Theoretically possible scenarios resulting from early treatment of smoldering myeloma. Progression of untreated high-risk SMM to full-blown MM is shown on the left. SMM patients with two or three risk factors (see Table 1) have a median TTP of 5 and 2 years, respectively. Scenarios 1 to 3 illustrate possible scenarios resulting from early treatment of SMM: Scenario 1 (center left) represents a complete cure of MM, which has not yet been reliably achieved by any current treatment modalities. This would likely require more intense treatment, necessitating improved risk-stratification of patients. Ultimately, targeted therapies may be able to achieve cure. Scenario 2 (center right) represents the generation of a chronic, asymptomatic disease state requiring ongoing maintenance therapy. This is a likely outcome of using immunomodulatory and targeted agents available in the near future. Scenario 3 (right) illustrates the theoretical possibility of the selection of a particularly aggressive, resistant clone. While TTP is extended in this scenario, overall survival may not be improved, because symptomatic disease might progress unchecked if available treatments become less effective following early treatment. Future studies are needed to fully explore these possibilities. Taken together, we do not know which, if any, of these scenarios are true. Therefore, clinical trials aimed at developing treatments for SMM should incorporate well-designed correlative studies to examine the biology of treatment response. (Reprinted with permission from Waxman et al., 2010.⁴³ )