Can we combine teclistamab and nirogacestat for the treatment of RRMM?

High and deep response rates were observed for the combination of teclistamab and nirogacestat in patients with relapsed/refractory multiple myeloma (RRMM). Although the safety profile improved with delayed administration of lower-dose nirogacestat, evaluation is warranted when combining B-cell maturation antigen (BCMA)-targeted bispecific treatments with a gamma-secretase inhibitor.

Dr Jeffrey Matous (Colorado Blood Cancer Institute, Colorado, USA) presented the results from one arm of the phase 1b MajesTEC-2 trial (NCT04722146), evaluating the combination of teclistamab and nirogacestat in participants with RRMM [1]. Teclistamab is a bispecific antibody, targeting the B-cell maturation antigen and CD3 (approved for the treatment of triple-class exposed RRMM), and nirogacestat is an investigational gamma-secretase inhibitor. The 28 participants were assigned to one of three dose levels:

• teclistamab 0.72 mg/kg, every week plus 100 mg nirogacestat, twice daily (n=8)
• teclistamab 0.72 mg/kg, every week plus 100 mg nirogacestat, once daily (n=7)
• teclistamab 1.5 mg/kg, every week plus 100 mg nirogacestat, once daily (n=13)

The overall response rate was 74.1%, with a complete or stringent complete response rate of 51.9%. The time-to-first-response was 1.18 months and 87.2% of the participants maintained a response after 12 months of follow-up.

At low-dose teclistamab plus nirogacestat, twice daily, 3 dose-limiting toxicities were reported for 2 participants: one participant experienced grade 3 gastrointestinal bleeding plus grade 3 diarrhoea and another participant had grade 3 immune effector cell-associated neurotoxicity syndrome (ICANS). At the other two dose levels, no dose-limiting toxicities were observed. Dr Matous mentioned that there were 5 grade 5 events: sepsis, septic shock, COVID-19, cardiac arrest, and pneumonia. After a median follow-up of 14.7 months, 60.7% of all participants had discontinued nirogacestat due to adverse events (AEs). Teclistamab was discontinued by 7% of the participants due to AEs. Furthermore, grade 3 or 4 neutropenia was seen in 75% of the participants. The most common non-haematologic AEs were cytokine-release syndrome (75.0%), diarrhoea (64.3%), injection site erythema (53.6%), and decreased appetite (50.0%). “The rates of grade 3 or 4 AEs were relatively low, except for diarrhoea and pneumonia, which occurred in 25% and 21% of the participants, respectively,” added Dr Matous.

1. Offner F, et al. Teclistamab + nirogacestat in relapsed/refractory multiple myeloma: the phase 1b MajesTEC-2 study. MM clinical: new combinations and novel targets, EHA 2023 Annual Congress, 8─11 June, Frankfurt, Germany.

 

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Posted on 2 August 202318 March 2024