OA – 29: Mezigdomide (MEZI), tazemetostat (TAZ), and dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): preliminary results from the CA057-003 trial
Professor of Medicine University of Alabama at Birmingham, Birmingham, AL, USA Birmingham, Alabama, United States
Introduction: The CA057-003 phase 1/2 trial (NCT05372354) is evaluating oral, novel-novel targeted triplet combinations using a MEZI+DEX backbone in pts with RRMM refractory to, intolerant to, or not candidates for established MM therapies. The third agent in each combination intervenes on a key oncogenic pathway upregulated in RRMM: 1) EZH2 inhibitor TAZ for PRC2 complex dysregulation; 2) BET inhibitor BMS-986158 for CKS1B (on chromosome 1q) amplification; 3) or MEK inhibitor trametinib for RAS-RAF-MEK-ERK activation. Here we report results from the dose-finding cohort of MEZI+TAZ+DEX in RRMM.
Methods: Eligible pts had RRMM with progressive disease (PD) during or after the last regimen, ECOG PS score ≤1, absolute neutrophil count ≥1000/μL, and estimated glomerular filtration rate ≥45 mL/min/1.73 m2. Oral MEZI was given at 3 escalating doses (0.3, 0.6, and 1mg) on days (D) 1–21 of each 28-day cycle with oral TAZ (800mg) twice daily on D1–28 and weekly oral DEX (40mg; 20mg if ≥75 y of age). Primary objectives are to define the RP2D and dosing schedule, and to evaluate safety; secondary objectives are to assess efficacy and pharmacokinetics.
Results: As of April 5, 2024, 13 pts received MEZI+TAZ+DEX (3 pts 0.3mg; 3 pts 0.6mg; 7 pts 1.0mg). Median (range) age was 67 (51–80) y and median time since initial diagnosis was 8.3 (2.4–13.3) y. Extramedullary plasmacytomas were present in 6 (46.2%) pts. Median number of prior regimens was 5 (3–14), 10 (76.9%) pts had triple-class refractory MM, and 9 (69.2%) had prior T-cell–redirecting therapy.
Six (46.2%) pts continued treatment; 5 pts discontinued due to PD, 1 due to physician’s decision, and 1 due to an adverse event (AE). Median number of cycles received was 4 (2–9). Median follow-up was 4.2 (1.6–9.2) mo; median MEZI treatment duration was 4.1 (1.6–8.5) mo.
Grade (Gr) 3/4 treatment-emergent AEs (TEAEs) occurred in 9 (69.2%) pts; the most common hematologic TEAEs were neutropenia (46.2%) and anemia (15.4%). Most common (reported in >1 pt) non-hematologic Gr 3/4 TEAEs included infections (15.4%) and dyspnea (15.4%). No dose-limiting toxicities were observed. No TEAEs led to MEZI dose reduction or discontinuation. One pt died on study due to pulmonary sepsis.
Overall response rate was 53.8% (95% CI, 25.1–80.8) with 1 stringent complete response, 2 very good partial responses, and 4 partial responses; median time to response was 0.95 (0.9–3.0) mo. There were responses among pts who had T-cell–redirecting therapies as their last line and deeper responses were observed at the highest MEZI dose.
MEZI exposure increased in a more than dose-linear manner over the dose range. Coadministration of MEZI and TAZ did not alter MEZI exposure. MEZI remained pharmacodynamically active, inducing Ikaros/Aiolos degradation and B-cell reduction with TAZ at all dose levels (greatest effect observed at MEZI 1.0mg).
Conclusions: MEZI+TAZ+DEX showed promising preliminary efficacy and safety in pts with RRMM, with no new safety concerns. Previously presented at EHA 2024.
