Navigating the evolving management of smoldering multiple myeloma

Smoldering multiple myeloma (SMM) represents an intermediate clinical stage between monoclonal gammopathy of undetermined significance (MGUS) and symptomatic multiple myeloma (MM). SMM carries a highly variable risk of progression to MM, requiring individualized risk stratification to guide management. Historically, risk models relied on static clinical markers reflective of tumor burden to predict progression. While useful, these models failed to capture the underlying biological heterogeneity of the disease. Recent advances have incorporated dynamic biomarkers, cytogenetics, and genomic profiling, providing a more nuanced understanding of disease trajectory. Immune dysregulation and subclonal evolution are now recognized as key drivers of progression, enabling the development of biologically informed risk models. Clinical trials have begun to challenge the traditional watch-and-wait approach by exploring early therapeutic interventions for high-risk SMM patients. However, uncertainty persists as clinicians balance the risks of overtreatment against therapeutic delay in the absence of clearly defined high-risk criteria. This review charts the evolution of SMM from a clinically defined entity to a biologically characterized precursor state, highlighting emerging tools and strategies aimed at improving risk prediction and patient outcomes. As personalized medicine continues to advance, integrating evolving molecular, immunologic, and clinical data will be pivotal in refining the management of SMM.