Heavy Chain Ratio (HLCR) IgGκ/IgGλ or IgAκ/IgAλ: Experience and Clinical Implications In Multiple Myeloma at Diagnosis and During Disease Course
Authors: Koulieris Efstathios , Kyrtsonis Marie-Christine , Kafassi Nikolitsa , Maltezas Dimitris , Bartzis Vassiliki , Tzenou Tatiana , Dimou Maria , Georgiou George , Mirbahai Ladan , Panayiotidis Panayiotis , Bradwell Arthur , Harding Stephen 
Published: October 2019

Abstract
Abstract 5019
A new method for the quantification of IgGκ, IgGλ, IgAκ and IgAλ individually and of deriving IgGκ/IgGλ and IgAκ/IgAλ ratios (HLCR) has been recently made available, allowing measurements of the monoclonal component alone as well as of the polyclonal, non-tumor immunoglobulins (Ig) in plasma cell dyscrasias. The purpose of the present study was to retrospectively determine HLCR and to investigate its contribution in a series of 98 multiple myeloma patients at presentation and in 38 of them, during their disease's course. There were 45 women and 53 men (median age 67 years). Disease stages were evenly distributed (36%, 30%, and 34% in ISS stage 1, 2, and 3 respectively). Paraprotein was IgG in 74 patients (50 IgGκ, 24 IgGλ) and IgA in 24 (12 IgAκ, 12 IgAλ) of them. Seventy-one symptomatic patients received conventional treatment while the other 27 were asymptomatic and were regularly followed only. Of the 38 patients also studied during disease course, 28 had IgG- and 10 IgA-MM; the median number of disease fluctuation events studied (remision-relapse) was 3 (range 2–9). Patients' median follow-up was 31 months. HLC analyses were performed on a Dade Behring BN™II nephelometer using polyclonal sheep antibodies (Hevylite™, Binding Site, UK) and HLCR was calculated with the involved Ig (either G or A) as numerator. HLC and HLCR values were then compared with disease parameters and survival. Statistical analysis was performed by standard methods. At patients' presentation, median monoclonal HLC IgG and IgA were 25 g/L and 32 g/L respectively while in patients with IgG-MM median IgG HLCR was 24.5 and IgA HLCR 60 in IgA-MM. HLCR was not correlated to b2-microglobulin, hypercalcemia, LDH or bone disease, FLCs or FLCR. It strongly correlated with time to treatment (p=0.0000093) and with a shorter overall survival (p=0.03) using as cut-0ff HLCR values in the upper tertile of symptomatic patients (>56 for IgG and >228 for IgA). Of patients also studied during their disease course, 25 out of 38 patients responded at least partially (PR) to first line treatment and 9 to a subsequent one; 20 relapsed and then responded again. In most patients HLCR followed disease fluctuations. It normalized in 9 patients and was below normal in 1 patient that achieved a complete (CR) or stringent response (sCR). In some patients HLCR allowed a better evaluation of disease status. In 5 thought to be responding, ηLCR remained stable or increased and disease course confirmed the fragility of the believed response. Interestingly, more than 50% of patients that received VAD showed greater reduction of the polyclonal Ig than the tumor Ig during treatment and sometimes thereafter. In conclusion, we provide evidence that HLCR correlates with survival in MM and allows, in some patients, better disease monitoring.

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