Genomics-Guided Risk Stratification in Myeloma Precursor Conditions: Converging Frameworks From Whole-Genome Sequencing.

Abstract

Multiple myeloma (MM) remains incurable despite major therapeutic advances, underscoring the unmet need for earlier and genetically informed intervention. The rationale for such intervention lies in the stepwise evolution of MM from precursor states, including monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), during which genetic alterations accumulate and drive the emergence, expansion, and evolution of malignant clones. In 2025, three landmark cohort studies using whole-exome or whole-genome sequencing (WES/WGS) proposed distinct but relevant genomic frameworks for reclassifying disease risk in MGUS and SMM. Despite differences in design and analyses, these frameworks converge on several principles: (i) the malignant genomic architecture of myeloma is established well before clinical progression; (ii) a substantial fraction of clinically defined precursor disease already harbors the hallmarks of overt myeloma; and (iii) WES/WGS-derived features meaningfully improve clinical risk models. In this perspective, we critically reviewed these three contemporaneous frameworks and synthesize their convergent implications, not previously consolidated for clinical use, into a practical approach toward genomics-guided management of myeloma precursor conditions.