Immunoparesis in MGUS – Relationship of uninvolved immunoglobulin pair suppression and polyclonal immunoglobuline levels to MGUS risk categories

Abstract

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic, potentially malignant condition. It has been established that annually approximately 1-2% of MGUS cases transforms into one of the malignant forms of monoclonal gammopathies. Progression risk factors include the quantity and type of M-protein, and namely the ratio of free light immunoglobulin chains (FLC). These factors, enable purposeful stratification of MGUS individuals. Some authors consider suppression of polyclonal immunoglobulin levels to be another progression factor. The aim of the study was to compare polyclonal immunoglobulin (PIg) levels with uninvolved heavy/light chain pair (HLC) levels in order to verify the degree of immunoparesis depending on MGUS risk category (0-3). The analyzed set consisted of 159 serum samples from MGUS patients (102 IgG, 57 IgA), who were stratified into 4 risk groups (0 - low, 1 - low-intermediate, 2 - high-intermediate and 3 - high risk of transformation). The results of analysis showed that with increasing degree of MGUS increases risk of immune paresis defined by decreasing levels of polyclonal immunoglobulins, ie. IgA and IgM in the case of IgG MGUS, respectively, IgG and IgM in case of IgA MGUS. Significant differences were also found when analyzing the levels of uninvolved HLC pairs IgG kappa (resp. IgG lambda) in IgG lambda (IgG kappa) dominant secretion. In the case of MGUS with IgA isotype, the results were similar. Discovery of the connection between the degree of immunosuppression and the level of MGUS risk contributes to our understanding of the relationship between biology, development and potential malignant transformation of MGUS. It is apparent that uninvolved HLC pair assay enables more reliable identification of at-risk MGUS patients than a simple quantitative assay for polyclonal immunoglobulins alone.

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

“…On the other hand, the levels of the uninvolved Hevylite pair were also observed to progressively decrease with increasing risk group, indicating that immunosuppression is very likely related with a greater risk of progression. Similar observations were reported in previous studies (20,9), highlighting the relevance of a compromised host immune system in myelomagenesis. In the study of Pika et al (20), it is also apparent that there is a greater incidence of IMI over classical IP, although in the high-risk group the differences are only marginal (a result also seen in our study).…”

“…The first approach showed that both the frequency of Hevylite IMI and the frequency of classical IP correlated with the MGUS risk group, although significantly more patients had IMI than classical IP. The result obtained in this study with IMI (51%) is much higher than the value of 27% observed by Katzmann and coworkers (9) and closer to what Pika et al had (20). The difference might be related to the already mentioned underrepresentation of the lowest risk group when compared to the Minnesota cohort.…”

Serum Free Light Chain Assay and κ/λ Ratio: Performance in Patients With Monoclonal Gammopathy-High False Negative Rate for κ/λ Ratio

“…The predispositions for false negative and false positive results of SFLCA κ/λ ratio have been documented by others as well [32, 37, 43-53]. Factors contributing to the high error rate include hypergammaglobulinemia, hypogammaglobulinemia, ethnic variation in the reference range, renal failure, and propensity of light chains to aggregate or polymerize thereby potentially interfering with their measurement [55, 56, 62-65].…”

“…It is conceded that a normal serum and urine electrophoretic result does not rule out a neoplastic plasma cell disorder; however, detection of a monoclonal immunoglobulin by electrophoresis is proof positive of monoclonal gammopathy. The shortcomings of SFLCA in patients with and without monoclonal gammopathy have been demonstrated by other investigators as well [32, 37, 43-53]. It could be argued that being that electrophoretic method is the gold standard, other methods are not expected to perform as well, however, the high error rates, both false positive and false negative, for SFLCA, raise the question of its usefulness, and medical necessity of this test.…”

Laboratory testing in monoclonal gammopathy of renal significance (MGRS)

“…In some cases, a decrease in the γ peak is noted. This is the characteristic of hypogammaglobulinemia which is the result of immunoparesis from the M-protein [29].…”