Melflufen is able to trigger myeloma cell death regardless of p53 status, and thus overcome p53-deficiency-mediated melphalan resistance. It demonstrates better ex vivo efficacy in MM patient derived plasma cells harboring del17p or TP53 mutations. Melflufen response rates in the del17p patient subpopulation are comparable to the general patient population comprising RRMM exposed to IMiD- and proteasome inhibitors and resistant to daratumumab- and/or pomalidomide-based salvage therapies. Collectively, these data suggest that melflufen might provide a valuable therapeutic option for this difficult-to-treat patient group.