Mezigdomide, carfilzomib, and dexamethasone (MeziKd) vs carfilzomib and dexamethasone (Kd) in relapsed/refractory multiple myeloma (RRMM): Results from the phase 3 SUCCESSOR-2 trial.

LBA7506 Background: A growing number of patients (pts) entering second-line treatment (tx) are anti-CD38 monoclonal antibody (mAb)- and lenalidomide (LEN)-exposed, limiting tx options. Mezigdomide (Mezi), a potent oral CELMoD, induces maximal, rapid Ikaros/Aiolos degradation leading to enhanced MM cell death and immune stimulation vs IMiDs. We report initial results from SUCCESSOR-2 (NCT05552976), the first randomized phase 3 study of Mezi in RRMM, evaluating MeziKd vs Kd. Methods: In this phase 3, 2-stage, inferentially seamless trial, eligible adult pts had ≥1 prior line of therapy (LOT) including an anti-CD38 mAb and LEN. Pts were randomized 3:3:3:2 (Mezi 0.3, 0.6, 1.0 mg + Kd, or Kd) to identify the optimal Mezi dose in stage 1, and 3:2 to compare efficacy and safety of MeziKd vs Kd in stage 2. MeziKd was given in 28-day (D) cycles of Mezi (D1–21), 56 mg/m 2 carfilzomib (CFZ) weekly (QW), and 40 mg dexamethasone (DEX) QW. The Kd arm received CFZ 56 mg/m 2 twice weekly or 70 mg/m 2 QW + DEX. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, selected Mezi dose (stage 1), overall response rate (ORR), and safety. Results: The Mezi dose selected for stage 2 was 1.0 mg. In total, 479 pts (288 MeziKd at 1.0 mg Mezi; 191 Kd) were included in the analysis. Median (range) age was 68 (30–85) y with 25.1% of pts ≥75 y; median (range) number of prior LOTs was 2 (1–9); 92.1% of pts were triple-class-exposed, with 85.8% refractory to an anti-CD38 mAb and 75.8% to LEN; 37.2% were exposed to pomalidomide and 7.3% to anti-BCMA tx. At data cutoff, median follow-up was 10.6 mo with 52.4% (MeziKd) and 31.4% (Kd) of pts still on tx. Median tx duration was 8.9 (up to 32.1) mo for MeziKd vs 6.2 (up to 25.0) for Kd. MeziKd significantly improved PFS vs Kd (median [95% CI], 18.0 [14.5–22.1] vs 8.3 [5.6–10.7] mo; HR, 0.48 [95% CI, 0.36–0.63]; P <0.0001), which was consistent across subgroups, including pts with >2 prior LOTs, prior tx exposure/refractoriness, high-risk cytogenetics, extramedullary disease, and age ≥75 y. Higher ORR (80.2% vs 53.4%) and complete response or better (26.7% vs 8.9%) were seen with MeziKd. Deaths were reported in 21.5% (MeziKd) vs 26.7% (Kd) of pts, mostly due to progressive disease. Grade (Gr) 3–4 treatment-emergent adverse events were seen in 83.7% vs 56.5% of pts, neutropenia in 61.1% vs 9.1%, and infections in 34.0% vs 15.6% with MeziKd and Kd, respectively; Gr 5 infections in this high-risk population were few (2.4 vs 1.1%). Conclusions: MeziKd showed a clinically meaningful PFS benefit as early as first relapse in predominantly triple-class-exposed, anti-CD38 mAb- and LEN-refractory pts, a population with significant unmet need. These data support Mezi, a potent oral tx with a predictable and manageable safety profile, as a readily accessible, potential new standard of care for RRMM across multiple settings. Clinical trial information: NCT05552976 .