Severe Isotype-Matched Immunosuppression (IMI) as a Potential Risk Factor for Progression of MGUS Patients

Abstract

Background: Monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma in virtually every case. However, only a small percentage will progress and at very different rates. In addition, recent data have suggested that MGUS is associated with other comorbidities including infections, suggesting impaired immune function in some MGUS patients. Therefore, we aimed at assessing the value of isotype-matched immunosuppression (IMI; e.g., suppression of an IgAκ in an IgAλ patient), a type of immunosuppression more specific than classical immunoparesis (IP; e.g., IgG and/or IgM suppression in an IgA patient), as a prognostic marker for MGUS progression. Methods: The Hevylite assay was used to assess IMI and immunoglobulin ratios in 307 serum samples from a cohort of 248 MGUS patients. Follow-up clinical records were available for 154 individuals. Results: A greater incidence of IMI (51%) over classical IP (37%) was observed, although both show a progressive increase with higher risk groups. Survival analysis of 154 patients showed that severe IMI (>50% suppression) differentiates 2 groups with significantly different time to progression (P = 0.024) while severe IP does not (P = 0.48). Also, a combination of severe IMI and involved monoclonal immunoglobulin >1.5g/dL by Hevylite (both variables found to be independent prognostic markers in multivariate analysis) identified a group of patients with a median time to progression 6-fold shorter than the remaining group (P < 0.0001). Conclusions: These findings indicate a possible role for IMI in the malignant transformation of MGUS patients and a potential utility as a new risk factor. IMPACT STATEMENT Patients diagnosed with MGUS are at a greater risk of developing multiple myeloma or a related disease. Importantly, the conversion rate is highly heterogeneous, and hematologists rely on biomarkers to estimate the risk of progression and to decide on the clinical approach. We describe the role of a new type of immunosuppression as an independent indicator of early progression, contributing to a better characterization of the condition. This immunosuppression is characterized by decreased levels of the immunoglobulins of the same type of the tumor B-cells but of the alternative light chain, and is easily measured by a simple serum test called Hevylite ® .

The Current Role of the Heavy/Light Chain Assay in the Diagnosis, Prognosis and Monitoring of Multiple Myeloma: An Evidence-Based Approach

“…This finding did not reach statistical significance in IgA and IgM MGUS, probably due to the very low number of patients conforming some of the subsets. More importantly, as a result of a multivariate analysis, severe IMI, contrary to severe classical immunoparesis, was found to be an independent risk factor of progression from MGUS to symptomatic disease [53]. Similar results were obtained by Katzman and colleagues with IMI.…”

“…In asymptomatic patients, IMI seems to have an interesting role in identifying those patients with higher risk of progression. In MGUS, two large studies have found IMI to be an independent risk factor of progression [32,53]. In fact, the addition of the IMI to the stratification model developed by the Mayo Clinic resulted in the better identification of those patients at highest risk of progression.…”

Laboratory and Clinical Settings of Heavy/Light Chain (HLC) Assays in the Management of Monoclonal Gammopathies and Multiple Myeloma

“…Together with the free light-chain test and other serum markers, the Hevylite test guarantees the excellent monitoring of patients with plasma cell dyscrasias [ 54 ]. Interestingly, a multivariate analysis conducted by Jimenez and colleagues demonstrates that severe IMI, rather than classical immunoparesis, is an independent risk factor of progression from MGUS to MM [ 54 , 55 ]. Thus, the IMI is an additional risk factor that is able to discriminate between high-risk MGUS patients [ 52 , 55 ].…”

“…Interestingly, a multivariate analysis conducted by Jimenez and colleagues demonstrates that severe IMI, rather than classical immunoparesis, is an independent risk factor of progression from MGUS to MM [ 54 , 55 ]. Thus, the IMI is an additional risk factor that is able to discriminate between high-risk MGUS patients [ 52 , 55 ].…”