Belantamab mafodotin, carfilzomib, lenalidomide, and dexamethasone for relapsed or refractory multiple myeloma

Belantamab mafodotin (belamaf), an antibody-drug conjugate targeting B-cell maturation antigen, has demonstrated single-agent activity in relapsed/refractory multiple myeloma (RRMM) but is associated with ocular toxicity. This phase 1/2 study evaluated the safety and preliminary efficacy of belamaf administered every 8 weeks in combination with carfilzomib, lenalidomide, and dexamethasone (KRd-b) in patients with RRMM. Eligible patients had received at least 1 previous line of therapy and had not progressed on full-dose lenalidomide. In the dose-escalation phase (3+3 design), belamaf was administered at 1.4 or 1.9 mg/kg every 8 weeks. The recommended phase 2 dose was 1.9 mg/kg, with no dose-limiting toxicities at this level. Among 19 patients treated, the overall response rate was 89.5%, and 78.9% achieved very good partial response or better, with minimal residual disease negativity in all complete responders. At a median follow-up of 19.3 months, 24-month progression-free survival and overall survival rates were 74.3% and 85.1%, respectively. Keratopathy occurred in 94.7% of patients but was mostly grade 1 to 2, reversible, and manageable without permanent discontinuation. Grade ≥3 keratopathy (31.6%) was comparable with historical rates despite the less frequent dosing. Other adverse events, including hematologic and gastrointestinal toxicities, were manageable and consistent with known profiles of KRd or belamaf. The combination demonstrated deep and durable responses, including in patients at high-risk and with lenalidomide maintenance dose-refractory disease. These results support the feasibility of KRd-b with extended-interval belamaf and warrant further evaluation in phase 2 trials to confirm its clinical benefit in RRMM. This trial is registered at www.clinicaltrials.gov as NCT04822337.