Efficacy of melflufen in relapsed and refractory multiple myeloma patients with mutated or deleted TP53

Despite the development of several new treatments for multiple myeloma (MM) clinical challenges remain for patients with relapsed/refractory disease. This is especially so for the high-risk subgroup of patients with del(17p) who have poor response and significantly shorter survival compared to patients without this aberration. Here, we report the clinical efficacy of melphalan flufenamide (melflufen) in patients with del(17p) from the OCEAN randomized, open label, head-to-head, phase III clinical trial. In the del(17p) subgroup, melflufen plus dexamethasone treatment resulted in favorable progression free survival compared to the pomalidomide plus dexamethasone arm. To understand the superior efficacy of melflufen in TP53 mutated MM, we compared drug response between melflufen and melphalan in primary MM cells from patients with del(17p)/TP53 mutated disease. In line with the clinical data ex vivo sensitivity to melfufen was independent of the TP53 mutation status. To better understand the mechanism of action of melflufen, we investigated DNA damage, apoptosis kinetics and mitochondrial function in TP53 wild type and double mutant (TP53-/-) myeloma cells after treatment with melflufen, melphalan or cyclophosphamide. Melflufen demonstrated superior in vitro efficacy in comparison to the other two alkylators. Comparison of gene expression profiles and DNA damage pathway alterations upon drug treatment in the TP53 wild type and double mutant MM cell lines revealed qualitative differences between melflufen and melphalan. Our insights into the molecular mechanisms of melflufen activity in mutant TP53 genetic background support its clinical efficacy and application in the del(17p) and mutant TP53 MM patient population.