How I treat smoldering multiple myeloma

Abstract

Smoldering myeloma is a heterogeneous clinical entity where a subset of patients has an indolent course of disease that mimics monoclonal gammopathy of undermined significance, whereas others have a more aggressive course that has been described as "early myeloma." It is defined as either serum M-protein ≥ 3 g/L or ≥ 10% monoclonal plasma cells in the bone marrow. There are currently no molecular factors to differentiate risks of progression for these patients. Current recommendations of therapy continue to be patient observation or patient enrollment in clinical trials. However, new definitions of active multiple myeloma recently agreed upon by the International Myeloma Working Group may alter the timing of therapy. On the basis of emerging data of therapy in these patients, it seems reasonable to believe that future recommendations for therapy of patients with smoldering myeloma will become an increasingly important topic. In this article, we review the current knowledge of this disease and risk factors associated with progression. We also examine biological insights and alterations that occur in the tumor clone and the surrounding bone marrow niche. Finally, we review clinical trials that have been performed in these patients and provide recommendations for follow-up of patients with this unique disease entity.

Figure 1

Clonal evolution in a permissive microenvironment. Progression from MGUS to SMM to symptomatic MM involves clonal evolution and heterogeneity, which is not only cell autonomous but also dependent on the interactions of the tumor cells with the bone marrow microenvironment. This includes immune cells such as T-regulatory cells (Tregs), myeloid derived suppressor cells (MDSCs), natural killer (NK) cells, osteoclasts, osteoblasts, angiogenesis, and MSCs.

Figure 2

Proposed guidelines of follow-up and management of SMM. Patients suspected to have MM should first be defined as having MGUS, SMM, or myeloma requiring therapy. This includes the new classification of patients with MDE. For patients with SMM, these should then be stratified based on the Mayo Clinic criteria or PETHEMA criteria as having low-risk, intermediate-risk, or high-risk SMM. For high-risk SMM, we would highly recommend clinical trials or very close observation if not enrolled in a trial. We would consider redefining these patients in the future as early myeloma. For low-risk SMM, we would recommend less frequent monitoring if clinically stable and consider redefining these patients as MGUS-like. CRAB is defined as hypercalcemia (serum calcium ≥11.5 mg/dL), renal failure (defined by creatinine ≥1.95 with no other etiology), anemia (hemoglobin ≤10 g/dL or >2 g/dL below the lower limit of normal), or skeletal lesions (lytic lesions by skeletal survey, osteoporosis with pathologic fractures, or cord compression).