Impact of renal impairment (RI) on pharmacokinetics (PK) and clinical outcomes with mezigdomide plus dexamethasone (DEX) in relapsed/refractory multiple myeloma (RRMM).

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7539 Background: RI is a common complication in MM and may alter drug elimination, leading to increased systemic exposures, risk of adverse events (AEs), and dosing adjustments. The novel CELMoD agent mezigdomide (MEZI) is being investigated alone or with DEX in the CC-92480-MM-001 (NCT03374085) phase 1/2 trial. MEZI has shown dose-dependent linear PK with rapid absorption and is mainly eliminated through hepatic metabolism, with renal elimination playing a smaller role. Here we investigate the impact of RI on the efficacy, safety, and PK of MEZI + DEX in RRMM. Methods: Eligible patients (pts) had RRMM, ≥ 3 prior lines of therapy, triple-class refractoriness, and disease progression ≤ 60 days of last therapy. Pts were stratified by creatinine clearance (CrCl), excluding those with CrCl < 45 mL/min or needing dialysis. Oral MEZI (1 mg) was given on days 1–21 per 28-day cycle + weekly DEX. MEZI doses were not adjusted based on RI. Responses, AEs, and PK were assessed descriptively over the full population and in pts with no RI (CrCl ≥ 90 mL/min), mild RI (CrCl 60–< 90 mL/min), and moderate RI (CrCl 30–< 60 mL/min) at baseline. MEZI clearance and PK exposure were estimated from an integrated population PK model. PK exposure parameters were stratified by chronic kidney disease (CKD) staging. Results: 101 pts received MEZI + DEX in the dose-expansion cohort; 37 had no RI, 41 had mild RI, and 23 had moderate RI. Grade (Gr) 3/4 treatment-emergent AEs (TEAEs) were similar, occurring in 91.1% (overall), 89.2% (no RI), 90.2% (mild RI), and 95.7% (moderate RI) of pts. TEAEs were mostly hematologic, with neutropenia the most common Gr 3/4 TEAE; its occurrence did not differ in no RI (75.7%), mild RI (75.6%), and moderate RI (73.9%) cohorts. Non-hematologic Gr 3/4 TEAEs were low. Eighty-nine (88.1%) and 32 (31.7%) pts had MEZI dose interruptions and reductions, respectively. Overall response rate (ORR) was 40.6% in all pts, 56.8% in no-RI pts, 29.3% in mild-RI pts, and 34.8% in moderate-RI pts (Table). Evaluated as a continuous variable, CrCl showed no apparent relationship with MEZI oral clearance or systemic exposures. This was supported by subgroup evaluation of MEZI exposures by CKD stage. Results showed MEZI exposures in mild or moderate RI are consistent with no RI. Conclusions: Based on renal function, there was no adverse trend between efficacy, safety, and PK of MEZI + DEX. MEZI dose modifications are likely not required for pts with mild to moderate RI. Clinical trial information: NCT03374085 . [Table: see text]

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