The Changing Landscape of Smoldering Multiple Myeloma: A European Perspective

Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder and bridges monoclonal gammopathyof undeterminedsignificance tomultiplemyeloma(MM),
based on higher levels of circulating monoclonal immunoglobulin and bone marrow plasmocytosis without end-organ damage. Until a Spanish study reported fewer MM-related
events and better overall survival among patients with highrisk SMM treated with lenalidomide and dexamethasone, prior studies had failed to show improved survival with earlier intervention, although a reduction in skeletal-related events (without any impact on disease progression) has been described with bisphosphonate use. Risk factors have now been defined, and a subset of ultra-high-risk patients have been reclassified by the International Myeloma Working Group asMM, and thus will require optimalMMtreatment, based on biomarkers that identify patients with a.80% risk of progression. The number of these redefined patients is
small (∼10%), but important to unravel, because their risk of progression to overt MM is substantial ($80% within 2 years). Patients with a high-risk cytogenetic profile are not yet considered for early treatment, because groups are heterogeneous and risk factors other than cytogenetics are deemed to weight higher. Because patients with ultra-highrisk SMM are now considered as MMand may be treated as such, concerns exist that earlier therapy may increase the risk of selecting resistant clones and induce side effects and costs. Therefore, an even more accurate identification of patients who would benefit from interventions needs to be
performed, and clinical judgment and careful discussion of pros and cons of treatment initiation needs to be undertaken. For the greater majority ofSMMpatients, the standard of care
remains observation until development of symptomatic MM occurs, encouraging participation in ongoing and upcoming SMM/early MM clinical trials, as well as consideration of bisphosphonate use in patients with early bone loss.