Abstract
Simple SummaryPatients with asymptomatic IgM monoclonal gammopathies include IgM monoclonal gammopathy of undetermined significance (IgM MGUS) and smoldering Waldenström macroglobulinemia (SWM), all with some risk of progression to symptomatic Waldenström macroglobulinemia, amyloidosis, or other lymphoproliferative disorder. Due to their low incidence, few studies have focused on the risk of progression, with SWM being the most studied. As both are recognized clinical-pathological entities that share similar clonal and phenotypical features, we focus on defining new biomarkers of progression in this population with long follow-up.We analyzed 171 patients with asymptomatic IgM monoclonal gammopathies (64 with IgM monoclonal gammopathy of undetermined significance—MGUS and 107 with smoldering Waldenström macroglobulinemia - SWM) who had a bone marrow (BM) evaluation performed at diagnosis. Abnormal free-light chain ratio (53% vs. 31%) and MYD88 mutation prevalence (66% vs. 30%) were higher in patients with SWM. No other differences were found among groups. With a median follow-up of 4.3 years, 14 patients progressed to Waldenström macroglobulinemia, 1 to amyloidosis, and 28 died without progression. The MYD88 mutation was found in 53% of patients (available in 160 patients). Multivariate analysis showed that immunoparesis (subhazard ratio—SHR 10.2, 95% confidence interval—CI: 4.2–24.8; p < 0.001) and BM lymphoplasmacytic infiltration ≥ 20% (SHR: 6, 95% CI: 1.6–22.1; p = 0.007) were associated with higher risk of progression. We developed a risk model based on these two risk factors. In the absence of both variables, an ultra-low risk group was identified (SHR 0.1, 95% CI 0.02–0.5; p = 0.004), with 3% and 6% of cumulative incidence of progression at 10 and 20 years, respectively. Bootstrap analysis confirmed the reproducibility of these results. This study finds immunoparesis and BM infiltration as biomarkers of progression as well as a low-risk group of progression in asymptomatic IgM monoclonal gammopathies.
Highlights
Waldenström macroglobulinemia (WM) is a lymphoproliferative disorder characterized by the presence of an IgM monoclonal protein (M-protein) and bone marrow (BM)
The aim of this study was to investigate predictors of progression in patients with asymptomatic IgM monoclonal gammopathies observed over a long period, incorporating immunoparesis, BM infiltration, and the presence of MYD88 L265P mutation with an intention to find an accessible and reproducible risk model overtaking the definition gap and highlighting a population of patients that may be categorized as IgM monoclonal gammopathy of undetermined significance (MGUS) or smoldering WM (SWM)
With an MYD88 mutation prevalence of 52.5% in the whole series, we found a trend for this mutation to be associated with than 20% of lymphoplasmacytic infiltration (38% vs. 77%; p < 0.001)
Summary
Lymphoplasmacytic infiltration [1,2] It is preceded by two asymptomatic clinicopathological entities such as IgM monoclonal gammopathy of undetermined significance (MGUS) and smoldering WM (SWM) [2,3,4]. The Mayo Clinic criteria established a cut-off of 10% while the Second International Consensus on Waldenström macroglobulinemia defined SWM as any BM lymphoplasmacytic infiltration in the absence of symptoms [1,2,3]. Risk models have been developed under these definitions applied to each clinical entity among centers. One study proposed the inclusion of IgM MGUS and SWM in a unique and feasible risk model as both entities share some prognostic determinants but it has not been replicated [7]
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