OAB-050: OCEAN (OP-103): a Phase 3, randomized, global, head-to-head comparison study of Melflufen and Dexamethasone (Dex) versus Pomalidomide (Pom) and Dex in Relapsed Refractory Multiple Myeloma (RRMM)

Background Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumor cells. Accelerated approval in the United States of melflufen + dex for patients (pts) with RRMM was based on promising data from the phase 2 HORIZON study (Richardson, et al. J Clin Oncol. 2021;39:757-767). The phase 3, randomized, head-to-head OCEAN study (NCT03151811) assessed melflufen + dex vs pom + dex in RRMM. Methods Pts with RRMM (2-4 prior lines of therapy [LoTs] including lenalidomide [len] and a proteasome inhibitor) refractory to len within 18 mo of randomization and last LoT were randomized 1:1 (stratified by age, no. of prior LoTs, and International Staging System score) to receive 28-d cycles of melflufen 40 mg intravenously on d1 or pom 4 mg orally (PO) daily on d1 to 21. All pts received dex 40 mg (20 mg for pts ≥75 y) PO on d1, 8, 15, and 22. Pts received therapy until disease progression or unacceptable toxicity (Schjesvold, et al. Future Oncol. 2020;16:631-641). The primary endpoint was progression-free survival (PFS), assessed by independent review committee per International Myeloma Working Group Uniform Response Criteria, with superiority of melflufen vs pom measured using a log-rank P value. Key secondary endpoints were overall response rate (ORR), overall survival (OS), and safety. Results As of 3 Feb 2021, 495 pts were randomized (246 to melflufen; 249 to pom); median age was 68 y (range, 39-91), median prior LoTs was 3, and >99% of pts were len-refractory. In the melflufen and pom groups, median PFS was 6.8 mo vs 4.9 mo (hazard ratio [HR], 0.79 [95% CI, 0.64-0.98]; P=0.0311); median follow-up was 15.5 mo vs 16.3 mo; ORR was 33% (95% CI, 27-39) vs 27% (95% CI, 22-33; complete response, 3% vs 1%; very good partial response, 9% vs 7%; partial response, 20% vs 18%); and OS was 19.8 mo vs 25.0 mo (HR, 1.10 [95% CI, 0.85-1.44]), respectively. With melflufen (n=228) and pom (n=246), grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 90% vs 74%; most commonly thrombocytopenia* (76% vs 13%; occurring with grade 3/4 hemorrhage* in 1% vs 0%), neutropenia* (64% vs 49%; occurring with grade 3/4 infections* in 3% vs 7%), anemia* (43% vs 18%), and infection* (13% vs 22%); and 42% vs 46% of pts had serious TEAEs, respectively. With melflufen and pom, TEAEs led to dose reductions in 47% vs 15% of pts (most commonly thrombocytopenia [31% vs 2%] and neutropenia [12% vs 8%]) and discontinuations in 26% vs 22% of pts, respectively. Deaths occurred in 46% vs 43% of pts with melflufen and pom, with AEs the primary cause of death ≤30 d after last dose in 7% and 9%, respectively. Conclusion Melflufen had superior PFS vs pom, suggesting that melflufen + dex may be an alternative treatment option with a novel mechanism of action for pts with RRMM with len-refractory disease and 2-4 prior LoTs. Analyses of factors impacting OS are ongoing. *Grouped term.