Review Series MULTIPLE MYELOMA: FROM THE BENCH TO BEDSIDE Smoldering multiple myeloma

Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell (PC) disorder. Kyle and Greipp initially described the entity as an intermediate stage between monoclonal gammopathy of undermined significance (MGUS) andmultiplemyeloma (MM) on the basis of 6 patients with increased bone marrow PCs ($10%) who remained stable for$5 years without chemotherapy. SMM has since beenwell characterized, and high-risk subsets of SMMare increasingly recognized as the optimal phase ofMMevolution in which to test early treatment strategies. SMM is distinguished from MGUS primarily for clinical reasons, because the risk of progression to malignancy in the first 5 years after diagnosis is different: 10%per year in SMMvs 1%per year inMGUS. SMM is biologically heterogeneous; it is a clinically defined entity comprisinga subset of patientswithbiological premalignancy (ie,MGUS) and a subset with biological malignancy (ie, MM) who have not yet developed hypercalcemia, renal failure, anemia, or lytic bone lesions (CRAB) and/or other myeloma-defining events (MDE). Thus, SMM includes patients who behave like those with MGUS (with a very low rate of progression) and thosewho develop clinical symptoms and end-organ damage within the first 2 years of diagnosis. It is unfortunate that at the current time, there is no single pathological or molecular feature that reliably can be used to distinguish SMM patients who have only clonal premalignant PCs from those who have clonal malignant myeloma cells.