Smoldering multiple myeloma: advances in diagnosis and risk stratification, and evolving therapeutic strategies

Smoldering multiple myeloma (SMM) represents a heterogeneous precursor stage between monoclonal gammopathy of undetermined significance and symptomatic multiple myeloma (MM). Advances in diagnostic criteria, particularly the adoption of the SLiM-CRAB framework, have improved the distinction between SMM and MM and reduced the risk of misclassification. Contemporary risk stratification models, such as the Mayo 20/2/20 criteria and International Myeloma Working Group refinements, integrate both static and dynamic biomarkers to provide more accurate predictions of progression. Genomic and immunological studies have further revealed key drivers of disease evolution, patterns of clonal evolution, and immune dysregulation, which may guide therapeutic decisions. Clinical trials have demonstrated that early intervention with lenalidomide or daratumumab can delay progression. In contrast, intensive multi-agent regimens, such as those used in the GEM-CESAR and ASCENT trials, have achieved high rates of minimal residual disease negativity and suggest curative potential. Nevertheless, the long-term survival benefits of these strategies remain uncertain, and the risks of toxicity in asymptomatic patients require careful consideration. Ongoing studies, including CAR-PRISM and ImmunoPRISM, are evaluating cellular and antibody-based therapies for high-risk SMM. Collectively, these advances highlight the need for refined, individualized approaches that balance the benefits and risks in the management of SMM.