Smoldering and Early Disease Interception

Smoldering multiple myeloma (SMM) is an asymptomatic precursor of multiple myeloma characterized by marked heterogeneity in the risk of progression. Current management relies on clinical risk stratification to identify patients who might benefit from early intervention. Models such as the 20/2/20 score and its International Myeloma Working Group refinement incorporate tumor burden and cytogenetic abnormalities, whereas emerging approaches integrating dynamic biomarkers, circulating tumor cells, genomic alterations, and immune signatures could further improve the prediction of progression if validated in larger cohorts. Randomized trials suggest that early treatment with lenalidomide-based regimens or anti-CD38 monoclonal antibodies delays progression and possibly improves survival in high-risk SMM, and daratumumab has been approved as an early intervention in high-risk SMM. More intensive immunotherapy-based strategies can achieve high rates of sustained measurable residual disease negativity, which might translate into durable disease control or even a cure. Future management will likely depend on biologically informed, risk-adapted strategies to balance early treatment benefits against overtreatment, together with safety profile and patients' preferences.