Emerging mezigdomide-based options for heavily pre-treated MM

Three novel mezigdomide-based triplet therapies appeared to be tolerated and were associated with anti-tumour activity in a population of patients with relapsed or refractory multiple myeloma who were not suitable to receive available therapies.

The phase 1/2 CA057-003 study (NCT05372354) assessed various all-oral triplet therapies for patients with relapsed or refractory MM who were not suitable to receive available therapies [1]. Mezigdomide, an oral cereblon E3 ligase modulator (CELMoD), plus dexamethasone was the backbone of all treatments. This backbone was combined with either the EZH2 inhibitor tazemetostat (n=16), the BET inhibitor BMS-986158 (n=20), or the MEK inhibitor trametinib (n=20). The primary outcomes were safety, tolerability, and determining the recommended phase 2 dose. “Over a third of the enrolled participants had extramedullary disease and most were triple-class refractory,” emphasised Prof. Luciano Costa (University of Alabama at Birmingham, AL, USA).

The CA057-003 study did not reveal new safety signals for the investigated agents. According to Prof. Costa, all combinations and dose levels were tolerated, except for the highest dose level of the BMS-986158 triplet combination. “Overall, neutropenia was the most common grade 3 or 4 adverse event [occuring in 50–80% of the participants], which was manageable trough dose interruptions or dose reductions,” said Prof. Costa. The grade 3 or 4 infection rate was between 15% and 25%. “Other grade 3 or 4 non-haematologic treatment-emergent adverse events were uncommon,” said Prof. Costa.

The overall response rate (ORR) was 50.0% with the tazemetostat triplet therapy, reaching up to 60.0% at the highest dose level. Prof. Costa and colleagues reported an ORR of 35.0% in the BMS-986158 triplet therapy cohort. The highest ORR was observed in the trametinib triplet therapy cohort (75%). “Higher dose levels may lead to even higher response rates,” Prof. Costa noted.

“All combinations showed promising efficacy in this population of heavily pre-treated patients with relapsed or refractory MM, providing a rationale for further investigation of these triplet therapies,” concluded Prof. Costa.

1. Costa LJ, et al. Mezigdomide in novel-novel combinations for relapsed/refractory multiple myeloma: preliminary results from the CA057-003 trial. Abstract 677, 66^th ASH Annual Meeting, 7–10 December 2024, San Diego, CA, USA.

Medical writing support was provided by Robert van den Heuvel.

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Posted on 11 December 202411 December 2024