2021 European Myeloma Network review and consensus statement on smoldering multiple myeloma: How to distinguish (and manage) Dr. Jekyll and Mr. Hyde


According to the updated IMWG criteria, smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by M-component >3 g/dl, bone marrow plasma cell infiltration >10%/<60%, and absence of any myeloma defining event. Active multiple myeloma (MM) is preceded by SMM, with a median time to progression (TTP) of approximately 5 years. SMM ranges from the extremes of “MGUS-like” cases, where patients will never progress during their lives, to “early MM”, in which transformation into symptomatic disease, based on genomic evolution, may be rapid and devastating. Such a “split personality” challenges the prognosis and management of individual patients, particularly for the identification and possible early treatment of high-risk SMM. Outside of clinical trials, the conventional approach to SMM generally remains close observation until progression to active MM. However, two prospective, randomized trials have recently demonstrated a significant clinical benefit in terms of TTP (and of overall survival in one of the two studies) for some patients with higher risk SMM treated with lenalidomide +/- dexamethasone, raising the question of whether such an approach should be considered a new standard of care. In this paper, experts from the European Myeloma Network (EMN) describe current biological and clinical knowledge in SMM, focusing on novel insights in its molecular pathogenesis, new prognostic scoring systems proposed to identify SMM patients at higher risk of early transformation, and updated results of completed or ongoing clinical trials. Finally, some practical recommendations for the real-life management of these patients, based on Delphi consensus methodology, are provided.