Mezigdomide (MEZI) Plus Dexamethasone (DEX) and Bortezomib (BORT) or Carfilzomib (CFZ) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Updated Results from the CC-92480-MM-002 Trial

Introduction: MEZI is a novel, potent, oral CELMoD™ agent with enhanced tumoricidal and immune-stimulatory effects compared with immunomodulatory drugs (IMiDs®). Preclinically, MEZI has shown marked synergy with DEX and other antimyeloma therapies, including proteasome inhibitors (PIs). In the phase 1/2 CC-92480-MM-002 trial (NCT03989414), MEZI combined with DEX and BORT (MeziVd) or DEX and CFZ (MeziKd) showed meaningful clinical activity and manageable tolerability in pts with RRMM. Here we report updated results with longer follow-up from the MeziVd and MeziKd dose-escalation cohorts (A and C) and the MeziVd dose-expansion cohort (D). Methods: Eligible pts had RRMM, 2-4 (Cohorts A and C) or 1-3 (Cohort D) prior regimens including lenalidomide, and documented progressive disease (PD) during or after the last myeloma therapy. Oral MEZI was given at escalating doses of 0.3, 0.6, or 1.0 mg (Cohort A) or at 0.6 or 1.0 mg (Cohort D) on days (D)1-14 of each 21-D cycle with BORT + DEX, or at escalating doses (0.3, 0.6, or 1.0 mg) on D1-21 of each 28-D cycle with CFZ + DEX (Cohort C). Pharmacokinetics samples were collected on D1 and D8 of cycle (C)1 and D8 of C2-8, and also on C1D11 for Cohorts A and D. Biomarker analyses included peripheral blood samples collected on C1D1 to mid-C3 for substrate degradation and immunomodulation by flow cytometry. The primary objectives were to determine the recommended dose and regimen (dose-escalation cohorts) and evaluate safety and efficacy. Results: As of May 9, 2024, 104 pts were enrolled in Cohorts A, C, and D; 28 pts received MeziVd (Cohort A) and 27 pts received MeziKd (Cohort C) in the dose-escalation cohorts. Median (range) age was 65.5 (46-86) and 68 (41-76) years (y), median time since diagnosis was 4.8 (1.9-17.1) and 5.4 (0.7-15.7) y, median number of prior regimens was 3 (2-4) and 2 (2-4), 24 (85.7%) and 24 (88.9%) pts were refractory to IMiD agents, and 14 (50.0%) and 14 (51.9%) to PIs, respectively. Median follow-up was 13.6 (MeziVd) and 15.2 months (mo) (MeziKd); 3 (10.7%) and 5 (18.5%) pts continue on treatment, with 12.5 and 12 median cycles received, and PD being the main reason for discontinuation (64.3% and 48.1%), respectively. In the dose-escalation cohorts, the most common grade 3/4 treatment-emergent adverse events (TEAEs) were neutropenia (35.7%), thrombocytopenia (21.4%), and infections (17.9%) with MeziVd; and neutropenia (44.4%) and infections (33.3%) with MeziKd. Grade 3/4 non-hematologic TEAEs, including rash and diarrhea, were low or absent. MEZI dose reductions due to TEAEs were needed in 7 (25.0%) and 8 (29.6%) pts. The overall response rate (ORR) was 75.0% (21/28 pts) and 85.2% (23/27 pts), with ≥ very good partial responses (VGPR) in 39.3% and 44.4% pts. Median (95% CI) duration of response (DOR) was 10.9 (8.1-18.7) and 11.9 (6.4-NA) mo and median (95% CI) progression-free survival (PFS) was 11.8 (9.0-18.0) and 13.5 (8.4-19.7) mo, respectively. As of May 9, 2024, 49 pts received MeziVd in the Cohort D dose-expansion cohort. Median age was 64 (43-83) y, median time since diagnosis was 4.2 (0.9-20.5) y, and median number of prior regimens was 1 (1-3). Overall, 31 (63.3%) pts were refractory to IMiD agents, and 8 (16.3%) to PIs. Median follow-up was 18.3 mo; 9 (18.4%) pts continue on treatment, with 15 median cycles received. Discontinuations were mainly due to PD (53.1%). The most common grade 3/4 TEAEs were neutropenia (63.3%), infections (32.7%), and thrombocytopenia (26.5%); grade 3/4 non-hematologic TEAEs remained low or absent. MEZI dose reductions due to TEAEs were needed in 18 (36.7%) pts. ORR was 85.7% (42/49 pts) with ≥ VGPR in 63.3% of pts; median DOR was 19.4 (9.7-NA) mo, median PFS was 17.5 (9.4-24.0) mo. MEZI exposure increased in a dose-linear manner over the dose range, and exposures were similar when comparing pts treated with MeziVd and MeziKd. MEZI showed pharmacodynamic activity with BORT or CFZ across all doses tested, with 1.0 mg MEZI inducing the greatest pharmacodynamic effects including substrate degradation and T-cell proliferation, supporting the use of 1.0 mg MEZI in combination with PIs. Conclusions: With longer follow-up, MeziVd and MeziKd in RRMM confirmed promising efficacy and a manageable safety profile at all dose levels tested, with no cumulative toxicity and low grade 3/4 non-hematologic TEAEs (including rash and diarrhea). These results informed ongoing and planned phase 3 trials. Updated data will be presented at the meeting.

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