Background: Mezigdomide (MEZI), a novel oral cereblon E3 ligase modulator(CELMoD), induces maximal degradation of Ikaros/Aiolos leading to increased MM cell apoptosis and immune-stimulatory effects. MeziKd has shown potent synergistic antiproliferative activity in MM cell lines resistant to lenalidomide (LEN), and in a phase 1/2 study showed promising preliminary efficacy and safety in RRMM. The SUCCESSOR-2 phase 3 trial (NCT05552976) will compare the efficacy and safety of MeziKd vs Kd in patients (pts) with RRMM. Methods: This multicenter, open-label study comprises 2 stages. In Stage 1, ≥ 128 pts will be randomized 3:3:3:2 to 1 of 3 MEZI doses (1.0, 0.6, or 0.3 mg) + Kd, or to the Kd arm to select the optimal MEZI dose in combination with Kd for Stage 2. In Stage 2, ≈ 397 additional pts will be randomized 3:2 to MeziKd at the selected MEZI dose or to Kd, for efficacy and safety analyses (Stage 1 pts in the selected MeziKd dose cohort and Kd arm will also be included in these analyses). Pts will be stratified by age (≤ 70 vs > 70 y), number of prior lines of treatment (Tx; ≤ 2 vs > 2), and ISS stage at screening (I vs II vs III). MEZI dose selection will be based on Stage 1 efficacy, safety, pharmacokinetic and pharmacodynamic data, and exposure–response analyses. Primary efficacy endpoint is progression-free survival (PFS). Assuming a decrease in PFS risk by 33.3% (HR = 0.667) with MeziKd, under exponential distribution assumption of PFS (1-sided α = 0.025) and adjusted for 3 interim analyses, ≥ 273 PFS events will have ≈ 89% power to detect improvement in Tx effect. The planned interim analyses are for: MEZI dose selection at end of Stage 1, and to examine PFS futility and superiority when ≈ 82 (30%) and ≈ 205 (75%) events, respectively, have been accumulated. Secondary endpoints include determination of the recommended MEZI dose plus Kd (Stage 1 only), and assessment of overall survival, overall response rate, time to response, duration of response, time to progression, safety, and quality of life. MeziKd arm Tx consists of 28-day (D) cycles (C) with MEZI on D1–21; 20 mg/m² intravenous (IV) carfilzomib (CFZ) on D1 of C1, then 56 mg/m² on D8 and 15 of C1, on D1, 8, and 15 of C2–12, and on D1 and 15 of ≥ C13; and 40 mg oral/IV DEX (20 mg optional in certain pt groups) on D1, 8, 15, and 22. Tx in the Kd arm consists of 28-D cycles with 20 mg/m² IV CFZ on D1 and 2 of C1, then 56 mg/m² on D8, 9, 15, and 16 of C1, and on D1, 2, 8, 9, 15, and 16 of ≥ C2; and 20 mg oral/IV DEX (10 mg optional in certain pt groups) on D1, 2, 8, 9, 15, 16, 22, and 23. Tx will continue until progressive disease (PD) or unacceptable toxicity. Key eligibility criteria include age ≥ 18 y, ≥ 1 prior line of anti-MM Tx including LEN and an anti-CD38 monoclonal antibody, minimal response or better to ≥ 1 prior Tx, documented PD during or after last regimen, and no prior CFZ Tx. Enrollment began in October 2022 and is ongoing. Clinical trial information: NCT05552976.