Genetic Subtypes of Smoldering Multiple Myeloma are associated with Distinct Pathogenic Phenotypes and Clinical Outcomes

Abstract Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with significant heterogeneity in disease progression. Existing clinical models of progression risk do not fully capture this heterogeneity. Here we integrated 42 genetic alterations from 214 SMM patients using unsupervised binary matrix factorization (BMF) clustering and identified six distinct genetic subtypes. These subtypes were differentially associated with established MM-related RNA signatures, oncogenic and immune transcriptional profiles, and evolving clinical biomarkers. Three subtypes were associated with increased risk of progression to active MM in both the primary and validation cohorts, indicating they can be used to better predict high and low-risk patients within the currently used clinical risk stratification model.