Efficacy of melflufen in multiple myeloma with mutated or deleted TP53

Patients with multiple myeloma bearing a deletion of chromosome 17p (del(17p)), mutation of TP53, or both have poorer prognosis compared to patients without these aberrations. We investigated the activity and mechanism of melflufen (melphalan flufenamide) in myeloma models with wild type TP53 (TP53wt) and complete TP53 deletion (TP53^−/−) and assessed the efficacy of melflufen in patients with del(17p) and/or TP53 mutation. Ex vivo data from myeloma plasma cells (PC) showed comparable activity of melflufen in del(17p), TP53^−/−, and TP53wt samples. scRNAseq data demonstrated that melflufen sensitive PCs had lower expression of p53 target genes and higher expression of genes associated with DNA damage repair and cell cycle checkpoints. Irrespective of TP53 status, melflufen induced apoptosis, DNA damage, and mitochondrial dysfunction, while only in TP53^−/− cells, it led to changes in expression of cell cycle checkpoint and apoptosis genes. Post-hoc analysis of the OCEAN trial melflufen-treated del(17p) patient population also demonstrated favorable progression free survival compared to pomalidomide-treated cohort. Our insights into the molecular mechanisms of melflufen activity in TP53^−/− myeloma support its clinical efficacy and application in the del(17p) and TP53^−/− patient population. Trial registration NCT03151811, registration 2017-05-09.