Are IgM Hevylite® Immunoglobulin Heavy Chain/Light Chain Analysis a Useful Tool to Differentiate IgM MGUS From Waldenström Macroglobulinemia?

Monoclonal IgM is the biomarker that characterize to Waldenstrom's macroglobulinemia (WM), a rare low grade B-cell lymphoma derived of the lymphoplasmacytic cell, even serum IgM component also is presented in MGUS. Recently new determinations of heavy chain/light chain immunoglobulins pairs (HLC) have been developed as biomarkers to apply to every day clinical practice. The diagnostic and prognostic potential of these biomarkers is under investigation. The aim of this study is to present our experience in the use of free light chain assay (sFLC) and HLC as biomarkers at diagnostic in order to discriminate between MGUS and WM, and to evaluate their potential prognostic value during disease course.

A total of 43 patients (pts) were detected as having a serum monoclonal IgM in the Hematology Department of MSUH. Pts were classified as MGUS or WM according to the morphological, immunophenotype characteristics of lymphoplasmacitic bone marrow cells and CT-scan data. Pts were examined every 3–6 months following our clinical protocol in order to detect progression or transformation. Serum samples were collected prior and during treatment and were kept frozen at −70°C since collection and incorporate to our regional Biobank. Analysis of IgM were performed with the sFLC, (Freelite® test, the Binding Site, Birmingham, UK) and the HLC (Hevylite® immunoassay the Binding Site). Freelite® test is a nephelometric measurement of kappa and lambda light chains that circulate not bound to immunoglobulin heavy chain. Hevylite® immunoassay is based on specific polyclonal antibodies that recognize epitopes spanning the junction of the heavy and light chains of the individual immunoglobulin isotypes, it measures specifically IgMkappa and IgMlambda, separately. A normal range of IgM Hevylite assay was produced from normal (blood donor) sera, median (CI 95%) were: IgMkappa, 0. 634 g/L (0. 29–1. 82); IgMlambda, 0. 42g/L (0. 17–0. 94); HLC ratio (HLCR), 1. 6 (0. 95–2. 3). For ease of comparison IgM HLCR was expressed as the involved monoclonal immunoglobulin (iHLC)/uninvolved polyclonal immunoglobulin (uHLC).

The study included a series of 25 WM, 18 IgM-MGUS (included 2 IgM-cryoglobulinemia), 36 at diagnosis and 7 at relapse/refractory. The median age was 67. 1 years (13–85); IgM HLCR was 114. 68 (1. 02 – 353) in WM symptomatic, 71. 55 (1. 02 – 286. 43) in WM asymptomatic and 9. 5 (0. 45 – 50. 74) in IgM MGUS (p=0. 003). HLCR was higher in WM patients requiring treatment (n=13) at diagnosis than in pts (n=30) not requiring treatment (113 v 15. 77 p=0. 019) and also HLCR was significantly higher at relapse/refractory (n=9) than in pts (n=34) not relapse (113 v 17. 17 p=0. 012) uHLC was significantly higher in IgM-MGUS than WM to IgMkappa (n=28) and IgMlambda (n=15) iHLC: 0. 37 g/L (0. 11–1. 25) v 0. 1 g/L (0. 02–4. 03), p=0. 022; and 0. 69 g/L (0. 08–4. 09) v 0. 32 g/L (0. 22–0. 63), p=0. 05 respectively. sFLC level was 64 mg/L (10. 88–993) in WM and 31. 7 mg/L (6. 08–141) in IgM MGUS (p=0. 05). sFLC level was higher in WM requiring treatment at diagnosis than in pts not requiring treatment (73. 7 v 36. 85 p=0. 039). sFLC level was not significative in relapse/refractory (p=0. 168), it was not separate between WM asymptomatic and WM symptomatic (p=0. 092). There was a good correlation between HLCR and sFLC ratio (r=0. 3, p=0. 044) but not with sFLC level, HLCR, sFLC level and sFLC ratio did not predict for overall survival (OS) and progression free survival (PFS) in our study. Mean estimated OS was 78. 3 months (95% CI: 53. 67–102. 94) and PFS 69. 7 months (95% CI: 47. 28–92. 13).

It seems that HLCR and sFLC could be good biomarkers to differentiate between IgM-MGUS and WM at diagnostic. High levels of HLC and sFLC were also seen in pts requiring treatment. HLCR discriminates WM symptomatic/asymptomatic and progressing pts uHLC levels were significantly higher in IgM-MGUS than WM pts showing that IgM-MGUS have a more robust immune system. Further studies are needed to evaluate their prognostic value.

This work has been partially sponsored by a grant from FEHHA

No relevant conflicts of interest to declare.