In the phase 1/2 CA057-003 study, three novel mezigdomide-based triplet therapies appeared to be tolerated. They were associated with anti-tumor 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 therapies1. 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,” emphasized Luciano Costa, MD, PhD, from the University of Alabama at Birmingham.
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 AE [occuring in 50–80% of the participants], which was manageable through 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-hematologic treatment-emergent AEs were uncommon,” said Prof. Costa.
The overall response rate (ORR) was 50.0% with the tazemetostat triplet therapy, reaching 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.
Medical writing support was provided by Robert van den Heuvel.
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