Panel Discusses Use of Bispecifics to Treat Relapsed/Refractory Myeloma

By Saad Z. Usmani, MD, MBA, FACP, Shambavi Richard, MD, Meera Mohan, MD, Yi Lin, MD - Last Updated: June 26, 2023

A roundtable discussion, moderated by Saad Usmani, MD, of Memorial Sloan Kettering Cancer Center, focused on treatment considerations for relapsed or refractory multiple myeloma, including updated data from the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. Dr. Usmani was joined by a panel that included Yi Lin, MD; Shambavi Richard, MD; and Meera Mohan, MD.

In this segment of the roundtable series, the panel discusses the new and emerging bispecific antibody treatment options for multiple myeloma, including talquetamab and teclistamab.

Watch the next segment in this roundtable series.

Dr. Usmani: How about we pivot to the other therapies? When I say other therapies, I’m talking about the bispecifics. We are all cellular therapy people, but we also treat our patients with bispecific antibodies on clinical trials. There’s been this debate, is it chimeric antigen receptor (CAR), is it bispecific, is it both? How do you decide? And should you sequence? In some debates, it becomes a competition. But it’s not a competition, I think all these things are good for our patients.

We have had several constructs targeting BCMA that have been presented. We have one product that’s already US Food and Drug Administration (FDA) approved with teclistamab, and then we have GPRC5D. Again, Ajai [Chari, MD] led the talquetamab program and hopefully we’ll hear some good news from the FDA later this year about it. But at ASCO we have several updates in bispecifics, and in fact, we also have the first data of combining a BCMA and GPRC5D bispecific, the RedirecTT-1 trial.

Meera, I’ll start with you. Your thoughts about some of the bispecific data that’s being presented? What are the things that caught your eye?

Dr. Mohan: The clinical efficacy is really unprecedented. We’ve seen the high response rate of anywhere between 60% to 70% and [they are] very durable too. The one thing obviously that stands out is the infection rate, especially when we use combination therapy and particularly with the BCMA-directed bispecific antibodies. Otherwise, very impressive clinical efficacy.

Dr. Usmani: What do you think?

Dr. Richard: I think that’s a very interesting concept. I want to hear more. We’ll hear more about the infection rate and things like that, but certainly the neutropenia was quite significant with that combination. It seems like they had a 75% grade 3 neutropenia [rate], grade 3 to 4.

The other combinations that are really interesting too is the updates with the TRiMM-2, for instance, where they have the daratumumab/talquetamab combination. I mean, talquetamab looked great with the infection rate when it was monotherapy, unlike the other BCMAs. You had very few grade 3 to 4 infections, but the minute you threw daratumumab into it, it just became like a BCMA. We have to watch out for things like that. Certainly, the response rate upped from 70% to 78% or so. I think that’s very interesting.

It looked like MagnetisMM trials kind of took over a whole bunch of the ASCO abstracts. They’re doing every kind of possibility there is with that. That’s another very interesting [one]. It’s good news for our patients to have all of these various possibilities.

Dr. Usmani: One thing I do want to touch upon: the infection risk piece, because we’ve been talking about how long do you need to keep on redirecting the T cells? Can [we] space out [and] change the dosing schedule? Can you even give breaks to patients who’ve got sustained responses for little time?

All of us have those anecdotes where we had to stop treatment with bispecifics on a patient because of infections, and they went on in sustained responses for months. I have this one outlier patient who was off for three years, and he had never been off of any treatment, and that was his sixteenth line of treatment. He got only a few cycles and then nothing for three years, because we took him off, because of infections on the MajesTEC-1 study. But that’s the next challenge.

We have some data that I’m presenting with the MajesTEC-1 study where after about median of 11 cycles of treatment patients who had a VGPR [very good partial response] or better that was sustained, they were moved to Q2 week [dosing]. During their second year on study compared to those patients who were getting weekly treatment, the grade 3 or higher infection risk was 16% versus 32.5%. How about we apply that principle much sooner than that, because the median time to best response with teclistamab, and with talquetamab as well, is three months. Can we not space out the dosing? Can we not do that early on? I think that’s what we have to [do].

Dr. Lin: I absolutely agree. It’s great to see that initial proof of concept, these things work, even a single agent has impressive activities. Now let’s refine how we use them. Maybe the initial data was based on the half-life and the pharmacokinetics of the drugs, but now we know the actions of these immune cells, potential side effects. And we have tons of information with MRD [measurable residual disease], let’s say sustained negativity, across myeloma therapy, but also now data with CAR-T, bispecific. Can we combine those? We can dose them a little bit differently. And can we consider stops? Absolutely.

The other thing I would also just caution: You look across these studies and it’s been very variable in terms of some monitoring for infections, certain prophylaxis across institutions, a little bit up to institutional preferences. I think maybe to some degree with CAR-T—and maybe that just might be my impression—but I feel like, because that’s so heavily regulated between FACT [Foundation for the Accreditation of Cellular Therapy], and FDA, and all these, there’s a lot of guidelines in place. Even though there can be institution-to-institution variations, but there’s a recognition; we’re getting chemo, and then this CAR-T can have an ongoing effect, so let’s monitor for a lot of things, let’s have standard prophylaxis.

Some of those might have been carried over, extrapolated, from transplant experience, but with bispecifics, there may not been as much of that going on, because people are thinking, “It’s one drug I’m giving, and we have a lot of experience giving daratumumab, isatuximab, and so on.” But it is different. I think IMWG [International Myeloma Working Group] has a guideline that is coming out with infection management with bispecifics. Maybe if some of these are a little bit more standardized across studies, we may see some improvements.

Dr. Usmani: I agree. And I think that there are some things that are almost allogeneic stem cell transplant-like, so cytomegalovirus (CMV) reactivations that we’ve been seeing with the continued bispecifics. I think elranatamab came out with that initial data, where there was a lot of CMV reactivation. And then all of us started to look into other bispecifics, because we weren’t really looking at that, and patients were getting sicker, and you couldn’t realize what was the reason behind it.

Going back to the teclistamab/talquetamab combination there too, I think I was very impressed with the activity in high-risk and extramedullary disease. I think that signal was really good, and I’m really looking forward to hearing more about it, and I hope that as a next step, I want to see what they’re doing with the schema. Are they going to start backing off of treatment and reduce that infection risk or the neutropenia risk? That’s the other thing that I’m looking forward to.

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