Prognostic risk and survival of asymptomatic IgM monoclonal gammopathy: Results from a Spanish Multicenter Registry

Abstract

Asymptomatic IgM gammopathy encompasses IgM monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic Waldenström macroglobulinemia (AWM), both having a risk of progression to symptomatic disease. Here, we assessed the risk of progression and the mortality of 956 patients with asymptomatic IgM gammopathy across 25 Spanish centers. After a median follow-up of 5.7 years, 156 patients progressed, most of them to symptomatic WM (SWM). The cumulative incidence of progression was 13% and 20% at 5 and 10 years, respectively. The serum IgM ≥10 g/L, bone marrow (BM) infiltration ≥20%, β2-microglobulin ≥3 mg/L, and albumin <4 g/dL were the most potent predictors of disease progression in a multivariate Cox regression model, allowing the identification of three risk categories. The probability of progression to symptomatic disease at 5 years was 4.5%, 15.7%, and 42.8% for low-, intermediate-, and high-risk groups, respectively. In patients without a BM evaluation, the presence of none or 1 risk factor and 2 or 3 risk factors conferred a progression risk of 6% and 27% at 5 years, respectively. The model was independent of the presence of MYD88 L265P, which conferred a negative impact only in AWM patients. The relative survival (RS) ratio at 5 years of asymptomatic patients was similar to the Spanish population, which contrasted with the 0.76 5-year RS of SWM patients. Overall, the Spanish Multicenter Model comprehensively describes the risk of progression of asymptomatic patients and shows that the excess mortality is increased only in the symptomatic stage of the disease.

Figure 1

Flowchart and design of the study of the Spanish registry of asymptomatic IgM monoclonal gammopathy patients. n, number of patients.

Figure 2

Progression‐free survival (PFS) in the Spanish multicenter registry and according to each prognostic risk model. Each plot reflects a Kaplan–Meier survival curve of the progression risk in the Spanish Cohort (A), the Italian group (B), the Dana Farber Cancer Institute (DFCI) group (C), and the Barcelona group (D).

Figure 3

The new proposed model of the risk of progression in the entire series of patients with complete data with (A) and without a bone marrow aspirate (B). Below are depicted the 270 patients with an available bone marrow biopsy, allowing to study the different risks of progression of IgM monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic Waldenström macroglobulinemia (AWM) (C), and the performance of the proposed model based on bone marrow aspirate in patients with bone marrow biopsy (D). PFS, progression‐free survival.

Figure 4

Longitudinal performance of the prognostic biomarkers. Each dot represents a separate time point per subject for the bone marrow infiltration by aspirate (A), serum IgM (B), albumin (C), and β2‐microglobulin (D). N, number of subjects.

Figure 5

Relative survival rates compared with the Spanish Health records from the Human Mortality Database. Each plot reflects the relative survival rate (in red), the Spanish population actuarial survival (in blue), and the patients' actuarial survival (in green) (A). Symptomatic Waldenström macroglobulinemia patients showed a survival curve below the Spanish population since diagnosis (B). CI, confidence interval.