ISABELA: A phase 2 study of isatuximab, belantamab mafodotin, pomalidomide, and dexamethasone in relapsed/refractory multiple myeloma.

Abstract

7562 Background: Combination therapies form the backbone of multiple myeloma (MM) care, and therapies targeting BCMA are now a cornerstone of treatment. We evaluated ISABELA, a phase 2 study that combines an established regimen of isatuximab (isa), pomalidomide (pom), and dexamethasone (dex) with the recently approved anti-BCMA antibody drug conjugate belantamab mafodotin (belamaf) in relapsed/refractory (RR) MM. Methods: ISABELA is an investigator-initiated study (NCT05922501) enrolling up to 50 patients (pts) with RRMM who have received at least 1 prior line of therapy including lenalidomide and a proteasome inhibitor. We gave belamaf 1.9 mg/kg iv q8 weeks; isa 10 mg/kg iv weekly for cycle 1 and then days 1 and 15 for cycle 2 onward; pom 4 mg on days 1-21, and dex 40 mg weekly divided over two days. Each cycle was 28 days. Treatment was until progression or unacceptable toxicity. Results: At data cutoff, the trial had enrolled 17 pts with a median follow-up of 9.6 months. Median age was 72 (range 55-91); 65% were male. ISS at study entry: I (59%), II (24%), III (18%). Median number of prior regimens was 2 (range 1-12). All pts were refractory to their last line of therapy and were previously treated with lenalidomide and a proteasome inhibitor. Prior therapies included pom (59%), bortezomib (82%), carfilzomib (41%), ixazomib (35%), CD38 antibody (59%) [daratumumab, 59%; isa 12%], and auto SCT (24%). Prior exposure to newer therapies included drugs that target BCMA (24%) [teclistamab 6%, elranatamab 18%, CAR T-cells 12%]; GPRC5D (12%) [talquetamab]; and cereblon (29%) [mezigdomide, 29%; cemsidomide, 12%]. Soft tissue plasmacytomas were present in 18%. The overall response rate (ORR) was 86% (12/14, not evaluable (NE) 3), ≥VGPR 43%, CR 7%, and 16-month PFS was 73% (95% CI 0.5-1). In CD38-antibody-naïve patients, ORR was 84% (5/6, NE 1) and 16-month PFS was 67% (95% CI 0.38-1). In triple-class exposed (BCMA naïve) pts, ORR was 75% (3/4, NE 2), and 12-month-PFS was 86% (95% CI 0.63-1). In quad-class exposed pts (including BCMA) (N=4), ORR was 100% and 12-month PFS was 75% (95% CI 0.43-1). Grade 3-4 hematologic adverse events (AEs) included neutropenia (53%), thrombocytopenia (29%), and anemia (12%). Common non-hematologic AEs (all; grade 3-4) included blurred vision (65%; 6%); fatigue (65%; 0%); hypertension (59%; 6%); diarrhea (53%; 0%); and AST/ALT increase (47%; 6%). Infections occurred in 35% with no grade ≥3 events. Ocular AEs by keratopathy visual acuity scale included grade 1 (14%), grade 2 (29%), grade 3 (36%). No patients discontinued treatment for AEs or ocular toxicity. Conclusions: This is the first report in RRMM for the combination of belamaf with a CD38 monoclonal antibody. The ISABELA regimen shows promising preliminary activity in RRMM with an ORR of 86% and 16-month PFS of 73%, including quad-class-exposed pts treated with anti-BCMA therapy, with manageable, reversible AEs. Clinical trial information: NCT05922501 .