Mezigdomide (MEZI) in Novel-Novel Combinations for Relapsed or Refractory Multiple Myeloma (RRMM): Preliminary Results from the CA057-003 Trial
Results: As of May 8, 2024, 14 pts received MEZId + TAZ, 16 MEZId + BMS-986158, and 15 MEZId + TRAM. Across all cohorts, median (range) age was 63 (37–83) y and median time since initial diagnosis was 7.5 (2.0–18.4) y. Eight (18%) pts were Black/African American, 35 (78%) White, and race was not collected/unknown (NA) in 2 (4%); 6 (13%) were Hispanic/Latino and 36 (80%) were not (NA = 3 [7%] pts); 56% were in the United States. Extramedullary plasmacytomas were present in 16 (36%) pts. The median number of prior antimyeloma regimens was 5 (2–20). Prior therapies included autologous stem cell transplantation (78%), IMiD agents (100%), proteasome inhibitors (PIs; 100%), anti-CD38 monoclonal antibodies (mAbs; 100%), and T cell-redirecting therapy (58%); 82% had triple-class refractory disease (to an IMiD agent, PI, and anti-CD38 mAb).
At data cutoff, 7 (50%) pts continued on treatment in the MEZId + TAZ cohort, 8 (50%) in the MEZId + BMS-986158 cohort, and 10 (67%) in the MEZId + TRAM cohort. The main reason for discontinuation in all 3 cohorts was PD. Median follow-up was 4.1 (1.0–11.0) mo (MEZId + TAZ), 2.9 (1.0–6.5) mo (MEZId + BMS-986158), and 3.6 (0–10.6) mo (MEZId + TRAM).
The most frequent grade (Gr) 3/4 treatment-emergent adverse event (TEAE) across all 3 cohorts was neutropenia (43–73%); Gr 3/4 non-hematologic TEAEs were low or absent. Three pts had dose-limiting toxicities (1 with 0.3 mg MEZId + BMS-986158, 1 with 1.0 mg MEZId + BMS-986158, and 1 with 1.0 mg MEZId + TRAM).
In the efficacy-evaluable population, overall response rate (≥ partial response [PR]) was 54% (7/13 pts) with MEZId + TAZ; 36% (5/14) with MEZId + BMS-986158; and 92% (11/12) with MEZId + TRAM. In the MEZId + TAZ and MEZId + BMS-986158 cohorts, deeper responses (≥ very good PR), including 1 stringent complete response (sCR) with MEZId + TAZ, were observed with 1.0 mg MEZI, and in the MEZId + TRAM cohort with ≥0.6 mg MEZI (including 1 sCR), and 100% (5/5 pts) at 1.0 mg MEZI were ongoing responses with this combination.
Exposures increased in a dose-linear manner over the dose range and were consistent across treatment cohorts, demonstrating no drug-drug interaction between MEZI and novel therapeutic agents. MEZI remained pharmacodynamically active, inducing Ikaros/Aiolos degradation and B-cell reduction with all combination agents at all dose levels, with the greatest effect observed at MEZI 1.0 mg.
Conclusions: MEZId combined with the novel therapeutic agents TAZ, BMS-986158, or TRAM showed promising efficacy and a manageable safety profile in patients with RRMM. No new safety signals were identified, with neutropenia being the most common Gr 3/4 TEAE in all 3 cohorts. These results provide a rationale for further exploration of these novel all-oral combinations. Accrual continues and updated results will be presented at the meeting.