Severe Isotype-Matched Immunosuppression By Hevylite® Is Predictive of Shorter Time to Progression in MGUS Patients
Authors: Jiménez Jiménez Juana , Pais Tiago M , Barbosa Nuno , Campos Luisa , Peñalver Maria Antonia , Hernando de Larramendi Carmen 
Published: October 2019

Abstract

Monoclonal gammopathy of undetermined significance (MGUS) accounts for c.a. 50% of all diagnosed plasma cell dyscrasias and is the precursor state of all multiple myelomas (MM). However, only a small number of cases will progress to a malignant state. The challenge is on how to identify these patients and, specifically, those that are at imminent risk of developing symptomatic disease. Presently, two main bio-marker based models are used in the risk assessment of MGUS patients (Mayo Clinic group and Spanish Myeloma group), however, some patients are very differently assessed by the two models. The recently developed Hevylite assay allowed, for the first time, to easily quantify the uninvolved immunoglobulin associated with the tumor isotype and therefore study the presence of isotype-matched immunosuppression (IMI). In this study we aimed at assessing the utility of this assay for MGUS risk stratification.
Methods:
309 stored serum samples from 248 MGUS (164 IgG, 44 IgA, and 40 IgM) patients attending different services from our hospital. Patients were previously risk stratified according to the 2010 IMWG guidelines (Kyle et al Leukemia). Samples were analyzed with Hevylite® (The Binding Site, UK) in a BNII analyzer (Siemens) according to the monoclonal protein isotype. Normal ranges were those provided by the manufacturer. Values 50% below the lower normal ranges of the immunoglobulins determined by Hevylite were defined as severe IMI.
Results:
Ninety percent of the patients showed an abnormal Hevylite Ig'k/Ig'λ ratio (i.e. IgGk/IgGL for an IgG-MGUS) with the greatest percentage observed for IgA and IgM isotypes (95% abnormal ratios). Regarding the isotype-matched immunosuppression, it was observed in 56% of the samples. The frequency of IMI by Hevylite was strongly associated with MGUS risk group (p=0.013) showing a greater prevalence in the highest risk group (Fig.1). Additionally, no significant difference was observed in relation to monoclonal isotype: IgG=60%, IgA=69%, IgM=57%, (p=0.37). Classical immunoparesis (i.e., suppression of IgG and/or IgM in an IgA patient), was less frequent than IMI (43% vs 56%, p<0.0001) but it also increased among higher risk MGUS patients (p=0.0064).
Of the 248 MGUS patients, follow-up clinical records were recovered from for 127 (107 IgG, 20 IgA) allowing us to perform a progression free survival (PFS) based on Hevylite first sample results. Severe IMI was able to differentiate two groups of patients with significantly different PFS (p=0.023) (Fig.2). On the contrary, severe suppression of either one of the non-involved immunoglobulins (e.g. classical immunoparesis) was not associated with significant greater risk of progression (p=0.309). Interestingly, there was almost the double of patients with severe IMI in comparison with severe classical immunoparesis.
Conclusions
The results obtained are in line with a previous study from Katzmann et al (Leukemia 2103) where Hevylite pair suppression greater than 50% predicts progression of MGUS, thus reinforcing the potential utility of this parameter as a marker for the risk assessment of monoclonal gammopathies. It also suggests that, in this context, the predictive value of IMI is more useful than that of classical immunoparesis.
Figure 1 Percentage of patients with immunosuppression by MGUS risk group.*p<0.038 for IMI vs IP Figure 1. Percentage of patients with immunosuppression by MGUS risk group.*p<0.038 for IMI vs IP Figure 2 Time to progression according to severe isotype-matched immunosuppression by Hevylite. Figure 2. Time to progression according to severe isotype-matched immunosuppression by Hevylite.

Disclosures
Pais: The Binding Site: Employment. Barbosa:The Binding Site: Employment. Campos:The Binding Site: Employment.