^2,8 But what about in the very beginning when someone’s newly diagnosed? This has been going on in myeloma for years where we said, “oh, well, you should do a doublet and not a single drug and do a triplet and not a doublet.” And then if you talk to us a couple of years ago, we said, “I’ll do a quadruplet and not a triplet” and we keep going more and more and more. Here, this is the reverse, this is teclistamab, daratumumab, barely any dexamethasone. ⁸ This is an antibody-based, steroid-free combination in patients who did not get transplanted. ⁸

There was a time when transplant was the only effective tool we had in myeloma, and now we’re bypassing that entirely. These patients were truly transplant-ineligible, many of them were [in their] late 60s and 70s, some of them are [or were] frail. ⁸ This combination did amazingly; 79% of patients achieved a deep response after only four months [or four cycles] of treatment, 100% of patients eventually received some level of response. ⁸ 100% of the patients who could be checked for MRD, that is the best, most sensitive test we have for myeloma being residually present in the bone marrow, 100% of patients were still in remission and still alive at 10 months. ⁸

Two points I’ll make about this particular study: one, tec dara [teclistamab plus daratumumab], seems to work in newly diagnosed patients quite well. ⁸ My suspicion is that the long-term data will look similar to MajesTEC-3, maybe even slightly better. This is a provocative combination steroid-free, IMiD-free, proteasome inhibitor-free, transplant-free; may work better than our current treatments that include transplant. This may be the future of myeloma for everybody someday. The difference between MajesTEC-3 and this study, interestingly, is that here they mandated the use of IVIg, which is intravenous immunoglobulin, basically an antibody transfusion to help prevent infections. Any BCMA binding bispecific you knock out anything that expresses that protein. The T-cells do not discriminate between the bad cells expressing it, meaning the myeloma, and the good ones, meaning the new plasma cells that normally make good antibodies.

Patients on BCMA bispecifics are not making antibodies, and [are] profoundly at risk of viral infection so we give them an antibody transfusion. Anyone who has donated blood we take those antibodies, that protection, pull them together, sterilize them and give that to the patient; something called IVIg. In MajesTEC-3, we didn’t know to give that to everybody from the get-go, and there were infectious deaths in the first couple of months. ² The physicians realized that and quickly started mandating IVIg from the beginning and that trend went away. ⁸

In this study [IFM2021-01], you start getting antibody transfusions [of] IVIg immediately, and it worked quite well; only about 15% of patients got serious infections that landed them in the hospital, versus over 50% [54%] [in] the MajesTEC-3.^2,8 That’s really remarkable, and I think proof that using immunoglobulin replacement or IVIg really should be the norm. Is it expensive? Yes. But is it essential for safety? Also, yes.

Todd:

That’s incredible, and I love the way you present these two studies. When you put data and [an] expert opinion like yours together, [it] move[s] our understanding of how we use these combinations in different treatment populations. I applaud you for being such a clear and powerful voice regarding the need for IVIg to minimize the infection risk. Voices like yours have really helped the community and patients appreciate the power of proactively going after this risk.

Rahul:

We really have to push for it. People used to be naysayers, but now it’s a no-brainer from a safety perspective to keep our patients safe and out of the hospital.

Todd:

I’ve been on IVIg for six years, and I will tell you, my infection rate went down dramatically once I started it on a regular cadence.

Rahul:

That’s the most powerful story that I need is I can keep you out of the hospital.

Todd:

You talked about how we’re moving towards more of doublet, triplet, quadruplet, but there was another study, the LINKER-MM4 study that moved the opposite direction, it looked at single agent. So, can you give us a brief highlight on the LINKER-MM4 trial. ⁹

Rahul:

LINKER-MM4 looked at linvoseltamab by itself, a single drug for induction of myeloma. ⁹ It worked very well—86% of patients had a response, 100% of patients who could be checked for MRD, which is the deepest depth of response, did achieve MRD negativity. ⁹

One of the most interesting studies from ASH, was the IMMUNOPLANT study of the same drug, linvoseltamab; this was fixed duration [paradigm]. ¹⁰ Every study we’ve talked about so far, the bispecific antibodies are continued until progressive disease or horrible toxicity, etc., and so that could be years, right? IMMUNOPLANT used a fixed duration [paradigm] where patients who are newly diagnosed got [therapy] induction [type decided via patient and physician shared decision making]. ¹⁰ If they were still MRD positive, meaning that if we could still see some disease deep within the bone marrow, they went on to get four cycles of linvoseltamab. ¹⁰ If they were then MRD negative, no trace of myeloma, then you were done. If not, you went on to get two more cycles. ¹⁰ Long story short, all patients [who had MRD testing] did achieve MRD negativity with this strategy. ¹⁰ [It] only took 4 to 6 months. ¹⁰ They used prophylactic tocilizumab, and none of these patients had inflammation-driven side effects, the most common being cytokine release syndrome or CRS fevers, nobody got that. ¹⁰ The reason this matters to me is, we’ve never been in an era where drugs worked this well for myeloma.

So, transplant generally has been the great equalizer, where if you don’t achieve MRD negativity or your response is not quite optimal, we say, let’s do a transplant. It’s a lot of work, it’s a lot of time for patients, a lot of side effects for patients and it works, transplant can actually equalize outcomes, it can push people to MRD negativity who are not MRD negative beforehand, but it’s a lot. It may be that linvoseltamab can do the same thing, it can equalize outcomes. Patients who are not MRD negative, it can push them into MRD negative after only 4 to 6 months of infusions once a week or less often in clinic. No high dose chemotherapy, no losing your hair, no needing vaccines so, I think it’s a really fascinating paradigm. This is only 25 patients’ single arm, but I think there’s more to come. ¹⁰

Todd:

I think that will resonate with any listeners, especially patients. Those principles of fixed duration, that’s very attractive to patients and then MRD-guided decision making is critically important not only in clinical trials like you just described, but also in clinical practice. I’m hoping trials like this will quickly evolve towards MRD- guided decision making in clinical practice because as you mentioned, transplant may go away, but unless you’re doing the MRD test you don’t know so I’m hoping that gets further uptake sooner rather than later in the community.

We talked a lot about the bispecifics, so let’s shift gears on the CAR T therapies. Tell us more about the new data presented.

Rahul:

To reorient the audience here, CAR T therapy or chimeric antigen receptor T-cell therapy [is] the same strategy as bispecifics but different tactics so to speak. So, bispecifics, as I alluded to, it’s off the shelf, we give the drug temporarily [and] for as long as that drug is in the system, and bound to the T-cell, the immune cell is blindfolded from whatever it’s supposed to be doing and attacks the target instead. With CAR T-cell therapy, you take out the T-cells from the patient, you genetically modify them with a virus, you put them [genetically modified CAR T-cells] back into the patient, and it’s a living drug for the next 6 to 9 months, if not longer, those T-cells live inside the patient cleaning up wherever they see the target, including the myeloma. The most important part is that CAR T therapy in our current paradigm does not require maintenance treatment, patients with CAR T therapy get a one-time infusion. They may need some IVIg afterwards [and other medications], but they’re not on maintenance treatment, which is really nice.

You had talked about functional cure with bispecifics earlier, which I love. Functional cure I define as living as long as your age-, gender-matched counterpart would live even if you’re still on treatment or not. CAR T therapy moved the needle even further, why not just not be on treatment and have those excellent long-term outcomes?

Is CAR T therapy curative for patients? Yes. Does it mean that most patients are being cured with CAR T therapy currently? No. We still have a lot of work to do. We already know from ASCO [2025] from last year, that in CARTITUDE-1 the first study in the US of cilta-cel [ciltacabtagene autoleucel], which is one of the most commonly used CAR T therapies, 33% of patients five years out are alive, disease free, in remission, doing well. ¹¹ But those are patients who were heavily pretreated, [a median of] six prior lines of treatment, what about in earlier lines?

The CARTITUDE-4 study was a study of CAR T [cilta-cel] versus standard treatments in earlier lines [1–3 prior lines of therapy] that has shown both PFS, OS [overall survival], and quality of life benefit, meaning patients are in remission for longer, living longer and feeling better.^12,13 What Dr. Costa presented [at ASH 2025], was data for patients [in CARTITUDE-4] with standard risk myeloma, what are the odds of these patients doing well long term? ¹⁴ We know that patients with high risk, the myeloma may come back earlier, or a lot of them have more treatments and more transplants and double maintenance, so they may not do as well just because their T-cells are beaten up, but what about the standard risk patients? [So, in this study] at the two-and-a-half-year mark, 80% of patients were still alive [and] disease free [measured by PFS], ¹⁴ which is amazing. So, I think for those patients, the number at the five-year mark will not be 33%, ¹¹ probably will end up being a lot higher.

The question, and other data presented this with cilta-cel, how do you move that needle? How do we get that number to 100% for our patients? We do know, and several studies have now shown this, that the earlier you give CAR T therapy, the better patients do.^15,16 One, because the myeloma cells are not as inherently resistant as they are over time. And two, the T-cells are healthier, they have not been beaten up the way that they often have been for someone who’s gotten transplant and chemotherapy. It’s a lot for the patient to handle, it’s a lot for their T-cells to handle, so the earlier we can get to CAR T-cells, the better.

So, for me, even at first relapse in the US, I have that discussion about CAR T therapy. For some patients it is not practical to go straight to CAR T at first relapse. They have to be on something else, or now’s not a good time to come to a center and relocate to get CAR T—so real life is messier. I don’t think that everybody needs CAR-T therapy at first relapse, but I think it’s a reasonable proposition and should be the default consideration to at least talk about because of how well it works.

Todd:

That’s really an excellent overview of some very promising research, so thanks for that. I think one thing that struck me when I was listening to Dr. Costa present, he shared that that low rate of progression in patients with standard risk is indicative of a potential cure fraction. ¹⁴ Everybody’s always hesitant about using the cure word, it’s becoming more part of the language, we are moving from incurable to cured in the language, and language matters.

To wrap up this section, I would say, what this means for me as a patient as I hear all this extraordinary data, the earlier access to both bispecific and CAR T therapies, just as you outlined, can give us those deeper and more durable responses in relapse. But also, in earlier lines of therapy, when the immune system is stronger and therefore more responsive. The other amazing part is, we just talked about CAR T and standard risk patients, but we also know that these results [may] apply to those that are more difficult to treat.

We get better responses, longer remissions in earlier utilization that reduces the treatment burden for patients. It improves quality of life. We should not have to choose between length of life and quality of life, it’s not a discrete choice, we can have both, and I think that’s important. This type of result can really impact the psychosocial impact of frequent relapse, and all of us have seen that. You [patients] [typically] go through the cycle of remission, relapse, and each response gets less and less. This research gives me immense hope. Any closing words on this section?

Rahul:

The last thing I will say, for patients [and] physicians listening, the only reason we’re at this juncture in time is because CAR T and bispecifics were only recently approved, and older treatments were approved earlier. In a different world, if CAR T and bispecific antibodies were already the norm for myeloma, there would be no standard treatments of any type because they just don’t work as well. I think it’s important to remember the impetus appears to be what evidence do you have to move these excellent immune-based therapies [bispecifics and CAR T therapies] to earlier lines? I would say that they’re better for patients. And everyone keeps talking about: “well what should I choose, should I choose bispecifics or should I choose CAR T?” but it’s an extremely personal decision, everything’s nuanced because different strategies work for different patients.

Todd:

One last thing on that is you mentioned things are messy, life is tough and each patient is different, it just further reinforces the importance of having a myeloma expert on your team so that they can figure out how to incorporate this latest research into a personalized strategy that works for you.

Segment 2: Proactive strategies to optimize patient outcomes and experiences with T-cell-redirecting therapies

Todd:

As we’re talking about moving from later lines of use to earlier use of T-cell engagers, some of the most important research coming out of ASH was around proactive strategies to optimize patient outcomes and their experience. Can you give us some highlights?

Rahul:

Absolutely. These are ‘pie in the sky’ principles, CAR T for everybody, but in real life things are tougher, we need to figure out how to make treatments safer. How do I reduce the risk of cytokine release syndrome, fevers, infections, etc.? So, bridging therapy is important. Bridging therapy means that after the T-cells are collected, but before the CAR T-cells are infused, they [patients] get a little bit of chemotherapy beforehand called lymphodepletion to get the myeloma in shape and prevent it from causing problems for the patient before the CAR T-cells go in. There was data [presented at ASH], two complementary abstracts—one from the US Multiple Myeloma Immunotherapy Consortium, it’s an investigator led group of doctors putting de-identified, anonymous patient level data together. ¹⁷ And one from the CARTITUDE-4 study that I alluded to earlier. ¹⁸ In brief, bridging therapy makes CAR T therapy safer and probably more effective as well, the more you can debulk the patient’s myeloma before going into CAR T-cell therapy, the more long-lived and more active these T-cells are, because they’re not getting exhausted. And [if you] can reduce the burden of disease they do better, which is wonderful.

What we could see in the CARTITUDE-4 data, they showed that patients who had a response to bridging therapy, so reduced the amount of disease before bridging [therapy] versus after bridging [therapy] going into CAR T therapy, they did better. ¹⁸ Progression-free survival at three years was better, overall survival was better. ¹⁸ More importantly, from a safety perspective, typically about 3 to 5% of patients get some type of delayed toxicity [rare side effects that can occur weeks to months after treatment] something that we can’t predict, that can happen after they go home from the CAR T center. ¹⁹ That includes nerve palsy or people can’t smile properly. About 0.6% of patients can get Parkinsonism where they can’t walk properly, have a tremor and that typically is not reversible. ¹³ About 1 to 2% of patients might get enterocolitis, which is the type of diarrhea that could present after CAR T-cell therapy. ²⁰

We have a sense that patients with very rapid lymphocyte count proliferation, where lymphocyte count goes up, lymphocytes are a kind of white blood cell, including T-cells, when they go up very rapidly after CAR T those patients appear to be [at] a higher risk of these toxicities. If we see the lymphocyte count, which is a marker of T-cell activation, go up too quickly, we actually give some steroids to damp things down to prevent toxicities. But I think more importantly, the other risk factor for this delayed toxicity is tumor burden, that patients who had a lot of disease burden or had a non-response to bridging therapy, had a much higher risk of these delayed toxicities thereafter. ¹⁷ So, probably in real life, it’s a mix of both the T-cells being too active and non-responsive bridging therapy where if there’s a lot of myeloma, that puts patients at risk of the delayed side effects.

So, what do I take away from this? A lot of this is for doctors, and how are we are operationalizing CAR T therapy. But I would say that even for a patient with very little disease going into CAR T therapy, I often do still try to give them some [bridging] therapy both because of efficacy, but also in terms of safety.

Todd:

As a patient, that’s still in my first remission after eight years, which is unbelievable, my next line of therapy could quite possibly be either tec dara combo [teclistamab plus daratumumab] or it could be CAR T. I’m weighing these different[ly] not only [in] efficacy, but side effect profiles. Personally, and then talking to other patients, even though the incidence is low of Parkinsonism, it’s a concern that a lot of patients think about. This research was particularly powerful because it showed the importance of bridging [therapy], and it also showed some strategies by monitoring the ALC [absolute lymphocyte count] that you could actually perhaps give steroids and minimize that risk. For me, that gave me peace of mind about the risk of going with a CAR T strategy, so I thought this was extremely powerful. What was really important, and you alluded to it too, is have a conversation regarding CAR T earlier with an expert in a center that has access [to CAR T therapy, rather] than letting your myeloma be a raging out of control disease. You’ll have better bridging [therapy] if you have an earlier conversation and can get it sooner, and that’s a significant practical takeaway that patients need to hear.

Rahul:

Absolutely agree. We have strategies to get the myeloma down, but a lot of them take a big toll on the patient. Patients often get prolonged cytopenias, meaning low blood counts afterwards, so it often comes with more harm than good if you have to really lean too heavily on bridging [therapy]. If you can bridge smarter, not harder, so to speak, and bridging smarter means using novel therapies proactively and getting the CAR T therapy ideally earlier, where you’re not in a position where you’re out of options to bridge.

Todd:

So, let’s talk about cytopenia. You mentioned the prolonged low levels of blood cells. I’ve got a bunch of stem cells stored in the freezer at my cancer center. How might those be put to use for people on CAR T therapy?

Rahul:

In terms of the real-world significance of this, the US Multiple Myeloma Immunotherapy Consortium [de-identified data] looking at what’s called a stem cell boost for patients with cytopenias, meaning low blood counts after CAR T. ²¹ This is probably one of the most stubborn side effects of CAR T therapy, low blood counts can persist for months. Why? In some patients one, they get a little bit of chemotherapy before CAR T therapy, two if you get CAR T therapy as your sixth or seventh line of treatment the bone marrow itself starts to burn out and it’s harder for it to make new baby blood cells, and three, for myeloma in particular, stem cells go hide in the bone marrow; they’re suppressed by the inflammation.

In this study they looked at patients who got a stem cell boost. ²¹ So many of these patients, as you alluded to, Todd, have had stem cells collected at the very beginning. The idea is if someone’s bone marrow has been through the ringer too many times at this point and it cannot recover on its own, what if you give them back the fresh stem cells from five, six years ago? This is just the stem cells right into the blood. Stem cells are like salmon returning home, they know how to get back and they rejuvenate the bone marrow.

They compared patients with similar levels of low blood counts who got the stem cell boost versus those who didn’t. Their blood counts improved dramatically within a couple of weeks [in those who got a stem cell boost]. Within [a median of] 30 days, 97% of them improved. ²¹ Importantly, and there’s some confounders [factors that may affect the outcome besides treatment] it wasnt a randomized study, but the patients who got the stem cell boost appeared to live longer at 12 months compared to those who didn’t, probably because they weren’t getting as many infections or bleeding complications, etc., ²¹ which is really remarkable.

What does this mean for patients? For doctors, I think this means that we should talk about using stem cell boosts more regularly. How quickly do we do this? Do we wait until six months of low blood counts? Do we do it within one month of low blood counts? Where do you decide that you need some extra help from the other stem cells? If you don’t want to do transplant, should you still collect the stem cells? I generally say yes; stem cell boosts can be life changing for patients.

Todd:

We’ve been hearing more and more data about this topic, and this was helpful. So, let’s pivot here, over the last several years we’ve learned more about managing CRS, but there were a couple [of] points on toci [tocilizumab] and steroids. Maybe we touch on some of the more relevant research presented at ASH

Rahul:

So, for cytokine release syndrome, that’s fevers, so when patients get CAR T therapy or bispecifics and not everybody, but some patients get fevers, for example, because the inflammation, T-cell is getting revved up, the other immune cells get ramped up [and] they get a fever. Fevers can be pretty scary, and sometimes you can get low blood pressure, and have to go to the ICU, etc. That’s historically why patients getting bispecifics have had to be in the hospital and it hasn’t been done in an outpatient setting. Giving tocilizumab prophylactically seems to make a big difference.^22,23

What do I mean by tocilizumab prophylaxis? Tocilizumab is an anti-cytokine drug. It helps to prevent fevers and is typically used to treat cytokine release syndrome. Instead of waiting to get a fever and then rushing to hospital and given tocilizumab, you give it [tocilizumab] ahead of time, like in the first dose [of CAR T or bispecific treatment] whether they get fevers or not. It’s extremely effective.

In this particular Danish study that looked at patients who got tocilizumab ahead of time [around] only 7% of them went on to get any grade fevers, versus [nearly] 70% who didn’t get it, a tenfold reduction. ²³ That is remarkable, that’s really cool to see. Other studies looked at giving lower doses of tocilizumab ahead of time. The cytokine release syndrome was only 24% versus 59%. ²² So, the principle is for bispecifics to be safe, I want it to be given in clinic and not have to go to the hospital, I want to limit how much chaos is going on for patients for their safety’s sake. The best way to do that is to give tocilizumab ahead of time as a preventative strategy, and I should add, this does not have any impact on the bispecific antibodies’ efficacy. ²³

The other pharmacist-led study, which is really cool to see a pharmacist on the podium at ASH leading data on behalf of their patients, they looked at patients getting a bispecific antibody and giving dexamethasone first. ²⁴ Dex [dexamethasone], is easy to give, super cheap, the patient can have it at home, dexamethasone works quite well in this regard. It didn’t knock out every last risk of CRS, some patients who got dex [dexamethasone] ended up getting another dose of dex [dexamethasone] later or tocilizumab later because the fevers persisted. ²⁴ Efficacy was comparable, it doesn’t matter whether you give dexamethasone first, tocilizumab first, whether you give it ahead of time or not, it doesn’t seem to impair efficacy. ²⁴ So, if you’re having a fever after bispecifics, taking dex [dexamethasone] now just reduces the tension everywhere. As the fever goes away, you have time to come into the clinic or an emergency room. For CRS, dexamethasone works quite well. ²⁴

Finally, we talked about it in the earlier section, any BCMA bispecific can certainly cause infections. IVIg seems to work where you give it prophylactically,^25,26 don’t wait for the infection, don’t wait for the antibody levels to fall, just give it during cycle one or cycle two, start it once a month, and it works extremely well to lower the risk of infections.^25,26

So, how will bispecifics look in the future? In my own practice, all of my patients get tocilizumab prophylactically, so they get the medication ahead of time to prevent CRS. Almost all my patients get step-up dosing in the outpatient setting. They don’t have to go to the hospital as they get a fever, tocilizumab lowers that risk. If they do get a fever, they take dexamethasone first at home and then come in to see us and that often works for a lot of patients. And for all my patients on bispecifics, they get IVIg after or within the first month, if not already on it. I don’t wait for them to get a high-grade infection. [I] start it right now. What are your takeaways here? In terms of making these side effects more manageable for patients and for doctors?

Todd:

I think the most important part is the proactive aspect; it’s a preventative use of some of these strategies. I know that they could potentially be expensive to use IVIg prophylactically independent of an IgG level, and same with toci [tocilizumab], but an inpatient admission is also extraordinarily expensive and has an impact on patients. Getting ahead makes a whole lot of sense, and we learned a lot of important takeaways on how to use these drugs safely. It’s not a choice between efficacy and quality of life, you can have both if you have expert management on not only the choice of drugs, but also how you administer them safely and think about preventative strategies. What you described, I hope, becomes standard of care not only in the academic setting but also in the community setting.

Rahul:

But also around the world. We have work to do, not just to spread the awareness, but to actually make it sustainable. We need to make this cost effective, to show that strategies make sense for the patient and keep them out of the hospital, and keeping out of the hospital makes them cost effective.

Segment 3: Round-up of novel T-cell-directed regimens in development for multiple myeloma

Todd:

Well, should we shift gears and go to our last section in the podcast? There was some great, breaking news on novel therapies, so let’s get into that. Early phase trials of novel bispecifics, including new combination approaches, new cell targets, promising safety and efficacy outcomes in heavily pretreated patients. RedirecTT-1, we had a phase 1b three year follow up, as well as a phase 2 update.^27,28 Tell us about the RedirecTT trial.

Rahul:

Yeah, there’s so many novel therapies that are not yet approved. Let’s talk about bispecifics first and then talk about novel CAR Ts next. So, for novel bispecifics, RedirecTT-1 is combining two different bispecific antibodies.

One is teclistamab, you’ve already heard before, a bispecific antibody targeting a protein called BCMA on all cells, primarily myeloma cells but also normal plasma cells and other immune cells, and then talquetamab. Talquetamab is a bispecific antibody targeting GPRC5D that is found on myeloma cells, not on other immune cells, but also found on skin, nail and tongue cells, so it can cause toxicities there unfortunately. We’re working on managing them.

This combination [of] teclistamab plus talquetamab works extremely well for patients. ²⁷ In particular, where you’ll hear a lot more about this, is extramedullary disease [or EMD]. ²⁸ EMD, is when myeloma is not contained within the bone marrow. Historically, we viewed anything where the myeloma is not physically within the bone marrow to be EMD and that has included patients with both a paraskeletal plasmacytoma as well as visceral EMD. Paraskeletal plasmacytoma is where the myeloma is causing the bone to bulge, it’s pushing out of the bone marrow into the hard bone, versus true EMD, or visceral EMD is growing in a lymph node in the layer, outside the lung, in the liver, somewhere where there’s truly no bones in sight. If it’s true EMD, sounds a bit scarier and it is, those patients historically conventional treatments and even CAR T therapy have not done that well. A lot of my patients with true EMD who go to CAR T therapy achieve MRD negativity but then they have a relapse thereafter within a couple of months or years—it’s tricky.

This combination with two drugs together may be a better bet; the phase two [study] patients who had any true extramedullary disease, 79% of them did achieve a response, and three quarters of them were alive one year out. ²⁸ Historically for these patients, overall survival has been much worse than that, so this is really encouraging. This combination is not yet FDA approved.

Todd:

It’s amazing. You’re right, because these patients need a treatment option, and this seems to actually be a very promising one, so it was important data presented at ASH. So, you’ve talked about the different bispecific agents and what they target on the myeloma cell.

There was another study, CAMMA 3, talking about a different target. Can you touch on CAMMA 3 and what we learned about cevostamab? ²⁹

Rahul:

So, moving to bispecific antibodies that are not yet FDA approved in any setting. So not just the combination not being FDA approved here, the drug is themselves not FDA approved.

Two I’ll briefly talk about. One, was called the CAMMA 3, cevostamab. ²⁹ So, cevostamab is targeting yet another protein called FcRH5. All of our commercially available CAR T therapies target BCMA, teclistamab, elranatamab, linvoseltamab, target BCMA. We’ve put a lot of our eggs into the BCMA basket in myeloma, and now we have one egg in a different basket called GPRC5D, it is nice to be diversifying our portfolio because in some patients the first drug doesn’t work, the second drug doesn’t work, you need to add a third target. Here cevostamab, which is targeting FcRH5, seems to work quite well. ²⁹ It is dosed subcutaneously. [For] cevostamab monotherapy, 39% of patients achieved the response, so it’s not a huge number but for bispecifics the bar is set higher. ²⁹

I will say that separately from this, they have presented data with cevostamab plus pomalidamide [cevostamab plus pomalidamide plus dexamethasone] for example, seemed to work quite better.^30,31 I think in the future cevostamab is coming, and likely will be dosed in combination with other drugs.

So that’s one investigational product, the other investigational T-cell redirector that’s not a CAR T is a trispecific. Why target just one protein on a myeloma cell if you can target two proteins? JNJ-5322, which is now called ramantamig, is a trispecific antibody.^32,33 So, it does target CD3 on the T-cell, but it can invoke one or both targets on a myeloma cell simultaneously; BCMA, and GPRC5D. So, it’s like getting both teclistamab and talquetamab at the same time; from the data we’ve seen single arm, it seems to work quite well. ³³ Importantly, this drug is dosed only once a month, after the second dose which is really nice, and it doesn’t seem to be more toxic than either teclistamab or talquetamab by itself, so the data are quite impressive. ³³ Randomized studies are coming (NCT07258511). ³⁴ In the future instead of a bispecific cocktail, maybe you could do a trispecific.

Early phase trials, these drugs are not ready for approval, but the future is bright.

Todd:

It really is. And then there are some really amazing CAR T therapies that are emerging. Can you tell us more about anito-cel ³⁵ [anitocabtagene autoleucel] and the AstraZeneca dual targeting ³⁶ and inMMyCAR? ³⁷

Rahul:

So, anito-cel [anitocabtagene autoleucel] is in phase three studies right now (NCT06413498), ³⁸ also targets BCMA, it is a synthetically designed CAR, designed to be on and off, not bind [to cells] for too long, [and] designed to not trigger as many host abilities to reject it. It seems to work quite well. So, in the phase one study we know so far 96% of patients achieved a response. ³⁵ Between the various studies so far,^35,39 none have developed delayed toxicities like colitis or Parkinsonism, nerve palsy. Not thousands of patients, not even 200 patients, but that does seem very promising because we need more options, and we need to figure out how to not have patients develop these delayed toxicities. Anito-cel [anitocabtagene autoleucel] may be part of that answer.

Separately there were two trials both in the relapse setting and the newly diagnosed setting of AZD0120, formerly known as GC012F, that is a dual targeting CAR T-cell therapy that targets both BCMA and yet another protein called CD19 that is typically found on B-cells. ³⁶ This particular drug targets both at the same time and can be manufactured very quickly within a couple of days as opposed to a couple of weeks. Single arm data seem to work quite well, but again, we need more follow up and a randomized study. ³⁶

Finally, the KLN-1010 study. ³⁷ This is an in vivo CAR. Everything else I’ve talked about, we take the T-cells out from the patient, we [genetically] modify them in a carefully controlled lab environment and then put them back into the patient again. With in vivo CARs, there is no T-cell collection at all, you inject a virus into the patient, the virus goes into the T-cells in the patient, turns the T-cells into CAR T-cells in the patient. There is no ex vivo manufacturing. The cool thing [is] it is off the shelf like bispecifics, but it is CAR T-cell therapy [so] you can get that one-time injection of a virus, may be enough to trigger CAR T-cells to last for a while, etc. There is a lot of unknowns, [only] four patients here. ³⁷ You don’t know, [if] there is some heterogeneity [or differences] within the patients in terms of how many of the cells became CAR T-cells. With traditional manufacturing, you know how many CAR T-cells went into the patient because you know that there is a dose-response relationship. If there aren’t enough CAR T-cells, they won’t work. Here you can’t control for that because the virus is infecting cells at its own rate. So, I think we need more data on how to do this. But at least with those four patients, all of them, achieve that MRD negativity, ³⁷ which is pretty cool.

I’ll pivot it back to you. Anything that stands out to you or anything that you think is exciting?

Todd:

It’s all extremely exciting. I agree it’s early, but not only was the efficacy very promising, but also the tolerability I thought was extraordinary. In all of these trials you mentioned, the CRS rates were reasonable, the ICANs rates were reasonable. So, it’s very, very exciting times across the bispecific space, the trispecific space, as well as these emerging CAR T therapies. We have great options now, but it just is getting brighter as we move forward.

Segment 4: Wrap up

Todd:

That takes us to wrapping it up. You covered some amazing stuff, my hope meter is off the charts. When we think about not only how well these drugs work in later lines of therapy, we’ve reviewed evidence from ASH about earlier use of bispecifics and CAR T and some really powerful insights that are practical, that go right from the podium into the practice. Information on, ALC and the power of bridging [therapy], and about the ways to mitigate infection risk. And when we think about the future, it’s just science-fiction at a whole other level, that’s actually coming to reality. I think it’s an extraordinary time. I’ve heard many people say it’s a great time to have a pretty crummy disease. And it is a great time and getting better for sure.

Rahul:

You’ve been braver than me to use the cure word in myeloma. The International Myeloma Society is doing a summit in February 2026 specifically about what would a cure mean in myeloma, ⁴⁰ not just semantically, but specifically, what end point will be used to say this patient can be considered cured of myeloma. That concept did not exist until the last handful of years because of CAR T and bispecific antibodies. So, what I would tell people, CAR T therapies and bispecifics [are] tiptoeing from later lines to earlier lines [for multiple myeloma]. There are people who are nervous “oh, well, who needs these new therapies. The old therapies work okay.” They work okay, but why do okay if you can do better? CAR T therapies and bispecifics truly will supplant all the other therapies in myeloma someday.

Todd:

I love that, for patients working okay is not okay, the job is not done, and I think that’s an important point.

Rahul:

That’s exactly right. We have work to do

Todd:

The words matter. When I was diagnosed eight years ago, you go on Google and it says it’s an incurable terminal disease, and I think we’ve got to stop using that word incurable. It’s curable. It’s not a matter of if, it’s a matter of when. Through the ongoing investment in these trials, the ongoing collaboration amongst experts like yourself, not only in the randomized trials but also in the real world, patients enrolling in these trials earlier rather than later, it moves that when up sooner, and we will feel all comfortable using the cure word in the not-too-distant future. I think the evidence is supportive of that, so let’s not be scared about using the word–it’s happening, it’s just a matter of when.

Rahul:

Very well stated. Well, thank you again for Therapeutic Advances in Hematology for this opportunity and thank you all for listening.

Todd:

Thank you all.