Serum Free Light Chain in Waldenstrom Macroglobulinemia.
Authors: Moreau Anne-Sophie , Leleu Xavier , Manning Robert , Coiteux Valérie , Darre Stéphane , Hatjiharisi Evdoxia , Hunter Zachary , Jia Xiaoying , Ngo Hai , O’Sullivan Garrett , Santos Daniel , Treon Steven , Facon Thierry , Anderson Kenneth , Ghobrial Irene 
Published: October 2019

Abstract
Background: Waldenstrom macroglobulinemia (WM) is a low-grade lymphoplasmacytic lymphoma characterized by the involvement of the bone marrow with lymphoplasmacytic cells and the production of IgM monoclonal protein. The serum IgM level is an important marker of diagnosis and response; however, it does not correlate with prognosis. Because of it’s long half-life, it is not a sensitive test for response, indicating the need for more sensitive serum markers that predict tumor burden. The level of serum beta 2 microglobulin (B2M), cytopenias, and age are poor prognostic markers in WM. In this study, we sought to determine the value of serum free light chain (sFLC) in WM.
Method: We analyzed 159 patients, 99 patients with WM and 70 patients with IgM-MGUS. sFLC levels were performed using Freelite™ reagents on a Dade-Behring Nephelometer. The Freelite assay (The Binding Site, UK) uses antibodies directed against the free light chain (FLC) epitopes. The clonal free light chain was considered the involved immunoglobulin free light chain (FLC), whether kappa or lambda.
Results: The median age at diagnosis was 63 years (range, 37–90). The male/female ratio was 1.5. Forty-one% of the patients with WM required therapy at the time of this study. In the patients diagnosed with WM, the median serum B2M was 2.3 mg/L, median hemoglobin 10 gm/dL, median serum viscosity 1.9 cp, and median platelet count 240 ×109/L. Kappa light chain was present in 74% of the total cohort, with no difference between WM and IgM-MGUS. The mean sFLC was significantly higher in WM as compared to IgM-MGUS, with131.2 mg/L (95% CI 72–189) in WM and 39.2 mg/L (95% CI 21–56) in IgM-MGUS, p=0.003. In addition, sFLC correlated with the serum IgM level (r=0.27; p=0.008). To determine whether sFLC predicted for poor prognosis, we analyzed the relation of sFLC with prognostic markers. Elevated sFLC strongly correlated with high serum B2M (r=0.33; p=0.001), anemia (hemoglobin <10 gm/dL) (r=0.39; p<0.001), and thrombocytopenia (platelet count <120×109/L) (r=0.22; p=0.034). There was no correlation with age at diagnosis. We next defined the threshold of sFLC 50 mg/L, based on its ability to correctly classify MGUS and WM with an 88% specificity to identify MGUS in the group with low sFLC. This cut off was able to correctly classify patients with low B2M (<= 3 mg/L) and high B2M (>3 mg/L), (p<0.001). Prognostic models were then developed based on B2M, anemia (hemoglobin <10gm/dL) and thrombocytopenia (platelet count <120×109/L). A point was given for elevated B2M of >3mg/L, anemia, or thrombocytopenia, with score of 3 indicating elevated B2M in combination with anemia and thrombocytopenia. Elevated sFLC (>=50 mg/L) was able to correctly classify patients with a score of 2 points or more versus 1 point in this model (p<0.005).
Conclusion: sFLC clearly differentiated patients with WM and IgM MGUS. In patients with WM, sFLC significantly correlated with poor prognostic markers. Future studies are needed to validate the role of sFLC as a prognostic marker of survival in WM. ASM and XL are co-first authors.