Mezigdomide (MEZI) in Novel-Novel Combinations for Relapsed or Refractory Multiple Myeloma (RRMM): Preliminary Results from the CA057-003 Trial

Introduction: MEZI, a novel, potent oral CELMoD™ agent, induces rapid and maximal degradation of Ikaros and Aiolos compared with immunomodulatory drugs (IMiDs^®), resulting in direct tumoricidal and immunomodulatory effects in myeloma cells. The CA057-003 phase 1/2 trial (NCT05372354) is evaluating all-oral, novel-novel targeted triplet combination regimens using a MEZI plus dexamethasone (DEX) (MEZId) backbone in patients (pts) with RRMM. The third agent in each combination intervenes on a key oncogenic pathway identified by The Myeloma Genome Project to be upregulated in RRMM: the EZH2 inhibitor tazemetostat (TAZ) for PRC2 complex dysregulation, the BET inhibitor BMS-986158 for CKS1b (located on Chr 1q) amplification, and the MEK inhibitor trametinib (TRAM) for RAS-RAF-MEK-ERK activation. Here we report preliminary results from the CA057-003 dose-finding cohorts of MEZId combined with TAZ, BMS-986158, or TRAM in pts with RRMM.

Methods: Eligible pts had RRMM with documented progressive disease (PD) during or after the last regimen, ECOG performance status score ≤1, and were intolerant to or ineligible for all available established therapies. Oral MEZI was given daily (QD) at escalating doses of 0.3, 0.6, or 1.0 mg on days (D)1–21 of each 28-D cycle with 40 mg (20 mg if ≥75 y of age) weekly DEX plus 800 mg twice daily oral TAZ on D1–28; 2 or 3 mg QD oral BMS-986158 5D-on-2D-off D1–14; or 1.5 or 2 mg QD oral TRAM on D1–21. Primary objectives included defining the recommended phase 2 dose and dosing schedule, and evaluating safety. Secondary objectives included efficacy and pharmacokinetics. There was no biomarker screening.

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.