Natural History of Asymptomatic IgM Monoclonal Gammopathies: Impact of the Bone Marrow Aspiration into the Classification and Prognosis
Authors: Fernandez de Larrea Carlos , Moreno David , Tovar Natalia , Cibeira Maria Teresa , Isola Ignacio , Magnano Laura , Rosinol Laura , Bladé Joan 
Published: October 2019

Abstract
Introduction: As in multiple myeloma, Waldenström macroglobulinemia (WM) is preceded by an asymptomatic phase, mainly as monoclonal gammopathy of undetermined significance (MGUS) or by a smoldering WM (SWM) phase. It has recently been reported that patients with IgM MGUS have a higher risk of progression in comparison to those with other MGUS isotypes. Moreover, it has been described that if the IgM MGUS is associated with adverse factors such as abnormal serum free light chains ratio and more than 15 g /L serum M-spike, the risk of progression at 20 years is as high as 55%. The aim of this study was to evaluate the risk of progression of asymptomatic IgM monoclonal gammopathies, using bone marrow aspiration as the main criteria for classification between SWM and IgM MGUS.
Methods: We reviewed retrospectively the medical records of 206 patients with asymptomatic IgM monoclonal gammopathies, 143 (69.4%) with IgM MGUS and 63 (30.6%) with SWM diagnosed in our institution from May 1982 to December 2017. In the absence of clinical manifestations, IgM MGUS was defined as the presence of less than 30 g/L of serum IgM monoclonal protein and less than 10% lymphoplasmacytic bone marrow (BM) infiltration. The diagnosis of SWM required the presence of any size IgM M spike associated with ≥10% lymphoplasmacytic bone marrow infiltration with no target organ involvement, constitutional symptoms, hyperviscosity, lymphadenopathies or peripheral neuropathy. Progression to WM was defined according to the 2014 International Consensus.
Results: The median age of the series was 70 years (range, 29 to 98) and the male/female distribution was 106/100. SWM group had a significantly higher median serum M spike than the MGUS group (9.2 vs. 4.6 g/L; p<0.001) as well as slightly higher serum IgM levels (median 12.6 g/L vs. 11 g/L, p< 0.001). We did not find differences either in the β2-microglobulin or albumin values between the two groups. IgG and IgA immunoparesis (low uninvolved immunoglobulin level) was similar between patients with IgM MGUS and SWM. MYD88 L265P presence was determined in 125 patients, being positive in 85% of the SWM cases compared to 34% in the IgM MGUS group (p < 0.001).
Only 6 (2.9%) of the patients had more than 30 g/L of serum M protein. For this reason, diagnosis of SWM was mainly based on results of BM aspiration. Median BM infiltration by plasma cells and lymphocytes was significantly higher in patients with SWM when compared to patients with MGUS (4 vs. 3%, p=0.027; 24 vs. 9%, p < 0.001, respectively), being the lymphocyte infiltration the most relevant difference. Thus, serum M protein correlated significantly with BM lymphocyte percentage (p=0.011) but not reaching significance when plasma cell infiltration (p=0.071) was analyzed.
Median time of follow up was of 3.3 years for living patients. The evolving pattern of the M-spike was identified in 21 patients (10.2%). This paraprotein behavior was associated with a shorter progression to symptomatic WM (p=0.026), but mainly due to its higher frequency in the SWM group than in the MGUS one (19% vs. 6.3%, p=0.005).
Diagnosis of SWM impacted negatively the prognosis of the patients, with a higher rate of progression to symptomatic disease at 3 years (15% vs. 2%). Thus, the risk of progression of SWM was 11 times greater than those with IgM MGUS (HR 11.7, p < 0.001; 95% CI 3.3-41.3) (Figure 1). There was also a significant difference on survival between both groups of patients (median overall survival 20 vs. 13 years; p=0.027).
Conclusions: In our series, the progression rate from IgM MGUS to symptomatic WM was clearly inferior to that reported in other historical series and quite similar to the progression rate of IgG MGUS (1% per year), being also significantly higher for patients with SWM. Evolving pattern is rare in IgM MGUS but it was identified in 19% of patients with SWM. These findings suggest that bone marrow evaluation is crucial in the prognosis of asymptomatic IgM monoclonal gammopathies.

Disclosures
Rosinol: Janssen, Celgene, Amgen, Takeda: Honoraria. Bladé:Janssen: Honoraria.