The evolving molecular landscape of Smoldering Multiple Myeloma (SMM) has underscored its complex nature and the urgent need for more refined diagnostic and treatment strategies. With an increased risk of progression to Multiple Myeloma (MM), it has become important to identify patients at the highest risk of progression for interception strategies. Risk evaluation has been a constantly moving target with rapidly changing approaches to classification being based predominantly based on imaging and biochemical data thus far. More recently, advances in whole genome sequencing and a deeper understanding of SMM's biology have led to the recognition of genomic variants impacting its evolutionary trajectory to MM. Genomic analysis and molecular models are delivering ongoing contributions towards predicting the risk of progression and bringing about a pivotal shift toward precision medicine. Conversely, these advances have also facilitated the recognition of lower-risk subtypes, which may guide a less interventional and more health management approach to its care. This nuanced approach highlights the dual promise of genomic insights: tailoring interventions to intercept disease progression and potentially to achieve a cure while avoiding the overtreatment of patients less likely to progress. We review ongoing clinical trials dedicated to optimizing therapy for high-risk SMM, showcasing a concerted effort to identify precision treatment strategies. Through a blend of wide-ranging clinical trials and the exploration of genomic-based risk classification, the SMM management paradigm is poised for transformation, aiming to extend progression-free survival and ultimately, to improve patient survival. 

Multiple myeloma, SMM, Smoldering multiple myeloma