Natural History and Outcomes of Asymptomatic IgM Monoclonal Gammopathy

Waldenström's macroglobulinemia (WM) is a distinct clinical entity defined by the presence of a serum monoclonal IgM and bone marrow (BM) infiltration of ≥10% lymphoplasmacytic cells. Asymptomatic (smoldering) WM (aWM) is defined by the presence of serum IgM ≥3 g/dL and/or ≥10% BM lymphoplasmacytic infiltration but no evidence of end-organ damage (symptomatic anemia/cytopenias, constitutional symptoms, lymphadenopathy, hepatosplenomegaly or IgM-related symptoms such as hyperviscosity, severe neuropathy etc) that can be attributed to the underlying clonal disorder (Kyle et al; Blood 2012). IgM monoclonal gammopathy of undetermined gammopathy (MGUS) is defined by the presence of a monoclonal IgM of <3 g/dL, <10% of clonal lymphoplasmacytic cells in the BM and the absence of symptoms related to the underlying clonal disorder or monoclonal IgM. Herein, we report the outcomes of IgM MGUS and aWM in a well-defined cohort of 103 consecutive subjects with asymptomatic IgM monoclonal gammopathy.

All patients were diagnosed and followed in the Department of Clinical Therapeutics (Athens, Greece) since 1995 and had BM biopsies available. Patients who presented with IgM-related complications (neuropathy, Schnitzler syndrome, IgM related amyloidosis etc) were not included. At the time of diagnosis of the IgM gammopathy, median age of all subjects was 71 years (range 25-86), 76% had IgMκ and 24% IgMλ; only one had a biclonal gammopathy (IgM and IgG). Median IgM was 1024 mg/dL (range 104 - 5320) and the monoclonal spike in the SPEP was 0.84 g/dL (ranging <0.1-4.35) and only 3% had M-monoclonal protein ≥3 g/dl. Median hemoglobin was 12.8 gr/dl, median platelet counts was 271 x 10⁹/L (range 104-499), median peripheral blood lymphocytes 1850/uL (range 220 - 5620) and median β2-microglobulin (β2M) was 2 mg/L (range 1.1-16.8). Among 71 patients with available free light chains at the time of initial diagnosis, 44 (63%) had abnormal FLC ratio. The median clonal cell BM infiltration was 20% (range 0-90%) and there was an association of serum IgM levels and extent of clonal cell infiltration (r=0.416, p<0.001). Immunoparesis (low levels of non-involved immunoglobulins) was present in 32% of the subjects; 22% hag low IgG, 28% low IgA and 18% had both IgG and IgA suppressed.

According to the definition by Kyle et al, 62 (61%) subjects had aWM and 41 (39%) IgM MGUS. Patients with aWM had higher M-protein (median 1.24 vs 0.55 g/dL) and more often monoclonal protein ≥1 g/dl (58% vs 13%, p<0.001) so that 42% of patients with <1 g/dL of monoclonal IgM had ≥10% clonal lymphoplasmacytic cells. There were no differences in other characteristics such as gender, age, hemoglobin levels or β2M. Median follow up of the whole cohort is 5 years (range 1-21); 15 (14%) patients have progressed to develop symptomatic disease and 8 (7%) have died without developing symptomatic disease. For patients with aWM the respective rate of PD to symptomatic disease and of unrelated death was 20% and 3% at 2 years and 39% and 8% at 5 years respectively. For those with IgM MGUS the PD rate and unrelated death rates were 0% and 3% at 2 years and 3% and 7% at 5 years. Thus, aWM was associated with a 7-fold increase of risk of progression to symptomatic disease compared to IgM MGUS (95% CI 3-27, p=0.001). Symptoms defining progression included peripheral neuropathy in 4 patients, B-symptoms in 5, anemia (<10 g/dl) in 8 and organomegaly (splenomegaly and lymphadenopathy) in two. The overall survival for all patients is 91% at 5 years, similar for IgM MGUS and aWM. In patients with aWM, hemoglobin <12 g/dl (p=0.004) and BM clonal cells ≥50% (p=0.04) were associated with higher risk of progression but not IgM levels or abnormal FLCs ratio or the presence of immunoparesis. In multivariate analysis, hemoglobin <12 g/dl (p=0.016) and BM clonal cells ≥50% (p=0.051) were independently associated with shorter time to PD.

In conclusion, patients with aWM should be followed without treatment unless symptoms develop. Bone marrow infiltration ≥50% and a hemoglobin <12 g/dL are the major risk factors for progression to symptomatic disease. For those with IgM MGUS the risk of progression is low but they should be evaluated periodically for the development of symptoms related to the underlying dyscrasia. Because 42% of patients with monoclonal IgM <1 g/dL had ≥10% lymphoplasmacytic cells, bone marrow biopsy is indicated in all patients.

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