Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria

Abstract

In 2014, the International Myeloma Working Group reclassified patients with smoldering multiple myeloma (SMM) and bone marrow-plasma cell percentage (BMPC%) ≥ 60%, or serum free light chain ratio (FLCr) ≥ 100 or >1 focal lesion on magnetic resonance imaging as multiple myeloma (MM). Predictors of progression in patients currently classified as SMM are not known. We identified 421 patients with SMM, diagnosed between 2003 and 2015. The median time to progression (TTP) was 57 months (CI, 45-72). BMPC% > 20% [hazard ratio (HR): 2.28 (CI, 1.63-3.20); p < 0.0001]; M-protein > 2g/dL [HR: 1.56 (CI, 1.11-2.20); p = 0.01], and FLCr > 20 [HR: 2.13 (CI, 1.55-2.93); p < 0.0001] independently predicted shorter TTP in multivariate analysis. Age and immunoparesis were not significant. We stratified patients into three groups: low risk (none of the three risk factors; n = 143); intermediate risk (one of the three risk factors; n = 121); and high risk (≥2 of the three risk factors; n = 153). The median TTP for low-, intermediate-, and high-risk groups were 110, 68, and 29 months, respectively (p < 0.0001). BMPC% > 20%, M-protein > 2 g/dL, and FLCr > 20 at diagnosis can be used to risk stratify patients with SMM. Patients with high-risk SMM need close follow-up and are candidates for clinical trials aiming to prevent progression.

Fig. 1. Time to progression in the three risk categories using the proposed and conventional Mayo Clinic models.

a Kaplan–Meier failure curves showing time to progression (TTP) in patients with none (low risk), one (intermediate risk), and two or more (high risk) of bone marrow-plasma cell percentage (BMPC%) > 20%, monoclonal protein > 2 g/dl, and free light chain ratio (FLCr) > 20 at diagnosis of smoldering multiple myeloma. The estimated median TTP in the low-risk, intermediate-risk, and high-risk groups were 109.8 months (95% CI, 78.3–not reached), 67.8 months (95% CI, 44.8–not reached), and 29.2 months (95% CI, 16.5–36.9), respectively (p < 0.0001). b Kaplan–Meier failure curves for patients stratified according to the conventional Mayo Clinic model by presence of one (low risk), two (intermediate risk), and three (high risk) of monoclonal protein ≥ 3 g/dL, BMPC% ≥ 10%, and FLCr ≥ 8 at diagnosis. The estimated median TTP in the three groups were 109.8 months (95% CI, 83.1–126.9), 45.1 months (95% CI, 35.8–62.1), and 22.6 months (95% CI, 12.4–41.0), respectively (p < 0.0001). The proposed classification system performed better than the conventional system by area under the curve analysis

Fig. 2. Risk stratification of smoldering multiple myeloma in a subset of patients with FISH testing and advanced imaging available at diagnosis.

a Kaplan–Meier failure curves showing time to progression (TTP) in patients with none (low risk), one (intermediate risk), and two or more (high risk) of bone marrow-plasma cell percentage (BMPC%) > 20%, free light chain ratio (FLCr) > 20, and high-risk cytogenetics [del17p, t(4;14) or hyperdiploidy]. The estimated median TTP in the three groups were not reached (95% CI, 33.3 months–NR), 63.0 months (95% CI, 29.8–NR), and 14.5 months (95% CI, 10.7–25.4), respectively (p < 0.0001). b Kaplan–Meier failure curves for patients stratified according to the conventional Mayo Clinic model by presence of one (low risk), two (intermediate risk), and three (high risk) of monoclonal protein ≥ 3 g/dL, BMPC% ≥ 10%, and FLCr ≥ 8 at diagnosis. The estimated median TTP in the three groups were NR (95% CI, 29.8 months–NR), 35.1 months (95% CI, 13.4–47.0), and 18.9 months (95% CI, 5.8–NR), respectively (p = 0.043)