From Germline Susceptibility to Therapeutic Vulnerability: DNA Damage Response Gene Mutations Driving Multiple Myeloma Evolution and Precision Therapy.

Multiple myeloma (MM) is characterized by genomic instability and therapeutic resistance. Emerging evidence indicates that germline DNA damage response (DDR) mutations, including BRCA1/2, ATM, and CHEK2 variants, contribute to MM susceptibility, clonal evolution, and treatment response. Inherited DDR defects promote chromosomal instability, reshape the immune microenvironment, and facilitate therapy-driven disease progression. Recent advances in multiomics profiling, single-cell sequencing, and liquid biopsy have improved the functional interpretation and clinical monitoring of DDR alterations. Moreover, DDR-associated vulnerabilities provide opportunities for precision therapies, including PARP inhibitor-based synthetic lethality strategies. This review summarizes the mechanistic and clinical significance of germline DDR alterations in MM and highlights their translational potential in precision oncology.