Background and Significance:Most patients with multiple myeloma (MM) will eventually experience relapse, resulting in poor prognosis. There thus remains an unmet need for novel treatment options to improve outcomes for patients with relapsed/refractory MM (RRMM). Mezigdomide (MEZI) is an oral CELMoD™ agent that induces enhanced degradation of Ikaros/Aiolos, leading to increased MM cell apoptosis and immunostimulatory effects, with potential to improve the efficacy of T-cell engagers (TCEs). Elranatamab (ELRA) is a B-cell maturation antigen (BCMA)-directed CD3 TCE approved in the USA for the treatment of patients with RRMM. The CA057-1040 study aims to determine the recommended dose and schedule and evaluate the safety and preliminary efficacy of MEZI plus ELRA in patients with RRMM.

Study Design and Methods: This multicenter, worldwide, open-label, phase 1b/2a study (NCT06988488) consists of 2 parts: phase 1 (dose escalation) will evaluate the safety and tolerability of increasing doses of MEZI in combination with ELRA to establish the recommended phase 2 doses (R2PDs) for dose expansion; phase 2 (dose expansion) will further evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD), and preliminary efficacy of MEZI plus ELRA at 2 preliminary R2PDs to establish the final R2PD. Eligible patients are ≥18 years of age and have a history of RRMM with documented disease progression and measurable disease. Patients in the USA must have received 2–4 prior lines of anti-myeloma therapy including an immunomodulatory drug (IMiD®) agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. In phase 1, patients will be assigned to dose-level cohorts and receive MEZI administered orally once daily on days 1–21 of 28-day cycles, plus ELRA 76 mg administered subcutaneously starting every 2 weeks. Prior to initiation of the combination treatment, patients will receive ELRA in a 14-day priming dose regimen (12 mg on day 1, 32 mg on day 4, and 76 mg on day 8 of cycle 0). Patients will be observed for dose-limiting toxicities (DLTs; defined as specific adverse events [AEs] excluding those related to disease progression or intercurrent illness) during days 1–28 of cycle 1. Two tolerated dose levels from phase 1 at or below the maximum tolerated dose will be recommended for selection by the Safety Review Committee as preliminary RP2Ds. In phase 2, patients will be randomized 1:1 to receive MEZI plus ELRA at 1 of the 2 preliminary RP2Ds. Each phase 2 arm will enroll approximately 22 patients, and randomization will be stratified by number of prior lines of therapy (1 vs 2 or 3). Patients will continue study treatment in 28-day cycles for up to 5 years or until progressive disease, unacceptable toxicity, withdrawal of consent, or other reason for treatment discontinuation. Following phase 2, a single dose level will be determined as the final RP2D based on the cumulative safety, PK, PD, and preliminary efficacy data. The primary endpoints are the incidences of AEs, serious AEs, AEs leading to discontinuation and deaths, and DLTs; secondary endpoints include response rate (including overall response rate, complete response rate, and very good partial response rate), time to response, duration of response, progression-free survival, and overall survival. Details of statistical analysis will be finalized and reported with the statistical analysis plan. Enrollment is targeted to begin in the 3rd quarter of 2025.

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2025
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