iwCAR-T 2025 | Practical considerations for T-cell engagers in multiple myeloma: recent data, sequencing, & more

Yi Lin:
Hi, I’m Yi Lin from Mayo Clinic and we are here at iwCAR-T 2025 and we’ve had a few very exciting sessions in multiple myeloma where we have a lot of agents coming both into clinic and clinical trials for CAR-T. So I have a number of colleagues with me here today where we will talk about some of the current pressing questions and hot topics in myeloma.

Rakesh Popat:
Thank you – I’m Rakish Popat, and I’m from University College London in the UK.

Doris Hansen:
Hi, I’m Doris Hanson. I’m from Moffitt Cancer Center in Tampa.

Sham Mailankody:
Hi, I’m Sham Mailankody from MSKCC in New York.

Yi Lin:
All right, so, you know, we had dedicated sessions talking about both real-world data and clinical trials for bispecific antibodies. Currently, we have two regulatory approved BCMA targeting bispecifics and one targeting GPRC5D. How are you guys thinking about using these bispecifics in your practice? Maybe I’ll start with you, Rakesh.

Rakesh Popat:
Yeah, great question. So currently, we’re using both teclistamab and elranatamab in our routine practice. We have access to both, at fourth line and triple-class exposed patients. And the way we’re actually splitting it up is that we have elranatamab in our outpatient setting for step-up dosing because it’s a little bit more amenable to do that with flat dosing. It means that our nurses can draw up the elranatamab very easily and deliver it to our patients. And teclistamab is given for those who need inpatient step-up dosing. And that goes through our pharmacy because it’s weight-based dosing. So that’s how we’re kind of using both of them. But that’s really just out of practicalities more than anything else.

Yi Lin:
And how are you thinking about GPRC5D versus BCMA?

Rakesh Popat:
Yeah, so that’s a tough question. I mean, both are very effective treatments. They have slightly different toxicity profiles, BCMA being more infectious and GPRC5D having the oral and skin toxicities. And we kind of take it on a case-by-case basis. So if we’re concerned about patients having a high infection risk, we may go for talquetamab first. But in the most part, we’re tending to go for the BCMA as initial therapy and then following up after a break to allow T-cell recovery with the GPRC5D. But that’s not necessarily the right thing to do. My colleagues may do differently.

Doris Hansen:
Yes. So we also use teclistamab and elranatamab in the beyond four lines of therapy. Generally, we do actually both of them in the outpatient setting, and we do prophylactic IVIG for everyone monthly, and we actually do prophylactic tocilizumab as well as we do the step-up dosing. We do try to antigen switch to a GPRC5D once these BCMA bispecifics don’t work as well. But generally, we’re using a lot of talquetamab in the bridging space prior to CAR T-cell therapies, just because we’re limiting the duration of talquetamab to about a month or so. And that has allowed us to limit some of those oral skin toxicities, weight loss, etc. and generally a lot of those appear at least 61% or so we’ve seen have resolved with a shorted or limited duration of talquetamab use.

Sham Mailankody:
I think similar thoughts and ideas. We have all three agents as well. In tec and elra, we use them both in or outpatient, similar to Moffitt, it looks like. We are also just recently started doing prophylactic toci, especially for our outpatients to try and avoid them from having to come back for admissions. So we are doing that with reasonably good results so far. It’s early days for us of using prophylactic toci. In terms of which drug or target to choose, BCMA, GPRC5D, I think there are no randomized comparisons, as we all know. But the efficacy data looks quite similar. They have upwards of 65%, 70% response rate, in the clinical trials in the real world. The side effect profiles, I think, are somewhat distinct. The CRS and ICANS, which are both low-grade and very manageable with all three products. Actually, once you’ve gotten familiar with the drugs, quite easy to manage.
Then there are two main groups of side effects we worry about with these drugs. With the BCMA, it’s infections, and that’s where IVIG, antibiotics or appropriate antibiotics, other viral prophylaxis, et cetera, really plays an important critical role. On the flip side with GPRC5D, the infection risk does seem to be lower, both in the trials and now in the real-world data. But it does have these unique toxicities given GPRC5D expression in keratinized tissue, skin, hair, nails. And so we do see patients with dysgeusia, weight loss, taste changes, appetite changes, nail changes, skin changes, which can be quite challenging to manage, especially with ongoing treatments. So I think more than the efficacy, it’s these safety toxicity profiles that might drive which agent to choose. Similar again to what Dr Hansen said, we do use talquetamab for bridging where necessary as a bridge to CAR-T cells. But otherwise, I think the default choice is largely BCMA first and then GPRC5D, one driven by the longer experience with BCMA and two driven by those distinct safety profiles.

Yi Lin:
Very interesting. Yeah. And so we may learn a little bit more with a longer follow-up with GPRC5D and perhaps how to manage that. Something that was discussed and it seems to be very uniform across the panelists was really trying to understand how to use these antibodies, particularly in a setting when patients achieve response, what’s the right dosing frequency or maybe even treatment-free period to reduce some of these toxicities. What we also heard is new data from cevostamab combinations and including multi-targeting bispecifics. So maybe we can start with you, Sham. What are you most excited about? What do you think are the opportunities with these new trial results?

Sham Mailankody:
Yeah, just thinking about the targets, I think the next obvious exciting thing is to target multiple things at the same time. That obviously comes with a lot of promise, but also significant amounts of challenges with side effects and also just not understanding fully the biology. Do we really need to target both BCMA and GPRC5D at the same time? Do we need to do it for all patients? Are there a select group of patients with high-risk features, extramedullary disease that might most benefit from this dual antigen targeting? So I do think that that’s an exciting area for the next few years. But then we’ve already talked about all these different treatments. Even if you wanted to target two antigens, there’s about 10 different ways you could do it. So how are we going to figure out what is the ideal way to target two antigens for the patients who most need it, I think will be the major challenge we will face in the coming years. I think we have some preliminary data from the RedirecTT study where Dr Cohen ran this clinical trial in Israel where patients got higher with relapsed myeloma, got teclistamab and talquetamab concurrently with very promising results in terms of responses, in terms of duration of responses, including in patients with high-risk features like extramedullary myeloma. The median duration of response was not reached on that study. Three-quarters of patients were progression-free at 18 months after response. So that looks quite promising. But what was also somewhat concerning was the side effect profiles. The infection risk appeared to be much, much higher than BCMA alone, with high rates of grade three, four, and five infections on that study, suggesting again that there’s probably a balance we need to strike in terms of targeting multi-antigens and try to optimize the efficacy, minimize the toxicity, and probably select patients that would most benefit from this approach.

Doris Hansen:
Yeah, so I agree. I think RedirecTT’s very exciting, combining teclistamab and talquetamab, particularly for the patients with visceral extramedullary disease with response rates of 60%, which is really quite impressive. But I also think we have other studies that are exciting, right? We talked about MajesTEC-4 and MajesTEC-5. We’re incorporating teclistamab in the induction setting, but also as maintenance in combination with lenalidomide. And we’re seeing like MRD negativity, about 100% responses that are outstanding. But again, infections are concerning, right? As we combine these with other agents like CD38 monoclonal antibodies. So I think, you know, being able to better manage supportive care, whether it be IVIG, antibiotic, prophylactic antibiotics, etc., is something that we’ll have to work on. The other exciting target, I think, is cevostamab, just because it’s a different target. We’ve talked a lot about BCMA. We’ve talked about GPRC5D. We’ve talked about combining with what’s available. But cevostamab is very unique. We have FcRH5 response rates in the prior BCMA exposed patients, which was over 50% of them on the trials, like 40%. And then the BCMA-naive, even better. So I think it’s exciting that we have more agents. And then we’re also looking into the tri-specific space. I think the future hasn’t looked so bright in our patients. I’m very excited for what’s to come.

Rakesh Popat:
And so what all this really highlights is the lack of diagnostics that we have. Because I completely agree with what my colleagues have said. We fall into the track of using dual-targeted therapies for a patient who may not need that and that end up being double refractory or potentially using a drug targeting FcRH5 when expression may not be so intense compared to BCMA or GPRC5D. And so really that’s where our diagnostics, there’s such a desperate need for that to catch up so that we can have a rapid test to understand the antigen expression. But also we’ve been hearing a bit about mutations that can occur on the binding site. So, for example, we heard that alnuctamab, which is a BCMA bispecific that’s no longer in development, was able to target receptors that had mutated to teclistamab and elranatamab. And again, you know, we need to understand a little bit more about that. So I’m really, really hoping that that field is going to move forward to a clinic near us.

Yi Lin:
Yeah, and certainly, I’m going to shift gears a little bit and moving to CAR-T, we have ide-cel and cilta-cel available, we certainly talked about it, and Doris, you really shared real-world comparison analysis for that, and we had a lot of discussion about sequencing of the bispecifics and CAR-T today in the way that it’s approved. So maybe, Doris, can you share how you’re thinking about it today in the clinic in terms of when are you considering ide-cel when are you considering cilta-cel, and the sequencing between the CAR-T and bispecific?

Doris Hansen:
Yeah, this is a great question. So in our analysis, essentially, just in a one-sentence summary, we showed, yes, cilta-cel does appear to work better from an efficacy perspective in terms of depth of response, in terms of progression-free/overall survival, but it does appear to come with a higher rate of certain toxicities, right? Whether that be the non-ICANS, the infections, and the grade 3 or higher CRS. With that being said, you know, cilta-cel is currently available as early as second line of therapy, particularly for patients who have, as we’ve talked about, extramedullary disease or very high risk, whether it be not just by cytogenetics, by functionally high risk, patients who are relapsing within 18 months of induction or prior transplant, for example, generally we are choosing to go with cilta-cel in that patient cohort. A lot of the time, cilta-cel is going to be your drug of choice because patients want to see efficacy and long-term results. But we are using ide-cel for generally kind of older, frailer patients with comorbidities. And certainly, you know, it’s a choice and decision that we make together with our patients while discussing safety and efficacy profile with them as well. In terms of the sequencing data, you know, we’ve had the small CARTITUDE-3 cohort C data with, you know, 20 patients receiving non-cellular BCMA. And then we have some real-world data with prior BCMA exposure, again, a small cohort of 50 patients. But all of them seem to suggest that prior BCMA exposure leads to inferior outcomes with CAR-T and also recent IMWG guidelines, analyzed and looked at all of the available data. And generally speaking, you know, with all else being equal, including access to CAR T-cell therapy, generally our preference will be to go with a CAR-T cell therapy first. That is, you know, BCMA CAR-T, that’s FDA approved, followed by a bispecific after.

Yi Lin:
Yeah, and how about Sham?

Sham Mailankody:
Yeah, I mean, the sequencing is the challenge that we’re all facing in clinic, I guess. But it’s driven largely by what’s available immediately for patients who need very urgent treatments or bispecifics have an obvious advantage or readily available. CAR-T cells, you have to wait for collection, you have to wait for manufacturing, etc. But for patients who can wait for it, who have access to both, I think most of us would agree, consistent with the IMS guidelines, that CAR-T probably has an advantage, both in terms of efficacy, in terms of the treatment-free interval that it can provide, in terms of the durability of responses, et cetera. So the default choice would be a CAR-T, but it’s more complicated than in the clinic where it’s not readily available and waiting times, et cetera. In terms of antigens, BCMA, GPRC5D, again, BCMA came to the scene first. Therefore, most of us are familiar and use that first and also has more FDA-approved options, both CAR-T and bispecific. For GPRC5D, we have talquetamab approved, but the CAR T-cells are not yet approved. At this conference, our colleague, Dr Bal, presented data from arlo-cel, the GPRC5D CAR T-cell looks quite promising. High responses, including in patients with prior BCMA exposure. Quite interestingly, the duration of response in PFS curves overlapped whether the patients had prior BCMA or not, which was encouraging. And if that holds with larger studies, that would be quite promising for this approach of sequential use of BCMA and GPRC5D treatments. And then with talquetamab, I think we already covered the side effect profile that makes it a little more challenging to use long term. So more and more, it’s being used as bridging or limited duration treatments after CAR T-cells. But I think we’ll continue to discuss what is the optimal sequencing for many meetings to come.

Yi Lin:
Well, and that’s a great segue. You know, we heard some trial results from next generation, other CAR T-cells, so arlo-cel, also anito-cel, very differently engineered, ddBCMA CAR-T, and Rakesh, I know, you know, the access to CAR-T hasn’t been quite the same in UK as US, but would we have too many BCMA CAR-T? Where do you see the opportunity for another BCMA CAR T like anito-cel to come into the treatment landscape?

Rakesh Popat:
So I’m super excited by the data that we’ve been seeing with anito-cel. And I think the main reason is that firstly, we’re seeing a strong efficacy signal from the Phase I study. But the second aspect is that whilst we don’t have huge access to CAR-T, unfortunately, many patients who are being offered Carvykti are a little bit concerned about the neurotoxicity. And what we do know in terms of the data is that the Parkinsonian type of neurotoxicity seems to have been reduced when you move from the later lines to the earlier lines. But nevertheless, it’s still present in the cranial nerve palsies, and there’s some other immune-related toxicities which are there. And the anito-cel data suggests that at the moment, there doesn’t seem to be any non-ICANs neurotoxicity. And so I think in that setting, it will be very reassuring, both for clinicians and patients, to be able to offer a product which may have a slightly improved safety profile. So I certainly do think that there’s room for these CAR-Ts to come through.

Yi Lin:
So one thought from each of you in terms of what data would you be most excited to see for iwCAR T 2026? You know, a year from now, what do you anticipate might be some information that might directly impact your practice or how you think about the use of these therapies for our patients? And I can start with you and go down the line. Would that be okay?

Rakesh Popat:
So we’re eagerly awaiting the first analysis of the tri-specific from J&J, which is the dual BCMA and GPRC5D targeting trispecific antibody that Sham mentioned. And I think we can discuss that next year once those results are out.

Doris Hansen:
From my standpoint, as a CAR-T provider, I’m actually very excited about the anito-cel data that you just discussed. But the follow-up is, you know, it’s 9.5 months. It looks very promising safety and efficacy-wise. I would like to see a little bit longer follow-up to really follow-up whether, you know, will the responses, will the PFS hold, and will we see any of the non-ICANS neurotoxicities and how that data will look long-term. So I think that’s one of the studies I’m very excited about. And then I think at ASCO, we might get some insight into the five-year follow-up from CARTITUDE-1 and cilta-cel. So I think that will give us a lot to think about because if we see patients at five years doing very well and getting some of the additional anito-cel data in later line. I think that data will be very intriguing and exciting to learn about.

Sham Mailankody:
The five-year landmark, I think, is exciting because there’s also a lot of talk about defining functional cures for myeloma. And one of the proposed definitions has been sustained five years of remission without needing any additional treatments, which is exactly where those CARTITUDE-1 patients are. If they’re out five-plus years without their disease and in ongoing remission without any ongoing treatment, they would meet this proposed definition for functional cure, which is an exciting landmark for that study and for our field, I think, in this late-line setting to talk about functional cure. In terms of other things, maybe 2026 is too soon, but there are some major randomized studies that have completed accrual. CARTITUDE-5 has completed accrual. That’s front-line use of cilta-cel. We don’t know when the data will be mature for results, but hopefully we’ll hear some initial results from that. Some of the bispecific antibody combination studies in the earlier line setting have also completed accrual. Again, depends on how long this needs to be followed for initial readouts. But I think those will set the stage for the coming years in terms of all of the questions we just discussed, sequencing earlier use of these treatments, which patients to select and when to do this and how to do it. So I think we’ll be left with many more topics. No doubt. No doubt.

Doris Hansen:
CARTITUDE-6, transplant versus CAR-T in the front line. I think that’s very exciting, but we need a few years.
Yeah, that’ll take a bit of time.

Yi Lin:
Yeah, so never a boring day for the myeloma immunotherapy doctors, and you have some teasers for iwCAR-T 2026. Thank you, everyone. Thank you.

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