[Current state of genetic analysis in multiple myeloma and future perspectives]

Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of plasma cells. Recent advances in next-generation sequencing technologies have facilitated in-depth genetic exploration of MM, unveiling a more comprehensive genomic landscape that extends beyond classical chromosomal alterations, such as IGH translocations and hyperdiploidy. These studies have elucidated recurrent mutations across various functional pathways including those involving MAPK, NF-κB, cell cycle regulation, and epigenetic modulation. With respect to clinical utility, studies have shown that the number of genetic alterations and biallelic events in TP53 are associated with worse prognosis, and CRBN mutations with resistance to immunomodulatory drugs. We recently analyzed the full landscape of genetic alterations in relapsed and refractory MM using circulating tumor DNA (ctDNA), revealing TP53 mutations as the most frequent driver mutation. Notably, more than half of TP53 mutations were present in only ctDNA, suggesting a subclonal origin. Mutations in six genes, including KRAS and TP53, were associated with poor progression-free survival. In addition, the number of ctDNA mutations was identified as a prognostic factor independent of IGH translocations and clinical factors. Here we summarize recent progress in genetic analysis of MM, focusing on clinical relevance.