Smoldering Multiple Myeloma: From Clinical to Immunogenomic Risk Stratification and Therapeutic Implications of Early Intervention

Smoldering multiple myeloma (SMM) is an asymptomatic precursor state that precedes the development of symptomatic active MM. Newer immunogenomic data highlight the monoclonal gammopathy of undetermined significance-SMM-MM spectrum as a continuous genomic gradient rather than a series of discrete clinical categories. Current risk stratifications to define high-risk SMM use a progression rate of ≥50% within 2 years. The International Myeloma Working Group uses the 20/2/20 model that identifies serum M-protein >2 g/dL, bone marrow plasma cells >20%, and involved/uninvolved free light chain ratio >20 as independent predictors for risk of progression to MM. Having ≥2 risk factors increases the 2-year risk of SMM progression to 40%-50%. This risk is further increased by the presence of adverse cytogenetics [del13, t(4;14), t(14;16), +1q]. The model is purely based on tumor burden and cytogenetics and could be further refined by using genomics that predict tumor evolution. Key genomic features identified as independent risk factors for SMM progression include mutations in the MAPK pathway (KRAS and NRAS single nucleotide variants [SNVs]), alterations of the DNA repair pathway (TP53, ATM SNVs, and deletion 17p), MYC alterations (translocations or copy number variations), and APOBEC-associated mutational signatures. Integrating the molecular and clinical determinants to define high-risk SMM is described as the holy grail of risk stratification in SMM. Three large, randomized phase III studies demonstrated the benefit of early intervention by meeting their primary end points, one demonstrating an overall survival (OS) benefit (QuiRedex) and another showing a trend toward OS benefit (AQUILA) favoring early intervention. In this context, identifying the patients with high-risk SMM is crucial as the optimal patient might benefit from a therapeutic intervention aimed at preventing progression to MM and prolonging OS.