SMM: toward better predictors of progression

Kyle and Greipp¹  coined the term “smoldering multiple myeloma” (SMM) for patients with a serum M-protein of at least 3 g/dL and a proportion of bone marrow plasma cells (BMPC) of at least 10% in the absence of clinical manifestations due to the monoclonal gammopathy. Since then, a number of studies on predictors for progression to active multiple myeloma (MM) have been reported.²  However, the definition of SMM has not been uniform and in most studies it has been different from the one in the original series.¹ 

In 2003, the International Myeloma Working Group³  agreed on a definition of SMM consisting of a serum M-protein of at least 3 g/dL and/or BMCP of at least 10% with no symptoms related to MM. Using this definition, the Mayo group⁴  reported a close relationship between initial tumor burden and risk, and they proposed a risk-stratification model with 3 different prognostic subgroups according to the proportion of BMPC and the serum M-protein level. We first recognized the so-called evolving SMM, characterized by a progressive increase in the serum M-protein and a short time to progression to overt MM, as opposed to nonevolving SMM with a long-lasting stable serum M-protein that abruptly increases when symptomatic MM develops.²  Most recently, Pérez-Persona and colleagues⁵  showed that the presence of an aberrant phenotype by multiparameter flow cytometry of BMPC was the most important variable for early progression from SMM to active MM.

In this issue of Blood, Dispenzieri and colleagues report the independent prognostic value of the FLC ratio for SMM progression. In their large series of 273 patients with a median follow-up longer than 12 years, the overall progression rate was 59%. In a previous report, the population was stratified in 3 risk categories based on the proportion of BMPC and the size of the M-protein.⁴  Considering that the FLC ratio is an independent predictor for malignant transformation in monoclonal gammopathy of undetermined significance,⁶  Dispenzieri and colleagues investigated its potential predictive role in further refining the outcome of SMM. The incorporation of the FLC ratio at breakpoints lower than 0.125 or higher than 8 into the previous SMM Mayo model resulted in an improved prognostic stratification with an even more balanced distribution of patients. Why an excess of clonotypic FLC is predictive for a poorer outcome in SMM is unclear, but it is a useful and simple prognostic test for asymptomatic monoclonal gammopathies.

It must be highlighted that we have just learned about several predictors of progression in SMM: (1) plasma cell mass, measured by the M-protein size and/or the proportion of BMPC; (2) evolution pattern (“evolving” versus “nonevolving”); (3) ratio between phenotypically aberrant and normal plasma cells; and (4) immunoglobulin FLC ratio. While the characterization of SMM by molecular genetic studies will likely result in a more accurate risk stratification, the recently recognized predictors of outcome will be helpful for a better monitoring and for the investigation of treatment strategies with novel non-cytotoxic drugs aimed at delaying the progression in high-risk patients.