We investigated the activity and mechanism of melflufen (melphalan flufenamide) in myeloma models with wild type TP53 (TP53wt) and complete TP53 deletion (TP53<sup>-/-</sup>) and assessed the efficacy of melflufen in patients with del(17p) and/or TP53 mutation. Here, TP53 is linked to plasma cell myeloma.