Isotype Matched Paired Immunoglobulin Suppression Identifies High Risk Multiple Myeloma Patients and Is Independent Of Bone Marrow Infiltration Suggesting Significant Variability In The HLC Matched Pair Suppressive Activity Of Individual Myeloma Clones
Authors: Ludwig Heinz , Milosavljevic Dejan , Young Philip , Zojer Niklas , Harding Stephen 
Published: October 2019

Abstract

Introduction
Multiple myeloma (MM) is characterised by the production of monoclonal immunoglobulins (MIg), both intact and a free light chain (FLC) component. The production of MIg can be associated with suppression of the non-involved isotypes which can easily be measured by conventional techniques while identification of a possible suppression of the HLC matched pair isotype was not possible before the introduction of the HLC assay. Here we assess the frequency and biologic relevance of the suppression of HLC pair matched isotypes and non-involved isotypes and correlate these findings and those of MIg measurements with bone marrow plasma cell (BMPC) infiltration.

Patients and Methods
113 previously untreated MM patients (72 IgG (46κ, 26λ) and 41 IgA (23κ, 18λ)) with a median age of 65 years (range 32-86 years) were enrolled and followed for up to 13 years (median: 4 range 0.25-13 years). Serum FLC (FLCκ/FLCλ) and HLC concentrations (IgGκ/IgGλ and IgAκ/IgAλ) measurements were made using polyclonal antisera assays (FreeliteTM, Binding Site, Birmingham, UK. and, HevyliteTM, Binding Site, Birmingham, UK) and results compared to standard serum assessments (SPE, IFE, β2M, Albumin, LDH and CRP) and bone marrow plasma cell (BMPC) infiltration. Severe non-involved isotype or HLC pair suppression was defined as >50% lower of than the published lower normal ranges for the relevant isotypes. Correlation and survival analysis was performed using the SPSS v 21 programme.

Results
Median overall survival was 46 months (range 3-158). IgA MIg production correlated weakly to BMPC infiltration at presentation (Pearsons 0.327; p=0.026) but to no other marker. Uninvolved IgA HLC did not correlate to BMPC infiltration but had a weak correlation to LDH (Pearsons 0.436; p=0.002). By contrast, IgG MIg production showed significant correlation to ß2M (Pearsons 0.53; p<0.001), with uninvolved IgG HLC having no significant correlations. There was a greater degree of monoclonal production in IgG patients than in IgA patients (p=0.049). Severe IgG and IgM suppression was noted in 13/41 (31%) of IgA patients with 78% of patients having either isotype suppressed. In IgA MM patients IgM suppression was more commonly identified than IgG (32/41 v 13/41 patients respectively) and IgG suppression was always concomitant with IgM suppression. Severe IgA and IgM suppression was noted in 36/72 (50%) of IgG patients with 69% of patients having either isotype suppressed. In contrast to IgA patients there was no difference between the incidence of IgA or IgM suppression. Severe isotype matched pair suppression was more frequently noted in IgG compared to IgA patients (66% vs. 60%, p<0.01). Severe HLC pair suppression correlated with a decreased OS (46.6 vs. 84.4 months, p<0.044). By contrast neither non-involved isotype nor monoclonal Ig production was correlated with outcome.

Discussion and Conclusion
The correlation between IgG MIg and BMPC infiltration indicates a greater uniformity in the inter-individual MIg production rate in patients with IgG compared to those with IgA MIg, which were only weakly correlated with BMPC infiltration. Part of this finding may also be due to greater variations in the catabolic rate of individual IgG MIgs. The absence of a correlation between the degree of HLC pair suppression and BMPC infiltration suggests significant variation in the ability of individual clones in suppressing the isotope matched pair. This uncoupling between the proportion of myeloma cells and isotype suppression was previously unknown. Myeloma clones with greater HLC matched isotype pair suppression reflect a more aggressive phenotype which correlates with short survival. Suppression of the non-involved isotype, in contradistinction, showed no prognostic relevance.

Disclosures:
Young: The Binding Site Group Ltd: Employment. Harding:The Binding Site Group Ltd: Employment.