The Role of Early Intervention in High-Risk Smoldering Myeloma

Smoldering multiple myeloma (SMM) is a precursor disease state that precedes the development of symptomatic myeloma. As we have learned more about the disease biology of SMM and risk factors for progression, updated risk stratification models, such as the Mayo 2018 model, or 20/2/20, have been developed. More accurate risk stratification and the development of effective and well-tolerated therapeutic agents have led to the investigation of early treatment of select patients with high-risk SMM with the aim of delaying time to progression to multiple myeloma. Ongoing debate surrounds which subset of patients with SMM to target, as well as the best treatment approach: preventative versus curative. Phase III data from the Spanish Myeloma Group/PETHEMA as well as the Eastern Cooperative Oncology Group (ECOG) E3A06 trial have shown the efficacy of lenalidomide with and without dexamethasone in high-risk SMM in delaying progression to symptomatic disease. Conversely, there exists an alternate strategy attempting to cure the disease prior to progression utilizing more intensive regimens similar to what is used for patients with newly diagnosed myeloma. However, our understanding of the disease biology of SMM and the role of immune regulation in preventing malignant transformation provides a strong rationale for an interventional strategy. Here, we review the definition of SMM, the current models for risk stratification, and the current data available supporting the early treatment of patients with high-risk SMM.