Teclistamab induces durable responses in relapsed or refractory multiple myeloma
Teclistamab showed encouraging efficacy among patients with relapsed or refractory multiple myeloma, according to results of the phase 1 MajesTEC-1 study presented during the virtual ASCO Annual Meeting.
Teclistamab (JNJ-64007957, Janssen) — an off-the-shelf, bispecific IgG4 antibody that binds B-cell maturation antigen (BCMA) and CD3 to redirect T cells to multiple myeloma cells — induced durable, deepening responses, results showed. The agent also appeared well-tolerated.
The efficacy of teclistamab is not surprising given the benefits observed with BCMA-targeting chimeric antigen receptor T-cell therapy, according to researcher Amrita Y. Krishnan, MD, director of Judy and Bernard Briskin Center for Multiple Myeloma Research and chief of the division of multiple myeloma at City of Hope.
“[That] shows us that targeting BCMA is a very effective strategy in myeloma, especially when there is concomitant immune activation,” Krishnan told Healio. “The durability of response is also not surprising as we know that loss of target is a rare reason for BCMA CAR-T failure.
“If we are continuing to engage the target with an active drug, we can see continued response,” Krishnan added. “One would assume this is also in part due to the continued T-cell activation.”
New therapies for multiple myeloma have helped extend survival; however, many patients still relapse and require additional treatment.
“There is still an unmet need for new therapies for patients with relapsed myeloma, especially those who are progressing after immunomodulatory drugs, proteasome inhibitors and anti-CD38 antibodies,” Krishnan said. “New targets and new mechanisms of action are needed.”
Krishnan and colleagues conducted a first-in-human phase 1 study to assess teclistamab for patients who had relapsed or refractory multiple myeloma or were intolerant to established therapies.
Identification of the recommended phase 2 dose served as the primary objective of the first part of the study.
Characterization of safety and tolerability at the recommended phase 2 dose served as the primary objective of the study’s second part. Researchers also assessed antitumor activity, pharmacokinetics and pharmacodynamics.
Patients received teclistamab in one of three dose ranges: 0.3–19.2 µg/kg biweekly via IV, 19.2-720 µg/kg weekly via IV, or 80–3000 µg/kg weekly via subcutaneous administration. Researchers followed step-up dosing for doses of 38.4 µg/kg or higher. They assessed response via International Myeloma Working Group criteria and graded adverse events by Common Terminology Criteria for Adverse Events version 4.03.
As of March, 157 patients had received teclistamab (IV, n = 84; subcutaneous, n = 73).
Forty patients (median age, 62.5 years; range, 39-84; 65% men) received the recommended phase 2 dose of 1,500 µg/kg weekly via subcutaneous administration, with 60 µg/kg and 300 µg/kg step-up doses to mitigate the risk for severe cytokine release syndrome (CRS). Median time since diagnosis was 5.7 years (range, 0.8-17.4) and patients had received a median five (range, 2-11) prior lines of therapy.
All patients were triple-class exposed (proteasome inhibitor, immunomodulatory drug and CD38 antibody) and 83% were triple-class refractory; 65% were penta-drug exposed (two proteasome inhibitors, two immuno-modulatory drugs and a CD38 antibody) and 38% were penta-drug refractory; and 83% were refractory to their last line of therapy.
Median follow-up for this group was more than 6 months.
Researchers reported no dose-limiting toxicities at the recommended phase 2 dose. The most common adverse events at this dose were CRS (all grade, 70%; grade 3/grade 4, 0%), neutropenia (all grade, 65%; grade 3/grade 4, 40%), anemia (all grade, 50%; grade 3/grade 4, 28%), thrombocytopenia (all grade, 45%; grade 3/grade 4, 20%) and leukopenia (all grade, 33%; grade 3/grade 4, 18%).
“This is not surprising given these patients were heavily pretreated,” Krishnan said during a presentation. “In the subset of patients who experienced grade 3 or grade 4 cytopenias, the onset generally was confined to the step-up dosing in cycles 1 and 2.”
Median time to CRS onset was 2 days (range, 1-6) and median duration was 2 days (range, 1-8). Supportive measures included tocilizumab [Actemra, Genentech (35%)], steroids (13%) and low-flow oxygen by nasal cannula (8%).
Nearly half of patients who received the recommended phase 2 dose developed infections (all grade, 45%; grade 3/grade 4, 23%).
Other nonhematologic adverse events included fatigue (all grade, 38%; grade 3/grade 4, 3%), nausea (all grade, 33%), injection site erythema (all grade, 33%) and diarrhea (all grade, 23%; grade 3/grade 4, 5%).
One patient (3%) developed grade 1 neurotoxicity that resolved without intervention.
Two patients who received subcutaneous teclistamab — neither of whom received the recommended phase 2 dose — died due to adverse events unrelated to the therapy. One died of general health deterioration and the other died of sepsis.
“The safety profile was very encouraging [with regard] to low rates of high-grade cytokine release syndrome when the drug was given with increased dosing,” Krishnan told Healio.
Median follow-up for patients who received the recommended phase 2 dose was 6.1 months (range, 1.2-12.2).
Twenty-six patients (65%) responded. More than half (58%) achieved a very good partial response or better, and 40% achieved a complete response or better.
Median time to first confirmed response was 1 month (range, 0.2-3.1), and the ORR among triple class-refractory patients was 61%.
Median duration of response had not been reached but 22 of 26 patients (85%) who responded to the recommended phase 2 dose remained alive and on treatment at data cutoff. Their responses deepened over time.
All six evaluable patients who received the recommended phase 2 dose achieved minimal residual disease negativity at sensitivity of 10-6 (n = 5) or 10-5 (n = 1).
The results support additional study of teclistamab as monotherapy and in combination with other agents, Krishnan and colleagues concluded.
“This agent has the potential for use in combination in early relapses, and even potentially as post-transplant consolidation or in combination in newly diagnosed patients,” Krishnan told Healio. “Immunomodulatory drugs would be an attractive combination with the bispecifics.”
Given the extended exposure profile at the recommended phase 2 dose, as well as delayed and low-grade CRS observed with subcutaneous administration, investigators are exploring alternative subcutaneous dosing strategies, Krishnan said.
Perspective
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There has been excitement for years about BCMA as a possible target, because it looks like it is exclusively on the malignant plasma cells and does not have broad off-target expression.
The FDA approved the first BCMA-targeted chimeric antigen receptor (CAR) T-cell therapy earlier this year. Now, especially in multiple myeloma — when many patients are older and have several comorbidities — the question becomes whether an antibody therapeutic can be as effective or almost effective as CAR T-cell therapy. Will it be safer, easier to use and less complex?
This abstract by Krishnan and colleagues is the first report that helps us begin to understand that. Researchers observed some very solid responses among heavily pretreated patients. This clearly was a poor-prognosis population, so the fact that more than 50% achieved very good partial response or better is quite promising.
Much like CAR-T, we’ll need to look at how long the benefit lasts. We’ll also need to see a comparison of the pluses and minuses of bispecific vs. the single infusion of CAR-T. It’s too early to say but, in this study, some patients achieved minimal residual disease negativity and responses were maintained, so there is some hope that this might be an alternative option. The question will be: How do we decide which population to treat with which approach?
Factors will include cost and where the patient is located. CAR-T certainly cannot be done in every hospital, but many of the patients in the MajesTEC-1 trial received treatment as an outpatient regimen. Seventy percent of patients developed CRS but it appeared manageable, so this may be an option that can be given at many more centers.
There are still many questions, including the potential use of this therapy in combination with other agents, and also whether it should be given earlier in the disease course. Like many other therapies, it may work better for patients who don’t have such heavily pretreated disease.
Another issue is mode of administration. The Leukemia & Lymphoma Society has spent considerable time advocating in several states for parity of reimbursement for different modes of administration of the same drug so physicians and hospitals don’t give it in one particular way — even if it’s not convenient for patients — simply because it is the easiest way to get reimbursed.
I’m interested to see whether it will prove too difficult to continue subcutaneous administration or whether researchers will pursue alternative dosing regimens to try to optimize it, because the benefits of subcutaneous administration for patients are considerable.
Despite these questions, these are exciting results. They confirm what we had hoped — BCMA is going to be a good target in multiple myeloma — and there are other options for patients who are not candidates for CAR-T.
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Krishnan AY, et al. Abstract 8007. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
