N-glycosylation of monoclonal light chains on routine MASS-FIX testing is a risk factor for MGUS progression

Abstract

Our group previously demonstrated that M-protein light chain (LC) glycosylation can be detected on routine MASS-FIX testing. Glycosylation is increased in patients with immunoglobulin light chain amyloidosis (AL) and rarely changes over the course of a patient’s lifetime. To determine the rates of progression to AL and other plasma cell disorders (PCDs), we used residual serum samples from the Olmsted monoclonal gammopathy of undetermined significance (MGUS) screening cohort. Four-hundred and fourteen patients with known MGUS were tested by MASS-FIX, and 25 (6%) were found to have glycosylated light chains (LCs). With a median follow-up of surviving patients of 22.2 years, the 20-year progression rates to a malignant PCD were 67% (95% CI 29%, 84%) and 13% (95% CI 9%, 18%) for patients with and without glycosylated LCs, respectively. The risk of progression was independent of Mayo MGUS risk score. The respective rates of progression to AL at 20-years were 21% (95% CI 0.0, 38%) and 3% (95% CI 0.6%, 5.5%). In summary, monoclonal LC glycosylation is a potent risk factor for progression to AL, myeloma, and other PCDs, an observation which could lead to earlier diagnoses and potentially reduced morbidity and mortality.

MASS-FIX for the detection of monoclonal proteins and light chain N-glycosylation in routine clinical practice: a cross-sectional study of 6315 patients

“…We confirm the findings of previous studies demonstrating high rates of LC N-glycosylation in CAD and AL amyloidosis 5,6,8 . We expand upon previous work in identifying additional PCD with LC N-glycosylation, including cryoglobulinemia, plasmacytoma, and monoclonal immunoglobulin deposition disease.…”

“…Of those who were evaluated, approximately half had a FA and two thirds had a BMB performed, which have individual sensitivities of 70-75% and combined sensitivities of 85-90% for the diagnosis of AL amyloidosis 16 . Follow-up on these patients is short, but prior studies have shown that patients with MGUS and N-glycosylation have a sixfold higher rate of progression to a malignant PCD than their non-glycosylated counterparts 8 .…”

“…LC N-glycosylation has diagnostic implications, as it is more common in immunoglobulin light chain (AL) amyloidosis and cold agglutinin disease (CAD) compared to other plasma cell disorders (PCD) 5,6 . In AL amyloidosis, LC N-glycosylation is present from the time of diagnosis of monoclonal gammopathy of undetermined significance (MGUS), and represents an independent risk factor for progression of MGUS to AL amyloidosis and other PCD 7,8 . Moreover, LC N-glycosylation has been implicated in the pathogenesis of amyloid fibril formation in AL amyloidosis 9 .…”

Mass spectrometry for the evaluation of monoclonal proteins in multiple myeloma and related disorders: an International Myeloma Working Group Mass Spectrometry Committee Report

“…A previously underappreciated finding of M-proteins when employing the intact LC method was the observation of M-proteins with a LC mass that was broad and outside the normal mass ranges of kappa and lambda LCs 25 , 28 , Additional studies demonstrated that these LCs contained N-linked glycosylation and were to be more prevalent in patients with AL-amyloidosis 37 and cold agglutinin disease 38 than other PCDs. Interestingly, LC glycosylation was also found to be an independent risk factor for the progression of MGUS to myeloma and related disorders 39 . These glycosylated LCs were demonstrated to be present years before the diagnosis of myeloma of related disorder and hence may allow for identification of patients at higher risk for PCDs 40 .…”

In from the cold: M‐protein light chain glycosylation is positively associated with cold agglutinin titer levels

“…In recent years, advanced molecular characterization of M‐proteins has become more commonplace with the advent of a routine mass spectrometric assay for M‐protein detection, characterization, and monitoring 11–16 . This assay is able to detect immunoglobulin modifications that are associated with specific disease processes, such as LC glycosylation, which is predictive of progression to AL amyloidosis and other plasma cell disorders 15,17 . Recently, a population‐based cohort study of patients with IgM M‐protein of undetermined significance (MGUS) demonstrated that patients with a clinical diagnosis of CAD were more likely to have M‐protein LC glycosylation than those without such a diagnosis 18 …”