Defining High-Risk Disease Biology in Multiple Myeloma: A Narrative Review

Mohammad Aljumaa,1,2 Hasan Hamam Refai,1,2 Yogesh Chawla,1 Wilson I Gonsalves1 1Division of Hematology, Mayo Clinic, Rochester, MN, USA; 2College of Medicine, Alfaisal University, Riyadh, Saudi ArabiaCorrespondence: Wilson I Gonsalves, Division of Hematology, Mayo Clinic, Rochester, MN, USA, Tel +1 507-284-2511, Email Gonsalves.Wilson@mayo.eduAbstract: Although modern therapies have significantly improved survival, multiple myeloma (MM) remains incurable and biologically heterogeneous, resulting in substantial variability in treatment response and outcomes. Effective risk stratification is therefore critical to guide therapy intensity, predict relapses, and inform prognosis. This review critically examines the current biological determinants of high-risk MM and their implications for treatment intensification, selection of novel therapeutic agents, and stratified clinical trial enrollment. High-risk MM is driven by three major biological determinants: (1) molecular and genomic abnormalities, including high-risk IgH translocations, del(17p), TP53 mutation, gain(1q), and high-risk gene expression signatures; (2) increased proliferative capacity, with an elevated plasma-cell S-phase fraction identifying a subgroup with markedly inferior survival independent of conventional staging; and (3) extramedullary dissemination biology, reflected by circulating tumor cells and soft-tissue extramedullary disease, both associated with marrow independence, clonal evolution, and poor outcomes. The 2024 IMS/IMWG framework integrates the genomic aspects of these biological markers and certain clinical factors into a more precisely defined disease. Complementing baseline classification, dynamic risk stratification using measurable residual disease (MRD) provides real-time prognostic refinement across the treatment course. Future advances will rely on comprehensive molecular profiling and AI-driven data integration to enable precision-guided treatment based on individualized disease biology.