Development of early treatment strategies for high-risk myeloma precursor disease in the future

Abstract

Smoldering myeloma (SMM) is a precursor state of multiple myeloma. It is defined by an M-protein concentration ≥3 g/dL and/or ≥10% clonal bone marrow plasma cells, in the absence of end-organ damage. Based on clinical observations, the natural history of SMM varies greatly, from stable, monoclonal gammopathy of undetermined significance (MGUS)-like disease to highly progressive disease. Using conventional clinical markers, SMM patients can be stratified into clinical risk groups. However, due to considerable molecular heterogeneity, we currently lack reliable markers to predict prognosis for individual SMM patients. Based on the International Myeloma Working Group 2010 guidelines, patients diagnosed with MGUS and SMM should not be treated outside of clinical trials. Overall, treatment trials for MGUS patients are complicated, as these individuals are relatively healthy and the majority has a low life-time risk of progression, especially when other causes of death are taken into account. In contrast to MGUS, early treatment strategies for SMM are particularly attractive, as the rate of progression to multiple myeloma is substantially higher. Until recently, potent drugs with reasonable toxicity profiles have not been available for the development of early multiple myeloma treatment strategies. This review discusses how the integration of novel biological markers and clinical monitoring of SMM could facilitate the development of early treatment strategies for high-risk SMM patients in the future.

Figure 1.

Three possible scenarios resulting from treatment of smoldering myeloma. Progression of untreated high risk SMM to full blown myeloma is shown on the left. SMM patients with two or three risk factors (see Pathogenesis and Prognosis) have a median TTP of 5 and 2 years, respectively. Scenarios no. 1–3 illustrate possible outcomes from early treatment of SMM. No. 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. No. 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. No. 3 (right) illustrates the theoretical possibility of the selection of a particularly aggressive, resistant clone. While time to progression is extended in this scenario, overall survival may not be improved, as 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. Reproduced from Waxman et al, 2010, with permission.