Studying the Promising Role of Bispecific Antibodies in Multiple Myeloma With Ajai Chari, MD

This podcast episode was recorded live by Oncology Data Advisor and ConveyMED at the 2022 ASH Annual Meeting in New Orleans.

Oncology Data Advisor: Welcome to Oncology Data Advisor. Today, we're here at the ASH Annual Meeting, and I'm here with Dr. Chari, who is here to discuss the MonumenTAL-1 study. Thanks so much for being here.

Ajai Chari, MD: Thank you for having me. It's a pleasure.

Oncology Data Advisor: Would you like to tell us a little bit about yourself and about what you do?

Dr. Chari: Sure. My name is Ajai Chari, I'm a Professor of Medicine and Director of Clinical Research at the Icahn School of Medicine at Mount Sinai, New York.

Oncology Data Advisor: Great. Would you like to tell us about the results of the MonumenTAL-1 study that were presented?

Dr. Chari: Yes. I'd like to start by saying, we're really excited that the phase 1 portion of the study just got published in the New England Journal this week. To distinguish that from what was presented at ASH, the phase 1 study was a mixture of both intravenous and subcutaneous administration of this drug, called talquetamab, and it studied a variety of dose levels. Here at ASH, we presented, for the first time, the phase 2 portion. Talquetamab is a bispecific antibody. Bispecific antibodies, we know, are of increasing importance and excitement. We've had naked monoclonal antibodies approved since 2015, and the first bispecific was approved this year for myeloma, teclistamab, but that targets B cell maturation antigen (BCMA), as do a lot of other mechanisms of action (MOAs) including antibody-drug conjugates (ADCs) and CAR Ts.

There's a dearth of other targets. That's why this product is so exciting. It targets G protein–coupled receptor family C group 5 member D (GPRC5D), which is a protein that's overexpressed primarily on malignant plasma cells, more so than normal, and not very much on hematopoietic stem cell compartment. We think that might factor into the adverse event (AE) profile. It is expressed heavily on keratinized tissues, such as nails and skin. Again, that may factor in, but what's exciting about this study is, really, that it's the first-in-class bispecific antibody targeting GPRC5D.

Oncology Data Advisor: That's great. Are there results that were presented?

Dr. Chari: In a patient population that was very heavily treated—five lines of therapy over six years—about 60% were high-risk, in some fashion, whether it's extramedullary International Staging System 3 (ISS3) or high-risk molecular. I would emphasize that, in particular, high-risk and extramedullary have been aggressive factors, even in the era of T-cell redirection, which have been amazing; even CAR Ts are showing worse outcomes in those subgroups. Almost every patient, 95%, was progressing on their last line of therapy. In this heavily treated population, which included triple-class refractory in three-quarters and penta-drug refractory in a quarter of patients, we saw a single-agent response rate of 73% to 74%, which is really outstanding. That response was maintained in this triple-class and penta-drug refractory. Also, when we looked at subgroup analyses, it was maintained in ISS, high-risk, refractory, and lines of therapy subgroup. The only subgroup that had slightly worse outcomes was the extramedullary, which is, we know, an unmet need in myeloma, but even those patients had a 50% response rate. I think the efficacy is an important part of the story.

Oncology Data Advisor: What was the safety profile of it?

Dr. Chari: I think that's equally exciting about this product. High-grade adverse events were primarily hematologic, and even those were in less than a third of patients, and they tend to happen early. Secondly, we're getting more and more concerned about the relentless increase in infections, particularly with BCMA-directed bispecifics. For example, most recently, we saw an update of 46% grade 3 and higher. Here, our grade 3 and higher infection rate was about 11% to 15%, so much lower. Second salient point about infections is COVID. About 10% of patients in both arms had COVID, but there were only two deaths—which of course, any death is a tragedy, but in context of other bispecifics, this is much less. Importantly, in the phase 1 New England paper, there was zero COVID deaths out of about 240 patients. I think this is another important signal, and it's supported by our own laboratory work at Sinai showing that when you check a COVID antibody response to patients who've gotten vaccinated, these patients have a good response, which BCMA bispecifics have not.

Finally, the rate of intravenous immune globulin (IVIg) use was relatively low at 10%. I think the hematologic and infection profile is excellent. There were some unique AEs that are worth highlighting, and probably, because of the expression of the target, we did see rashes, but typically, they were low-grade and quite manageable with topical or oral steroids. We saw nail changes, and we saw dysgeusia. For dysgeusia, we've been giving supportive care, but the main management, we think, has been modulating the dose intensity, either skipping, delaying, or reducing the dose. Fortunately, that's not with much consequence because the median time to response is one month, and the median time to best response is slightly over two months. When you have these AEs, you can reassure the patient that we can hold the drug and then you can recover from this AE. The median duration of response was nine-plus months, and then, for those patients who had stringent complete response (CR) and better, not even reached. That gives us comfort in the dose reductions and modulations.

Oncology Data Advisor: Definitely. What are the future next steps for the trial?

Dr. Chari: The first is the confirmatory phase 3. We're hoping that this will be reviewed favorably, and perhaps, get accelerated approval. However, we obviously need a confirmatory study, and that is accruing, so that's talquetamab compared to various combinations and comparator arms. Then, there are also a variety of phase 1 combination studies because of the excellent AE profile. The drug is being combined with standard backbone drugs. It's being combined with teclistamab, the sister bispecific, and checkpoint inhibitors. A lot of exciting studies are in the pipeline.

Oncology Data Advisor: Great. Putting this into context, there's been a lot of multiple myeloma research presented this week. What do you think are some of the other biggest studies, the most significant ones?

Dr. Chari: I would say, one of them is—staying with the theme of bispecifics—the use of prophylactic tocilizumab. We have to keep in mind, up till now, bispecifics have been done at large-volume academic centers, which also have CAR T experience. I think the whole point of the bispecifics, including the GPRC5D-targeting agent talquetamab, is they're off the shelf. They're ready to go. There's no reason why, theoretically, they couldn't be given in the community, but one of the barriers is the cytokine release syndrome. If we can reduce that with prophylactic tocilizumab, that's one step to getting closer. It still does require a lot of infrastructure.

The second thing was that we also saw, for the first time, an update of the cevostamab data. That bispecific is given for approximately one year and then discontinued, which is a paradigm shift, because in almost all myeloma patients, we treat till progression. The patients who had deep remissions, so far, have done well and not relapsed, which then tells us that maybe not every bispecific needs to be given till progression. You can balance that risk-benefit profile.

I think another interesting study was the IFM study, which compared daratumumab and lenalidomide to lenalidomide/dexamethasone. Relatively, the dexamethasone-sparing regimen for the frail and elderly showed favorable results. Dexamethasone is one of the least-liked products by patients, and yet, we throw it in every regimen. It's nice to see pulling back from that, especially for these older patients that may have a lot more toxicities with any drug. I think those are some of the things that were exciting.

Oncology Data Advisor: Great! Thanks so much.

Dr. Chari: Thank you.

Thank you for listening to this podcast, recorded live at the 2022 ASH Annual Meeting by Oncology Data Advisor and ConveyMED. For more expert perspectives on the latest in cancer research and treatment, be sure to subscribe to the podcast at conveymed.io and OncData.com. Don't forget to follow us on social media for news, exclusive interviews, and more.

About Dr. Chari

Ajai Chari, MD, is a Professor of Medicine and Director of Clinical Research in the Multiple Myeloma Program at the Icahn School of Medicine at Mount Sinai, New York. Dr. Chari's clinical interests and research encompass plasma cell disorders, such as multiple myeloma, AL amyloidosis, POEMS syndrome, plasmacytoma, and monoclonal gammopathies of uncertain significance (MGUS). He is remains active in clinical trials and has authored or coauthored a plethora of publications on these topics.

For More Information

Clinicaltrials.gov (2022). A study of talquetamab in participants with relapsed or refractory multiple myeloma. NLM identifier: NCT04634552.