Bispecifics in Multiple Myeloma: Translating Evidence to Clinical Practice - Episode 3

MajesTEC-1: Teclistamab in Relapsed or Refractory Multiple Myeloma


Expert perspectives on the MajesTEC-1 trial, a study of BCMA- and CD3-targeted agent teclistamab in relapsed/refractory multiple myeloma.


Luciano Costa, MD: You chose, along with the patient, to enroll in the MajesTEC-1 trial. Can you tell us a little about the design of that study, the population included, and the major findings?

Adriana Rossi, MD: This was a phase 1/2 study of teclistamab. They had their dose escalation followed by expansion. It caught us in this time of moving therapies from intravenous to subcutaneous. The dose escalation identified that the optimal phase 2 dose would be 1500 μg/kg subcutaneously, dosed weekly. In the dose expansion, they worked their way up from 80 to 3000 μg/kg. Encouragingly in these very heavily pre-exposed patients, they saw that at the phase 2 dose, the overall response rate was up to 65% and the CR [complete response] or greater was at 40%, which in such a relapsed setting is an encouraging place to be. Of note in the other dose levels, the overall response rate was still 60% with 35% CR or better, so these are very encouraging deep responses in this patient population. At the last time of presentation, the limitation is that follow-up is quite short, but patients tend to be, at least as far as we’ve seen them and being able to follow them, maintaining durable responses.

Luciano Costa, MD: Thank you, Dr Rossi. That’s an excellent summary. You gave us the experience and data that are unique to the MajesTEC-1 trial, but I would say a lot of those things are generalizable, and we have been seeing the observation across other BCMA [B‑cell maturation antigen]-directed T-cell engagers. Of course, the signature toxicity tends to be CRS [cytokine release syndrome], but because most of it is subcutaneous routing and with the use of step-up dosing, you don’t give the intended dose right on the first administration. You work toward the dose within the first week of therapy. The CRS has been overall mostly grade 1 or grade 2. Grade 3 CRS has been extremely rare, not only for teclistamab but also for other bispecifics. The important thing as we think about expanding the use of those agents, bringing them to earlier lines of therapy, and essentially getting those agents approved and put to broader use, is that the CRS is a phenomenon of the first week of therapy.

What we see in the MajesTEC-1 trial as well as in other bispecific trials is once you pass the first week, which we have watched the patients in the hospital for—but in the future, this probably won’t be the case— CRS becomes not an issue. It’s extremely rare, if not unheard of, to develop true cytokine release syndrome beyond that first week of therapy. I think that’s a very important thing because we didn’t know that, of course, when bispecifics started being developed. I would point out the subcutaneous route of our administration and the use of step-up dosing have been 2 highly successful strategies to mitigate the risk of CRS. Dr Rossi, other than the CRS, which is the first thing that comes to mind when you think those agents, what other toxicities do you think are important that people have to watch for or be aware of long term?

Adriana Rossi, MD: As I think my case highlighted, the second most telling are infections. As we are manipulating the immune system, in the study, about half of the patients at the phase 2 dose did develop infections, and the only patient death on the study was due to pneumonia. Fevers and differentiating infections and CRS, and being able to manage both, would be our focus. The rest are mostly hematologic toxicities that we’ve become all too accustomed to handling and managing.

Luciano Costa, MD: I think that’s very important. Currently, those agents are given until progression. Since the CRS is a phenomenon the first week or so, long-term factors like cytopenias and the risk of infection become more important. I think we’re going to need more mature data to refine the strategies to mitigate those risks. I think many of us do, of course, universal prophylaxis for VZV [varicella-zoster virus] and HSV [herpes simplex virus] with acyclovir, not unlike with any other patient with myeloma. But also, we’ve become quite cognizant of the hypogammaglobulinemia, which is very common with any highly potent antimyeloma agent. We tend to be quite liberal in using IVIG [intravenous immunoglobulin therapy], particularly a secondary prophylaxis for bacterial infection. Just be aware and use proper dose emission or growth factor support to deal with the neutropenia and thrombocytopenia, which tend to be transient and very responsive to supportive measures. In the future, we might find out that at least in some circumstances, the patients may not need indefinite therapy. They may need some limited-duration therapy when you have agents as potent as teclistamab, for example.

Transcript edited for clarity.