TP53 mutation drives unique transcriptional and functional vulnerabilities independent of del(17p) in multiple myeloma.

TP53 abnormalities contribute to treatment resistance and poor prognosis in multiple myeloma (MM), yet their functional consequences remain unclear. Here, we integrate ex vivo drug sensitivity profiling, genomics, transcriptomics, and proteomics across 167 CD138+ bone marrow patient samples to characterize TP53-associated vulnerabilities. Genome-wide CRISPR-Cas9 and RNAi screening identify vulnerabilities in TP53-mutated MM, with or without del(17p), highlighting the dependency on spindle organization, mitotic regulation, DNA synthesis, and transcriptional and metabolic regulation, but independence from MDM2. CD138+ cells with TP53 mutation exhibit increased sensitivity to chemotherapeutics, HDAC, HSP90, IGF1R, and PI3K/AKT/mTOR inhibitors as well as RNA synthesis inhibitor plicamycin, with distinct drug response profiles of MM with del(17p) and WT TP53. Our study provides new insights into refining TP53 classification to optimize treatment strategies for high-risk MM.