Bispecific Antibodies for Multiple Myeloma

Keith Stewart, MB, ChB: I want to review the data for bispecific antibodies, or BiTEs—slightly different technologies, but we’ll lump them together for today. Peter, you’ve had some experience with some of these. Do you want to talk us through that?

Peter Voorhees, MD: Sure. At LCI [Levine Cancer Institute in Charlotte, North Carolina], we’ve been involved in the phase 1 Janssen study of teclistamab. This is a BCMA-targeted bispecific antibody. This is a 2-pronged antibody, as I describe it. One prong of the antibody binds to BCMA on the surface of plasma cells. The other prong of the antibody binds CD3 on T cells and activates T cells, basically creates an immune synapse between the T cell and the myeloma cell, and engages that T cell to destroy the myeloma cell—the blinatumomab, if you will, of multiple myeloma.

There are several different products out there. There’s AMG 420, which was the first proof of concept of BiTEs in this specific space. The problem with AMG 420 was that it had to be administered as a 4-week continuous infusion, much like blinatumomab must be administered. These next-generation BCMA bispecifics have a longer half-life and can be dosed less frequently. In the teclistamab phase 1, the bispecific antibody was administered with step-up dosing during the first week and then weekly therapeutic dosing thereafter. My colleague presented this data at ASCO [American Society of Clinical Oncology Annual Meeting]. At the higher-dose level that they looked at with the IV [intravenous] formulation, they’re seeing response rates at this point of 67%—granted, with a very small number of patients, 12. But the patients I’ve treated on these things have very refractory disease and extramedullary involvement, and I’m seeing really quite impressive responses and durable responses with this agent.

Keith Stewart, MB, ChB: That seems to be a common theme to all the BiTEs. We have many of them in clinical trials, at least 6. Not to pick on anyone specific, but Tom, at ASH [American Society of Hematology Annual Meeting] you presented on a different one from a different company. Tell us about the results of that, and the toxicity.

Thomas G. Martin, MD: We have been part of the Celgene trial for their bispecific T-cell engager. And it was presented by Dr [Luciano] Costa at ASH. They did a first-in-human dose-escalation trial, then they treated 9 patients at what they believe is going to be the dose. They took to an expansion and then to a phase 2, which is a step-up dose of 6 to 10 mg, and then some patients at 10 mg. There were 9 patients treated at that higher dose, who had 8 of 9 responders. And 5 of those people are MRD [minimal residual disease] negative. It’s pretty impressive, actually—a response rate of almost 90% for these 9 patients.

I have a few patients on it. When patients get on it, it appears durable. The big question, in the waterfall plot that was shown at ASCO for teclistamab, there were patients out 19 months. Most of the patients who were out 12 months were still continuing in response. The question is, will it be as good as the CARs or not? We’re all really looking forward to seeing those data. This might be easier.

The problem is, it does require a hospital stay. The toxicity is the cytokine release syndrome, or CRS. It requires a hospital stay for the first dose and every step-up dose, because you might activate more T cells each time. But after you’re done with the step-up dosing and the first real dose and then the T cells, there is essentially no CRS. Patients may need to be hospitalized once, twice, or 3 times before they can continue, but then can continue in the outpatient clinic thereafter.

The neurotoxicity is also similar, but much less—less than 10% neurotoxicity. You still do see some cytopenias. About a third of the patients do get cytopenias. But as you said earlier, this is a really heavily pretreated population. Maybe it’ll be less if we do it in less heavily pretreated patients. Of all the agents, these are my favorite.

Keith Stewart, MB, ChB: We’ve used a couple of these agents targeting different companies, different agents. My impression is they’re a lot less toxic than CAR [chimeric antigen receptor] T cells, and I suspect they could probably be delivered safely as an outpatient from the majority of patients, particularly if you had some home monitoring system you could use. Also, to go back to CAR T, for some of those products on the horizon, they may not require hospitalization for everybody, at least initially. The other thing I’ve been a bit concerned about is unlike CAR T, at least in my experience, the remission duration has not been as long. The people do progress more quickly, at least in my short experience. This is something you have to pay attention to. But off the shelf, you don’t have to wait. There are good high response rates, and obviously this is going to be a very important addition to our therapy.

Transcript edited for clarity.