Quantification of Serum IgMκ and IgMλ In Patients with Waldenstrom's Macroglobulinemia (WM) at Diagnosis and During Disease Course; Clinical Correlations
Authors: Koulieris Efstathios , Kyrtsonis Marie-Christine , Maltezas Dimitris , Tzenou Tatiana , Mirbahai Ladan , Kafassi Nikolitsa , Bartzis Vassiliki , Dimou Maria , Georgiou George , Matsouka Charis , Pangalis Gerasimos , Panayiotidis Panayiotis , Bradwell Arthur , Harding Stephen 
Published: October 2019

Abstract
Abstract 3004
Resolution of IgM monoclonal proteins (M-proteins) on serum protein electrophoresis (SPE) can make accurate quantification difficult. The same applies to the determination of total IgM by nephelometry which inherently includes monoclonal and polyclonal immunoglobulins. Specific polyclonal antibodies, which recognise epitopes spanning the junction of the heavy and light chains of the individual immunoglobulin isotypes, have been produced and used to develop nephelometric assays (Hevylite™). The purpose of the present study is to evaluate the prognostic value IgMκ/IgMλ ratios (HLCR) at diagnosis and the role of HLCR in disease monitoring. Retrospective sera from 31 WM patients, 4 IgM-MGUS, 2 IgM-like syndrome at diagnosis and for 9 of them during disease course, were included in the study. Analysis of IgMκ and IgMλ was performed on a Siemens Dade-Behring BN™II nephelometer and results were compared with disease parameters such as blood count, beta2-microglobulin (β2M), serum albumin, lactate dehydrogenase (LDH), and lymphoplasmacytic bone marrow infiltration. Abnormal HLCR were reported in 30/31 WM patients. There was a good correlation between summated IgMκ + IgMλ and total IgM (r=0.832 p<0.0001), although in 12 patients there was considerable disagreement between total IgM (range 12.9–80.4) and summated IgMκ + IgMλ (range 22.2–150.8, p>0.01). These 12 patients presented polyclonal hypogammaglobulinemia (with regard to their IgG and IgA levels). Median IgM HLCR (expressed as IgMκ/IgMλ or IgMλ/IgMκ with the involved Ig as numerator) were 90.88 (range 1.91–1000) in WM v 17.65 (range 1.08–34.57) in IgM-MGUS (p=0.06). Median IgM HLCR was significantly higher in WM patients requiring treatment (n=24) at presentation than in patients not (n=7) requiring treatment (185.7 v 13.45 p=0.023). IgM HLCR correlated with bone marrow infiltration (p=0.029) and time to first treatment (p=0.003). A simple risk stratification model utilising: IgM HLCR>median, β2M>5 and abnormal LDH, identified 3 prognostic groups with respect to survival (p<0.0001) in this series with a median follow-up of 59 months. In the 9 patients followed during treatment, involved HLC IgM and IgM HLCR mostly followed disease fluctuations and never normalized but patient entered only partial remissions. In 1 IgMκ WM patient who presented “flare” during treatment with rituximab the IgMκ and the IgM HLCR increased while the IgMλ remained constant, indicating that the flare involves only the monoclonal paraprotein. In 2 patients with polyclonal uninvolved hypergammaglobulinemia, response was accompanied with normalization of the uninvolved components. In conclusion, HL IgM and IgM FLCR seems to separate patients with a more aggressive disease. Further studies will be needed to evaluate their utility for monitoring WM patients.

Disclosures:
Mirbahai: Binding Site Group Ltd: Employment. Bradwell:Binding Site: Equity Ownership, Patents & Royalties. Harding:Binding Site Group Ltd: Employment.