New approaches to smoldering myeloma.

Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by the presence of one or both features of serum M-protein ≥ 30 g/L and bone marrow plasma cell infiltration ≥ 10 %. However, myeloma-related symptomatology is absent from this condition. The risk of progression to active MM is not uniform, and several markers are useful for identifying SMM patients at high risk of progression to active MM. These include the size of the M-protein and the infiltration in the bone marrow, the serum-free light-chain ratio, the presence of immunoparesis and percentage of plasma cell with aberrant phenotype by flow cytometry, or the presence of focal lesions in magnetic resonance imaging. Overall, the presence of these factors identifies patients who have a 50 % probability of progression at 2 years, and the forthcoming challenge will be to identify ultra-high-risk patients who have an 80 % risk of progression at 2 years. The current standard of care is not to treat until progression to symptomatic disease occurs. Several trials of melphalan, thalidomide and bisphosphonates have been conducted in the overall SMM patient population to examine the delay in time to progression (TTP) to symptomatic disease, but these have shown no significant benefit. However, a randomized trial that focused on high-risk SMM patients allocated to receive early treatment with lenalidomide plus dexamethasone versus observation did report a significant benefit with respect to TTP and overall survival. In summary, high-risk SMM patients should be targetted for early treatment, and more so efforts should be made to identify the ultra-high-risk subgroup within the high-risk SMM patient population which may be considered as early MM and thereby candidates for receiving therapy before they develop myeloma-related symptomatology.