Genomics of Smoldering Multiple Myeloma: Time for Clinical Translation of Findings?

SIMPLE SUMMARY: In this review we summarized the most relevant biological features concerning smoldering multiple myeloma (SMM). We outlined the genetic architecture of the disease and how it is entering in the SMM risk stratification. In particular, we pointed out how the identification of a high-risk setting, meaning the population with the risk of faster progression to the symptomatic phase, is crucial and, despite huge improvements in recent years, still represents an unmet clinical need. Indeed, the correct identification of these patients will drive to an early therapeutical intervention. Moreover, we also discussed the role of the microenvironment, which is highly relevant in the symptomatic disease but still understudied in the SMM setting. Finally, we debated the state-of-the-art current available therapies and ongoing clinical trials, and envisioned possible strategies to introduce a biological-based stratification approach within the daily clinical practice. ABSTRACT: Smoldering multiple myeloma (SMM) is an asymptomatic disorder of clonal bone marrow (BM) plasma cells (PCs) in between the premalignant condition known as monoclonal gammopathy of undetermined significance and overt multiple myeloma (MM). It is characterized by a deep biological heterogeneity that is reflected in a markedly variable progression risk among patients. Recently proposed risk stratification models mainly rely on indirect markers of disease burden and are unable to identify cases in whom clonal PCs have already undergone the “malignant switch” but major clonal expansion has not occurred yet. In the last years, the application of next-generation sequencing (NGS) techniques has led to profound advances in the understanding of the molecular bases of SMM progression, and in all likelihood, it will contribute to the needed improvement of SMM prognostication. In this Review, we describe the recent advances in characterizing the genomic landscape of SMM and intrinsic determinants of its progression, highlighting their implications in terms of understanding of tumor evolution and prognostication. We also review the main studies investigating the role of the microenvironment in this early disease stage. Finally, we mention the results of the first randomized clinical trials and discuss the potential clinical translability of the genomic insights.