Updates on Bispecific Antibodies in Multiple Myeloma From IMS 2023 With Rahul Banerjee, MD, FACP, and Shonali Midha, MD

Rahul Banerjee, MD, FACP: Hi, everyone. Welcome back to Oncology Data Advisor. My name is Rahul Banerjee. I'm an Assistant Professor of Medicine at the Fred Hutchinson Cancer Center in Seattle, Washington.

Today, it's my pleasure to speak with Dr. Shonali Midha to get some updates from the 2023 International Myeloma Society Meeting that took place at the end of September in Athens, Greece. Dr. Midha is a myeloma expert at the Dana-Farber Cancer Institute in Boston, Massachusetts, and an Instructor in Medicine at Harvard Medical School. She was also one of the oral presenters at this conference, the IMS Meeting, at the end of September in Athens. Dr. Midha, Shonali, pleasure to have you joining us today.

Shonali Midha, MD: Thank you so much, Dr. Banerjee. It's my pleasure to be here today.

Dr. Banerjee: Wonderful. As I alluded, you were one of the oral presenters, and what you presented was real-world data with teclistamab. This is something I would love to spend some time on, so maybe we can start there. Teclistamab was approved in the US just about a year ago, in October 2022. Can you tell us a bit more about this drug and the MajesTEC-1 trial that led to its approval?

Dr. Midha: Absolutely. Teclistamab is a BCMA-CD3 bispecific T-cell engager that is approved in the relapsed/refractory setting after four lines of prior therapy in multiple myeloma. It was approved, as you mentioned, back in October 2022 based on the MajesTEC-1 study, which was a phase 1/phase 2 study of teclistamab in patients that have received three or more prior lines of therapy with relapsed/refractory disease.

In the MajesTEC-1 study, patients did not have any central nervous system (CNS) disease and were not considered eligible if they'd had significant kidney dysfunction with a creatinine clearance below 40. It did allow patients with a performance status of 1 or better, so relatively healthy patients overall. And I'll explain why I'm harping on that in a moment. In the phase 2 portion and overall, they included 165 patients with an overall response rate of 63%, which is very exciting for a single-agent therapy in this setting in patients that are so heavily pretreated and had received a median of five prior lines of therapy.

Dr. Banerjee: As you alluded to, setting the stage here, you presented your institution's real-world experience. Can you describe what the results were, how the patients were, and any surprises or lessons learned compared to the public results from MajesTEC-1?

Dr. Midha: We presented our data, a single-institution retrospective analysis of patients treated with teclistamab in the commercial setting, those that had received four or more prior lines of therapy. In regards to the demographics, age-wise, our populations were very similar. Our median age was 69 as compared to 64 with MajesTEC. Obviously, we did have more patients with a poor performance status at the time that they started therapy. About 30% of our patients had an Eastern Cooperative Oncology Group (ECOG) status of 2 or greater.

We had more patients that had high-risk disease, defined by either a stage II or III Revised International Staging System (R-ISS) stage or by high-risk cytogenetics. We had over a quarter of patients with a 17p deletion, and up to 40% of patients had a 1q gain or amplification. Overall, 49% had high-risk cytogenetics. We had 42% of patients with extramedullary disease, another high-risk feature in myeloma. Seven patients, about 12.5%, had experienced CNS disease.

Of the patients we treated, 20 had received prior BCMA therapy, 13 of which had received prior belantamab mafodotin, which is an antibody-drug conjugate, and 13 that had received prior BCMA-directed chimeric antigen receptor (CAR) T therapy. As you can tell, there were some patients that had received more than one BCMA-directed therapy in the past, so it definitely does go into some of the results that we see as well. Our patient population was 56 total patients treated between the time of FDA approval and our data cutoff of August 15. Of the 56 treated patients, 45 (80%), would not have been eligible for MajesTEC-1 based either on renal dysfunction, presence of CNS disease, or cytopenias at the time of treatment.

In regard to some of the toxicities that we're seeing and the safety signals, we actually saw very comparable rates. We had 52% of patients that had experienced any cytokine release syndrome, which was not too far off. That was seen in 72% in the MajesTEC-1 study. We had very few grade ≥3 events, only accounting for a little under 2% of all cases. Actually, our median onset of CRS was later than what was seen in MajesTEC-1. They had cited a median onset of two days. We had a median onset of five days and a duration of CRS that was about two days, similar to MajesTEC-1. We had very few neurotoxicity events. We actually had only one documented event (2%), no grade ≥3 neurotoxicity events, and 14 cases of tocilizumab use, about a quarter in regard to percentage. This was also something interesting, especially given the number of patients with CNS disease.

Dr. Banerjee: Before you get to efficacy, I was going to ask, was that one documented case someone who had CNS disease or didn't?

Dr. Midha: That one case was a patient who had received radiation for suspected CNS disease, and our thinking at the time was whether there could have been an abscopal effect. It was actually a very transient neurotoxicity event. It was wrist drop that only lasted for a couple hours. They actually did not receive any dexamethasone by the time it had improved. Their symptoms had actually improved prior to when they received radiation, and they had ongoing radiation during the time of the step-up, so we were wondering if there could have been an abscopal effect that we were seeing there.

Dr. Banerjee: Which is fascinating. Just for the audience, the abscopal effect would be that the radiation sensitizes other cells in the area or other immune cells to get in gear. Sorry, I interrupted you before the most exciting part. Now we'll see the data in this much sicker, much more real-world—literally real-world—population.

Dr. Midha: Exactly. What was exciting was that despite treating a very sick population and a heavily pretreated population, we saw a response rate of just under 54%. Obviously, this was better in patients that had not received prior BCMA-directed therapy, around 58.3%. In those that had received prior BCMA therapy, the response rate was at 45%. I think what was also really encouraging here was that we saw a response rate of 37.5% in patients with extramedullary disease.

But as expected, when you're looking at the breakdown of those patients that had received prior BCMA versus those that had not, the patients that had received prior BCMA-directed CAR had a lower response rate of about 30.8% as opposed to those that had received antibody drug-conjugates. It's definitely somewhat sobering to see a slightly decreased rate in patients that have received prior BCMA-directed therapy, but it's still a very good option even in patients that are heavily pretreated and with more comorbidities or greater disease burden at the time of treatment.

Dr. Banerjee: Agreed. If I may, I'll delve into what I found striking about it—that for us, our patients with CNS involvement often do very poorly. We talk about pomalidomide, we talk about selinexor, drugs that cross the blood-brain barrier, or chemo and that's it. I know it's a small N, but still, it's eight more patients than I've personally treated with teclistamab in this setting. Did some of those patients do okay or even have CNS clearance or a resolution of extramedullary disease (EMD) in the calvarium?

Dr. Midha: We actually did not include that as part of this cohort here, but we have looked at our patients we've treated that have had documented CNS involvement, either radiographically or by cerebrospinal fluid (CSF) or leptomeningeal disease radiographically. Out of the seven that were treated, five had a documented partial response (PR) or better, which was very encouraging. Two of those patients had received radiation for their CNS disease as well. I think this is a therapy that does provide those patients benefit.

Dr. Banerjee: This is very helpful. I did not know that, so thank you for sharing that on the fly. It's small and more studies are needed, but I think this shows that those patients—obviously, many patients benefit from teclistamab, as you alluded to—but with those patients in particular, everything scares us about them. We're so worried about neurotoxicity. It sounds like maybe the rates are low of immune effector cell–associated neurotoxicity syndrome (ICANS), and some of those patients do respond, which is wonderful.

Dr. Midha: Absolutely. Another thing which we saw, which has been very well documented with BCMA-directed bispecifics, is the infection risk. Out of our 56 patients, we had a documented 32 infections in 26 patients, of which almost half, 48% of those, were grade 3 or grade 4 infections. We did not have any teclistamab-related infectious deaths. However, we did see that a large proportion of those infections were respiratory, the majority being upper respiratory infections that comprised 37% of the infection seen. Pneumonia comprised another close to 20% of the respiratory infections, and under half, about 46%, were COVID cases. Then we did see, again, a decent amount of skin, soft tissue, gastrointestinal, and genitourinary (GU) infections. It's definitely something that we still have to keep an eye out for and learn a little bit better about how best to manage or mitigate them.

Dr. Banerjee: That's very helpful to hear. I think a lot of us often assume that part of the reason that the infection deaths were so bad with the BCMA trials was that they were running in the early days of COVID. Here, you said that all patients were treated commercially, so all in the last year. You could argue that we have COVID vaccines now, and the virus is mutated, but it still sounds like a serious threat. Maybe it's not life-threatening, not grade 5 thankfully, but patients are still getting ill.

Dr. Midha: I think it's something we still have to learn best how to manage and decrease the risk for, whether through alternative dosing or looking at other ways of scheduling dosing or prophylaxis.

Dr. Banerjee: That's exactly right. Hopefully by this time next year, we'll have more exciting COVID treatments, so we can use some Evusheld® (tixagevimab/cilgavimab) for prophylaxis. Switching gears, now we can talk about some of the other interesting abstracts at IMS that you and I had discussed briefly beforehand. You focused on teclistamab in the relapsed/refractory setting of heavily pretreated patients. You did allude to a lot of these patients being higher-risk, with more high-risk patients in your cohort than in MajesTEC-1. Let's focus on high risk and pivot now to frontline setting. The GMMG-CONCEPT study was also presented, looking at Isa-KRd (isatuximab, carfilzomib, lenalidomide, and dexamethasone) in high-risk myeloma. Any thoughts about that, either that trial or about anything from IMS that changes how you approach or how you treat high-risk myeloma?

Dr. Midha: I think it was definitely a very interesting trial. It was looking specifically at a high-risk population, and I think it's one of the few studies that has taken into account a 1q amplification. They did use the second iteration of the R-ISS staging that takes those factors into account. It's not a group that is very well studied, although it comprises a large proportion of myeloma patients. From that perspective, it was very encouraging to see incredibly high rates of measurable residual disease (MRD) negativity with isatuximab, carfilzomib, lenalidomide, and dexamethasone treatment upfront. Seeing MRD negativity rates for both transplant-ineligible and transplant-eligible that are above 54% and 67% is highly encouraging. As we learn more about the role of MRD negativity, it may not be the "be all, end all," but knowing that you can achieve a deeper level of response upfront, I think, is something that gives us pause, especially in a high-risk population.

Dr. Banerjee: Agreed, and that's helpful to hear. I know at least in the US, for our listeners, isatuximab is not yet FDA-approved for frontline therapy, but I think this is showing that maybe this type of approach works. Dr. Midha alluded to the transplant-ineligible patients who were included in this study as well. It's not just one pathway of using quadruplets and then rolling with it. The other study that comes to mind for me is CANOVA, which, for people listening to this, we're going to be doing another podcast with Dr. Andrew Yee from Mass General in Boston, specifically about translocation (11;14). I'm sure CANOVA is probably the trial that turned the most heads at IMS. Can you catch us up to speed on the CANOVA trial and how it informs or doesn't inform your practice since returning from Greece?

Dr. Midha: Absolutely. The CANOVA trial was a phase 3 study looking at venetoclax/dexamethasone as opposed to pomalidomide/dexamethasone in patients with relapsed/refractory myeloma who have received more than two lines of therapy. They looked at patients who did have translocation (11;14), which is suggestive of BCL-2 expression. Venetoclax is a BCL-2 inhibitor and one of the few targeted therapies available in the myeloma space. Patients in the venetoclax arm had a slightly higher median prior lines of therapy—I believe they had three as opposed to two prior lines in the pomalidomide/dex arm, and they did treat a variety of patients.

One thing I did want to point out here, and I think is something that we continue to work on in the myeloma space, is that they had a very low percentage of patients who were African in descent or Latin in descent. That's an area where we have to work a little bit harder, especially because we know that translocation (11;14) is more prevalent in those populations. I think we do have to take this data with a large grain of salt there. That being said, while they did see a numerically larger progression-free survival in patients treated with venetoclax and dexamethasone as opposed to pomalidomide and dexamethasone, it was not statistically significant for the physical analysis of this study.

In regard to how to take that, it's definitely hard to beat pomalidomide and dexamethasone. We've seen that in other studies. But I think it also shows us that maybe venetoclax is not a medication we can use as a doublet. We did see higher response rates in patients treated with venetoclax/dexamethasone as opposed to pomalidomide/dexamethasone, which was statistically significant, almost double what it was with pomalidomide/dexamethasone. So, there is a role for treatment with a BCL-2 inhibitor, but it may not be strong enough alone.

Dr. Banerjee: Very well stated, and that's true; the BELLINI study had bortezomib, and Dr. Kaufman presented with carfilzomib. If you do use it right now, it's off-label obviously, but if you use venetoclax in any scenario for translocation (11;14) myeloma, how do you typically do it in your personal practice?

Dr. Midha: In my personal practice, it's oftentimes in combination with a proteasome inhibitor, either bortezomib or carfilzomib, depending on tolerability and the patient's comorbidities.

Dr. Banerjee: Absolutely. Well, thank you, Shonali. This was so interesting. It was a very whirlwind meeting in Greece for all of us. And I always say that hopefully a year from now, everything we talked about will be out of date with more data—not the real-world teclistamab, but everything else will change, and we'll see more and more data unfold. With that, thank you again for your time. This has been another episode of Oncology Data Advisor. Thank you to everyone for listening.

Dr. Midha: Thanks for having me.

About Dr. Banerjee and Dr. Midha

Rahul Banerjee, MD, FACP, is an Assistant Professor in the Division of Medical Oncology at the University of Washington and Fred Hutchinson Cancer Center. He previously completed his Hematology/Oncology Fellowship and Advanced BMT/CAR-T Fellowship at the University of California, San Francisco. His clinical interests are in multiple myeloma, AL amyloidosis, and CAR T-cell therapy. His research interests are in toxicity management, digital health, and the patient experience.

Shonali Midha, MD, is a Medical Oncologist at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute and an Instructor in Medicine at Harvard Medical School. She specializes in the treatment of multiple myeloma and plasma cell disorders. Dr. Midha's research focuses on the role of immunotherapy and cellular therapies in multiple myeloma and on better understanding high-risk disease.

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Transcript edited for clarity. Any views expressed above are the speakers' own and do not necessarily reflect those of Oncology Data Advisor.