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MajesTEC-2: Future of BCMA-targeted Bispecific, Gamma Secretase Inhibitor Combo in Question

July 13, 2023

Mid-July 2023

Brandon May

Leah Lawrence is a freelance health writer and editor based in Delaware.

The combination of teclistamab and the gamma-​secretase inhibitor (GSI) nirogacestat resulted in high and deep response rates in patients with relapsed or refractory multiple myeloma (R/R MM), according to data from the phase Ib MajesTEC-2 study presented at the European Hematology Association (EHA) 2023 Congress on June 10.1

However, the clinical profile of this combination seen in the study “suggests careful evaluation is warranted when combining BCMA-targeted bispecific therapies with a GSI,” said presenter Jeffrey Matous, MD, of Colorado Blood Cancer Institute and Sarah Cannon Research Institute in Denver.

GSIs have been previously shown to increase cell surface density of membrane-bound BCMA and reduce soluble BCMA, and preclinical evidence suggests that they may enhance the activity of BCMA-targeted therapies.2

The MajesTEC-2 trial was designed to explore whether adding nirogacestat enhanced the clinical activity of teclistamab. The study enrolled 28 patients with R/R MM who had received at least three prior lines of therapy or were double refractory to a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) and triple exposed to a PI, an IMiD, and an anti-CD38 antibody with progressive disease within 12 months of their last therapy.

Three dose levels were tested: teclistamab 720 µg/kg weekly plus concurrent nirogacestat 100 mg twice daily starting with first dose of teclistamab (eight patients), teclistamab 720 µg/kg weekly plus once daily delayed low-dose nirogacestat (100 mg once daily starting after teclistamab step-up dosing; seven patients), and teclistamab 1,500 µg/kg weekly plus daily delayed low-dose nirogacestat (13 patients).

The median number of prior lines of therapy was four. One-fifth of patients had high-risk cytogenetics; 71% were triple-class refractory, and 93% were refractory to the last line of therapy.

The overall response rate was 74%, with 52% of patients achieving complete response. All responses were very good partial response or better. Median duration of response is not yet reached. Of those patients who did respond, 87.2% maintained response 12 months or longer.

Dr. Matous discussed the safety profile of the combination. There was an improved safety profile seen with delayed versus concurrent use of nirogacestat plus teclistamab. At dose level one with concurrent treatment, there were three dose-​limiting toxicities in two patients, including a grade 3 immune effector cell-associated neurotoxicity syndrome (ICANS). No dose-limiting toxicities or grade 3 cytokine release syndrome (CRS) occurred at dose level two or three with delayed-start, reduced-dose nirogacestat.

There were five grade 5 treatment-emergent adverse events: sepsis, septic shock, COVID-19, cardiac arrest, and Pneumocystis jirovecii pneumonia.

The rates of grade 3-4 hematologic adverse events (AEs) were generally low, with only one discontinuation due to neutropenia and one case of febrile neutropenia occurring at all dose levels.

Common non-hematologic AEs were CRS, diarrhea, injection-site erythema, decreased appetite, and fatigue. Grade 3 diarrhea occurred in 25% of patients. Two ICANS events occurred. The majority of patients (75%) experienced CRS, but only one patient had grade 3 CRS. There were no dose-limiting toxicities due to the injection, with only one discontinuation of teclistamab because of infection. However, there were four infection-related deaths.

After the presentation, Luciano Costa, MD, of the University of Alabama at Birmingham, a coauthor on the study, asked from the audience, “Do you really think there is a future for GSIs to potentiate BCMA-directed therapy?”

Dr. Matous replied that he is not sure where to go with GSIs. “It is hard to show any impact of GSI on soluble BCMA, and it is unclear what the effect of that will be clinically in a real-world population,” he said. “When I think of other combinations with bispecifics, others appear more attractive to me. I am not sure where the future of GSIs is going in terms of T-cell directed therapies.”

Any conflicts of interest declared by the authors can be found in the original abstract.

Reference

  1. Offner F, Decaux O, Hulin C, et al. Teclistamab (tec) + nirogacestat (niro) in relapsed/refractory multiple myeloma (RRMM): the phase 1b MajesTEC-2 study. Abstract S194. Presented at the European Hematology Association (EHA) 2023 Congress; June 10, 2023; Frankfurt, Germany.
  2. Pont MJ, Hill T, Cole GO, et al. γ-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma. Blood. 2019;134(19):1585-1597.

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