BCMA-Targeting Bispecific Antibodies in Relapsed/Refractory Multiple Myeloma


Expert perspectives on recent clinical data on BCMA-targeted bispecific antibody therapy in patients with relapsed/refractory multiple myeloma.


Sagar Lonial, MD: Let’s get to the belle of the ball at ASH [American Society of Hematology Annual Meeting]: T-cell engagers, or the bispecific antibodies. What did we hear at this meeting?

Sandy Wong, MD: This was an amazing meeting. T-cell engagers are still prom queen and king, just like last year. It’s an exciting time because we have 3 targets: BCMA, recently approved teclistamab, and other ones being developed in that class, including elranatamab, which is subcutaneous and has ease of administration. We also heard from the dark horse, alnuctamab, which is also given subcutaneously. We hadn’t heard an update since ASH 2019, so it was great to hear what happened to that drug. There are also the IV [intravenous] BCMA T-cell engagers, like ABBV-383 and the Regeneron [Pharmaceuticals] 1. There’s a lot of exciting activity in that class of drugs, and we’re seeing overall response rates of 60% to 70%, plus or minus a few points.

But we’re also starting to see some differences in terms of potential toxicity. It’s hard because teclistamab has had the longest median follow-up, 14 months, which is quite a long time. The second 1 is probably elranatamab in terms of median follow-up, and the others follow that. What was presented at this meeting was not only elranatamab but also alnuctamab. With alnuctamab, the median PFS [progression-free survival] was only 4 months. It’s hard to compare apples and oranges, but we’re going to do that anyway, so let’s delve into it.

We’re starting to see some differences, in terms of not just route of administration but adverse effects. With teclistamab, 1 thing that stands out is the rate of high-grade opportunistic infections. In the New England Journal of Medicine, there was a case of PML [progressive multifocal leukoencephalopathy]. PML is from JC [John Cunningham] virus, so that’s an opportunistic infection. There was PJP [pneumocystis pneumonia]. These are things we don’t typically see. There were even patients with adenovirus pneumonia, as well as CMV [cytomegalovirus] infections and reactivations. These aren’t typical things that we see. You wonder if it’s the drug or the frequency of its dose. It’s dosed every week according to the US label.

Samuel M. Rubinstein, MD: Every week indefinitely.

Sandy Wong, MD: Yes, every week indefinitely. That’s a long time to be coming in. With all the other regimens we have, we usually give them a week off. This is every week. With elranatamab, there are potential signals for neuropathy. This harkens back to the Amgen drug, which had neuropathy too. You’re wondering if that’s a signal. Are they enrolling patients with preexisting neuropathy and they got exacerbated? With alnuctamab, it’s very early in the subcutaneous cohort. In terms of the intravenous cohort, some patients are on this drug for a long time. For responders, the median PFS was 36 months; that’s a long time. In the IV cohort, there weren’t many opportunistic infections. There was thrush, but that’s easily treatable; 4 cases of CMV; and reactivation infection. Other than that, there was no PJP or PML. There was 1 case of adenovirus viremia. It’s hard to compare. That’s the IV cohort, but the subcutaneous cohort is the 1 that’s moving forward. It’s exciting. It’s great that we’re seeing options. These are the early days of alnuctamab, but I’m excited that we have teclistamab.

Sagar Lonial, MD: Before we get to the non-BCMA—I know that’s where you’re going next—we’re all excited to have teclistamab FDA approved and available. I haven’t given it. Have any of you guys given it commercially?

Timothy Schmidt, MD: Commercially, no.

Sandy Wong, MD: Yes. We just started this week.

Sagar Lonial, MD: This week?

Sandy Wong, MD: Yes. We dosed 2 patients.

Sagar Lonial, MD: All right. You’re ahead of the game.

Samuel M. Rubinstein, MD: Our first is coming in this week.

Sagar Lonial, MD: This week. All right. That’s good.

Timothy Schmidt, MD: Ours is next week.

Sagar Lonial, MD: Ours is next week too. The question is, let’s say you had the ones you just talked about at your commercially available off-study opportunity. What would you need to see to pick 1 vs another?

Caitlin Costello, MD: We’re starting to see similar overall response rates and CRS [cytokine release syndrome] rates. It comes down to operational logistics to some degree. I want to choose a drug that’s effective and safe and that I can have patients stay on for the long run, aware of all the adverse effects of the opportunistic infections. Some of the logistical challenges are getting patients in the hospital for step-up dosing and keeping them in the hospital. I don’t know about you, but I’m not discharging and bringing them back in. I’m hoping to get a bed back. When we have multiple drugs to decide between, we’re going to try to figure out which 1 we can potentially give as an outpatient, or what will keep them in the hospital the shortest duration of time. Assuming all other things are equal.

Samuel M. Rubinstein, MD: If all the BCMA bispecifics in development were available to any patient we wanted to give them to, that would drive my decision-making. To my eye, the easiest schedule to follow right now is 3-8-3, which is every 3 weeks and requires only 48-hour hospitalization for dose 1. Of course, all these bispecifics are going to be developed at variable schedules. All the folks developing these compounds know that convenience is a major driving factor, and they’re going to be looking at how to dose less frequently and mitigate the CRS risk that drives the need to hospitalize these patients.

Caitlin Costello, MD: Alnuctamab was nice. The schedule was set up as if it was daratumumab, the way that they started spacing it out. We do what we all do with all other drugs: we figure it out. We figure out how we can make dose changes so we can make it more convenient without losing effectiveness.

Sandy Wong, MD: The other thing to consider is that it’s hard to know. We don’t have PFS on the other BCMA drugs, except for teclistamab. It’s hard to know if there’s any PFS advantage for 1 or the other. What’s stood out to me in the alnuctamab study was that they had MRD [minimal residual disease] negativity. These are early days with small numbers, but MRD rates were 80% with a median follow-up of 4 months. That’s high for a short period of time. How will that play out? Time will tell. I’ll be curious to see if there are any differences in PFS with any of these agents.

Transcript edited for clarity.

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