OA-49: Mezigdomide (MEZI) plus dexamethasone (DEX) and bortezomib (BORT) or carfilzomib (CFZ) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): results from the CC-92480-MM-002 trial

Introduction: MEZI is a novel, potent oral cereblon E3 ligase modulator (CELMoD™) with enhanced antimyeloma effects compared with immunomodulatory drugs (IMiDs®). In the phase 1/2 CC-92480-MM-002 trial (NCT03989414), MEZI showed promising efficacy and safety with DEX+BORT (MeziVd) and DEX+CFZ (MeziKd) in pts with RRMM. In phase 1, a 1.0mg dose plus BORT+DEX (MeziVd-1.0mg) was selected for further investigation. Here we report updated results from the MeziVd and MeziKd dose-escalation cohorts and the MeziVd-1.0mg dose-expansion cohort.

Methods: Key eligibility criteria were: RRMM, 2–4 (MeziVd and MeziKd cohorts) or 1–3 (MeziVd-1.0mg cohort) prior regimens including lenalidomide (LEN), and documented progressive disease during or after last myeloma therapy. MEZI was given at escalating doses (0.3, 0.6, 1.0mg) or at 1.0mg on days (D)1–14 of each 21-D cycle with BORT+DEX, or at escalating doses on D1–21 of each 28-D cycle with CFZ+DEX. Primary objectives were to determine the recommended dose and regimen (dose-escalation cohorts) and to evaluate safety and efficacy.

Results: As of March 20, 2023, 28 pts received MeziVd, 38 MeziVd-1.0mg, and 27 MeziKd. Across all cohorts, 65.8–88.9% pts were IMiD agent–refractory, 18.4–51.9% pts were proteasome inhibitor (PI)–refractory, and 36.8–74.1% pts were anti-CD38 monoclonal antibody (mAb)–refractory; median follow-up was 10.8–13.2 months.
The most frequent grade 3‒4 treatment-emergent adverse events (TEAEs) were neutropenia (35.7%) and thrombocytopenia (21.4%) with MeziVd; neutropenia (57.9%) and all infections (34.2%) with MeziVd-1.0mg; and neutropenia (40.7%) and all infections (29.6%) with MeziKd. Excluding all infections, grade 3–4 non-hematologic TEAEs were low. MEZI dose reductions due to TEAEs were needed in 7 (25.0%), 15 (39.5%), and 7 (25.9%) pts with MeziVd, MeziVd-1.0mg, and MeziKd, respectively.
Overall response rate (ORR) was 75.0% with MeziVd (21/28); 84.2% with MeziVd-1.0mg (32/38); and 85.2% with MeziKd (23/27). In the MeziVd-1.0mg cohort, 2 pts were minimal residual disease–negative (10-4 threshold). In pts with prior LEN and anti-CD38 mAb exposure, ORR was 71.4% (10/14; MeziVd), 85.7% (12/14; MeziVd-1.0mg), and 86.4% (19/22; MeziKd). Median time to response was 1.38 (0.7–3.3), 0.89 (0.7–2.4), and 0.95 (0.9–5.1) months in the MeziVd, MeziVd-1.0mg, and MeziKd cohorts, respectively. Median duration of response was 10.4 and 11.9 months in the MeziVd and MeziKd cohorts and not reached in the MeziVd-1.0mg cohort.
MEZI showed pharmacodynamic activity with BORT or CFZ at all doses tested, with 1.0mg inducing the greatest substrate degradation and T-cell proliferation.

Conclusions: With longer follow-up, MeziVd and MeziKd continued to show promising efficacy at all dose levels tested with a manageable safety profile in pts with RRMM, consistent with previous reports. Dose optimization of MEZI+DEX in combination with PIs continues to be explored, and these data support further exploration in phase 3 studies.