Bispecifics-Based Combination Therapy in Multiple Myeloma

At the American Society of Clinical Oncology (ASCO) annual meeting, promising results were reported from two trials that evaluated a combination of two bispecific antibodies in patients with relapsed or refractory multiple myeloma.

The phase Ib RedirecTT-1 study evaluated a combination of teclistamab (Tecvayli), which targets BCMA (B-cell maturation antigen), and talquetamab, a GPRC5D-directed bispecific antibody, while the phase II TRIMM-2 study looked at a combination of talquetamab and subcutaneous daratumumab (Darzalex).

MedPage Today brought together three expert leaders in the field: Moderator Sarah A. Holstein, MD, PhD, from the University of Nebraska Medical Center in Omaha, is joined by Brea C. Lipe, MD, from the University of Rochester Medical Center in New York, and Monique Hartley-Brown, MD, MMSc, from the Dana-Farber Cancer Institute in Boston, for a virtual roundtable discussion. This final of four exclusive episodes focuses on the combination of novel bispecific therapies and where they may fit into the treatment paradigm of relapsed/refractory multiple myeloma.

Following is a transcript of their remarks:

Holstein: So we’ve been talking about single-agent bispecific antibodies, and it feels like we’ve just embarked on that as a field. Many of us just have some experience with one or two of these bispecific antibodies, and now we are quickly moving into the realm of combining bispecific antibodies with other agents, either with other bispecific antibodies or with things such as anti-CD38 monoclonal antibodies.

So on our last topic today, I wanted to discuss the RedirecTT-1 study, which is combining teclistamab and talquetamab as well as the TRIMM-2 study, which is combining talquetamab with daratumumab. So, Dr. Hartley-Brown, would you run us through the RedirecTT-1 study, which again is really novel in terms of taking a BCMA bispecific and combining it with a GPRC5D bispecific.

Hartley-Brown: Yes, I’m happy to do so. So, I just want to walk you through real quickly. As we just talked about, teclistamab is the first FDA-approved BCMA-directed bispecific antibody for triple-class exposed relapsed disease in multiple myeloma. And talquetamab is also bispecific antibody, but it targets a different antigen, which is a GPRC5D protein on the myeloma cells. And we’ve seen some early data about how well it works in terms of efficacy for our relapse myeloma population. And so the thought is what would happen in terms of the outcome by targeting both the BCMA and the GPRC5D antigens on the myeloma cell with these two novel agents? So this is a first-of-its-kind, phase Ib study in our patients who have been heavily pretreated, as we said before, refractory/intolerant to last line of therapy, exposed to proteasome inhibitor … and anti-CD38, and have measurable disease.

And we’re trying to see the response rates, and also the primary objective being identifying a recommended phase II regimen for that combination. Not surprising, in terms of some of the information I’m going to tell you, we have some updates in terms of the number of patients. About 63 patients received both agents with [teclistamab] and [talquetamab]. Again, median prior lines of therapy was around five. So highly pretreated patients, highly refractory patients, about a third of the patients had high-risk cytogenetics. Almost 80% were triple-class refractory, and more than 60% were penta-drug exposed with about 43% having extramedullary disease.

So we look at a median duration of follow-up of about 14 months with, again most common AEs (adverse events) were CRS [cytokine release syndrome]. Here we’re seeing CRS rates at about 80%, majority being grade I, II. We do have some grade III, no grade IV reported. And again, cytopenias. Neutropenia, as we alluded to before, very much leads the way with about 76% of patients having neutropenia. And about 75% were grade III/IV. And anemia being the next most common hematologic malignancy.

We did have some infectious complications with seeing a herpetic stomatitis. We did see some transaminitis and we saw ICANs [immune effector cell-associated neurotoxicity syndrome] at different dose levels, each of which were dose-limiting toxicities in this cohort. And we didn’t see any DLTs [dose-limiting toxicities] at the final RP2 [recommended phase II] dosing.

But the overall response rates, I do want to mention were pretty impressive. We saw overall response rates, of those 62 that were treated, 52 of them responded. So that’s about 84%, and 73% of those who had extramedullary disease responded. And we got some very good CR [complete response] rates in the 30% to 34% range. And when you look at the median duration of response, it has not been reached.

And so it looks like this combination is a very plausible combination to use, a very effective combination to use with a manageable safety profile. Everything that we’re seeing as far as complications thus far are things we’ve seen with the individual agents by themselves. So nothing surprising there. And I think we can talk a little bit more about what that means and how that’s going to translate into the future. But keep in mind, this is a phase Ib study — very early data.

Holstein: Thank you. Yeah, an overall response rate — even in a phase Ib study of a non-cellular therapy — of 96% is certainly eyebrow-raising and very encouraging, but clearly we’re going to need larger numbers. Dr. Lipe, what did you think of the extramedullary disease signal?

Lipe: I mean, I think this is exciting and I think this is sort of when all these things started coming out in myeloma — we always know that a drug is great — but what happens when you just add more? And so we’re starting to see some of that data, and it’s particularly relevant for this extramedullary disease patient population because this is a population of patients that’s hard to treat. They don’t get the same durability or rates of response that we’ve seen amongst the new trials that are looking at CAR-T [chimeric antigen receptor T-cell] and these other directed therapies. And so we all know that this is a really large unmet need. And so it’s really encouraging to have some data finally where we’re seeing these response rates this high in the extramedullary disease patient population. And we’ll have to see how durable it is. I mean, response is one thing, durability is another. But I think it’s really exciting and the science of this is just really incredibly cool.

Holstein: Absolutely agree. And in terms of — as Dr. Hartley-Brown mentioned — in terms of adverse events, there’s the infection risk, which I think we’re kind of expecting, but doesn’t look too terribly different than the BCMA bispecifics alone. So that was somewhat reassuring. And obviously we have the GPRC5D specific adverse events, such as the dysgeusia, the nail toxicity, the skin toxicity. I think I’m personally worried a little bit less about the skin and nail, but more about the dysgeusia and — especially if therapies are going to be continued for a long period of time — how that impacts quality of life. Dr. Hartley-Brown, do you have any thoughts about how we’re going to be optimally managing that?

Hartley-Brown: That’s a very good question. I’m not exactly sure how to manage dysgeusia. I mean, I think I have had lots of experience with managing other toxicities, but this is a new one. And we’re not very good in oncology in managing difficulty with eating and appetite, and now we have this additional layer on top.

So yeah, I think again, how this pans out in the future in regards to which patients are likely to be more affected and which patients may not be able to tolerate certain toxicities is going to play a role in which medications we choose for our patients and we’ll be a little bit more thoughtful about that in terms of our patient outcomes. So yeah, I don’t have a good answer for how to manage the dysgeusia. Not yet.

Holstein: I think we’re all going to be learning, and probably our head and neck colleagues will have a lot to teach us.

And then Dr. Lipe, if you could, I just wanted to have you touch on the TRIMM-2 study, which I thought was interesting because it’s one of the first times that we’re taking a GPRC5D bispecific antibody and combining it with daratumumab, particularly in patients who’d already been exposed to an anti-CD38.

Lipe: Yeah, so the idea behind this trial was if we combine the immunomodulatory effects of talquetamab and daratumumab, can we see some synergy? And so that’s what this trial sought to do. And so these patients were treated with both drugs. The patients had to have had three prior lines of therapy. They couldn’t have had any anti-CD38 therapy within 90 days, but most patients had had prior anti-CD38 therapy — 88% of patients had — and 77% of patients were already refractory to anti-CD38 therapy.

So in this trial, the patients had had a median of five lines of therapy. So again, a pretty heavily pretreated patient population. A lot of these patients had also already had anti-BCMA therapy. So 54% had had anti-BCMA directed therapy, 38% were refractory. And this included some anti-BCMA CAR-T patients who’d progressed after CAR-T.

So this trial enrolled 65 patients. There is currently a median of 11 and a half months of follow-up. And so the overall response rates that they saw was about 78%, 79%, but it was 100% in those patients who were naive to anti-CD38 therapy. They saw deepening responses over time.

So one of the things I really liked about this trial is that the overall response rates for patients who were refractory to anti-CD38 therapy, anti-BCMA therapy, bispecific antibodies, they were maintaining pretty decent responses in all of these patient populations at around 75%. And so currently the median PFS [progression-free survival] is 19.4 months, which I also think is really encouraging because again, this is a pretty heavily pretreated population. And when you compare it to some of the single-agent data, it looks like we’re seeing higher response rates here or greater durability in response compared to when we were just using the single agent.

And the other thing that I think is important with these types of trials to point out that we haven’t mentioned yet, is that these are steroid-sparing trials. And as we all know, especially in later lines of therapies, our patients are really sick and tired of [dexamethasone]. And so options that don’t mandate ongoing [dexamethasone] and the toxicities that that brings with it are welcomed.

Holstein: Yes, the median PFS of 19 months was really outstanding given, as you said, how incredibly pretreated this patient population was. And really we haven’t thought about those types of durations of response, except in the case of cellular therapy. So this is really interesting for off-the-shelf combination therapy. In particular, of course, our community colleagues are well-familiar with how to give daratumumab, so a little bit more experience in making sure that we can get bispecific antibody therapy in the community as well. This might be a really excellent regimen that patients in the community could easily get, hopefully in the future. Dr. Hartley-Brown, any thoughts about this combination and where you might see it fitting in in the future?

Hartley-Brown: I actually agree with you. I think there’s definitely centers that would appreciate this. They’re getting experience right now with the bispecifics. At our center, we do the inpatient step-up dosing and send them out for continued dosing of their bispecifics. So I think more and more as a community gets a little bit better experience with these medications — we already have a sub-q dara [subcutaneously administered daratumumab] that they know and love and can utilize very well and [are] very familiar with the toxicity profile. And the tolerability of these medications is also key, because we do have our patients that are over the age of 75 who still are doing great and have great performance status. So this might be something for them.

Holstein: Thank you. Well, thank you, Drs. Hartley-Brown and Lipe. I thought we had a great discussion today about some really interesting abstracts. And my main takeaway from all of this is that there’s incredible hope for the future for our patients who are suffering with myeloma. It’s really exciting to be truly on the cutting edge of novel cellular therapies being used in earlier lines of therapy, combination therapies with our bispecific antibodies yielding unprecedented responses. I think it’s going to make our lives even more complicated with all of these fantastic choices, but again, ultimately I really do believe that patients are going to live much longer and much better lives with these advances.

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