BCMA-Targeting Bispecifics in Multiple Myeloma: Teclistamab

Video

Opening its discussion on BCMA-targeting bispecific antibodies in multiple myeloma, a panel of expert oncologists highlights key clinical data behind teclistamab.

Transcript:
Amrita Krishnan, MD:
Hello everyone and welcome to the CancerNetwork® Training Academy. Today we’re going to be talking about BCMA- and non-BCMA–targeting bispecifics in multiple myeloma. We’ll review the clinical data and have a panel discussion with a terrific group of experts. My name’s AmritaKrishnan, I’m the director of the Judy and Bernard Briskin Center for Multiple Myeloma Research at the City of Hope Cancer Center. I’m joined today by Dr Sandy Wong. Sandy, do you want to go ahead and introduce yourself?

Sandy Wong, MD: Hi everyone. Nice to be you with all of you today. I’m at the University of California in San Francisco, and I’m an assistant professor here at this hospital [UCSF Helen Diller Family Comprehensive Cancer Center].

Amrita Krishnan, MD: We are also going across the world to Dr Philippe Moreau. Philippe.

Philippe Moreau, MD: Hi everyone. Thank you, Amrita, for giving me the opportunity to be part of this program. I’m working in the University Hospital of Nantes in France and working on the development of new agents and especially bispecific antibodies.

Amrita Krishnan, MD: Then across the country to Dr Alfred Garfall.

Alfred Garfall, MD: Hi, Amrita. It’s very nice to be here. Alfred Garfall from Abramson Cancer Center at the University of Pennsylvania. I’m a member of the multiple myeloma program in hematologic malignancies program here.

Amrita Krishnan, MD: Then last but not least, Dr Josh Richter.

Josh Richter, MD: I’m Josh Richter. I’m from the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai in New York. I direct my small part of the world of that program down at the Blavatnik Family Chelsea Medical Center. It’s great to be with this wonderful group today.

Amrita Krishnan, MD: Let’s briefly look at our learning objectives, but we are going to talk about some of the recent clinical trials with multiple bispecifics. We’ll talk about their safety, their clinical efficacy. We’ll talk about some of the combination regimens that are earlier in the phase of development, and we’ll talk about where bispecifics are going to fit into the treatment landscape of multiple myeloma. We will start with Dr Moreau, who led the MajesTEC trial. We’re really excited that we have him to present his work today. Thank you, Philippe.

Philippe Moreau, MD: Thank you, Amrita. As you know it’s very important to target BCMA if possible because BCMA is always expressed on myeloma cells with very little expression on normal tissue. Teclistamab is the first bispecific antibody targeting BCMA and CD3, and redirecting T cells close to the myeloma cells in order to induce tumor cell death. Teclistamab was approved by the FDA in October 2022. It is approved as well in Europe by EMA [European Medicines Agency] for patients with relapsed and refractory multiple myeloma who have received at least 4 prior lines of treatment, including a proteasome inhibitor [PI], an IMiD [immunomodulatory drug], and a CD38 antibody. This approval was based on the results of the MajesTEC-trial, that is a phase 1/2 single-arm multicohort, multicenter study. Teclistamab was also tested at earlier lines of treatment with different combinations, and we will speak about those combinations during this presentation.

This is the design of the MajesTEC-1 study. Patients very advanced in the course of their disease were enrolled. All of them were previously exposed to proteasome inhibitors, IMiDs, and CD38 antibodies, and they had to be refractory to the last line of treatment. We have 2 cohorts of patients; the great majority of them never received prior BCMA-targeted treatment. But we have a small cohort of patients who were previously exposed to BCMA-targeted treatments. We have enrolled into this study 165 patients treated at the optimal dose of teclistamab, which is 1.5 mg/kg weekly. During the first week of treatment, we are using step-up doses of teclistamab. The same is true for all bispecific antibodies to try to reduce cytokine release syndrome [CRS]. Patients are supposed to be treated until progression. The primary end point of the study was the overall response rate, with a number of key secondary end points, such as duration of response, progression-free survival [PFS], and obviously safety as well.

The primary end point was overall response rate. These are the results of 165 patients who received at least 1 dose of treatment. So this is really the intent-to-treat analysis, and the response rate was 63%. Those are very good results indeed, including a high rate of complete response, almost 40%. And the rate of patients with a VGPR [very good partial response] or better was almost 60%. They are amazing data, especially when looking at the patient population, very advanced, almost all of them triple-class refractory. And this response rate is very consistent across subgroups of patients, including patients with high-risk disease. But of note, patients with extramedullary disease responded less to teclistamab. We also looked at the depth of response with MRD [minimal residual disease] assessment, 10 to the minus 5, and you see that more than 25% of the patients were able to reach MRD negativity. The median progression-free survival is 11.3 months, and the median duration of response is 18 months. Definitely very good results, and when we are trying to compare those data with, for example, belantamab mafodotin, with selinexor, with melflufen, there is a big difference in favor of teclistamab.

From the safety point of view, we can notice immediately that we have very few cases of grade 3 or 4 CRS, almost no grade 3. That’s very good for the patients. We are using step-up doses during week 1, and indeed, the majority of patients experienced CRS, 72%, but that’s mostly grade 1 or 2. And this CRS is very easily controlled by tocilizumab in the majority of the cases. One safety concern to be honest is grade 3 or 4 infection, which is 44%. We know that we have here a very advanced patient population with very severe immunosuppression, and we are deepening the immunosuppression with an agent that is targeting BCMA. The hypogammaglobulinemia level is very low; when you are looking at the IVIG [intravenous immunoglobulin]level, that’s very often less than 4 g. The majority of patients will receive IVIG. In this study, 65 patients received IVIG, which was at physician discretion. But we have to keep in mind that the infection rate is quite important. The onset of infection is not only during the first cycles of treatment, but severe infection can occur later, after month 6 or month 9. This is the most important point in my opinion to keep in mind.

Teclistamab is very active in advanced patients, and is now approved in Europe and the United States for these patients, and also is being tested in combination. We have the early results of the MajesTEC-2 study with the combination of teclistamab with daratumumab plus lenalidomide in patients with relapsed myeloma. The data were presented for the first time during the last ASH [American Society of Hematology] meeting a few weeks ago. The key eligibility criteria were patients with relapsed myeloma, 1 to 3 prior lines of treatment, including an IMiD and a PI, so earlier in the course of the disease. The primary end point was safety and dose-limiting toxicity. You can see on this slide that we have tested different doses of teclistamab with the conventional dose of daratumumab sub-Q [subcutaneously] and the conventional dose of lenalidomide as well.

The most common toxicity was neutropenia. We don’t have any issue with cytokine release syndrome, that’s not an issue when combining teclistamab with lenalidomide and daratumumab, but some patients did experience severe infection. This is the issue with teclistamab and other bispecific antibodies that are targeting BCMA because as we will discuss later, teclistamab is not the only one targeting BCMA.

The response rate was amazing, more than 90% had a response, and more than 50% had complete response. And those responses were very quick. The median time to first response was 1 month only. We don’t have any PFS data because the follow-up is really short at the time of the presentation, but these are very promising results in patients with relapsed multiple myeloma.

Teclistamab was also combined with daratumumab in the TRIMM-2 study in patients with relapsed myeloma. The key eligibility criteria were relapsed multiple myeloma, at least 3 prior lines of treatment, and it was possible to be treated previously with a CD38 antibody, but a 90-day washout period was mandatory. When you’re looking at those combinations in the relapse setting, daratumumab was tested at the usual dose sub-Q, and 3 different doses of teclistamab were combined with daratumumab. When we are looking at the response rate on the next slide, you see that those data are very early, small numbers for sure. But the responses are really promising when we are combining teclistamab with daratumumab, and there is a strong rationale for this since daratumumab is able to increase a subpopulation of T cells that may increase the efficacy of teclistamab.

Again, with early data looking at the safety, CRS is not an issue, we can easily combine teclistamab with different agents, and there is no increased rate of cytokine release syndrome. But again, we have some cases of infection, and this is really the most important point. Be careful with infections when you’re using teclistamab. There were also different cohorts in the TRIMM-2 study. Teclistamab was combined with pomalidomide, and there are also combinations of daratumumab with other bispecific antibodies, such as talquetamab. The studies are ongoing, we don’t have a long follow-up. We don’t know anything regarding PFS, but these are promising data for sure.

Transcript edited for clarity.

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