(PA-349) EXENT QIP-MS Detection of Stable Monoclonal Light Chain Glycosylation Enables Risk-stratified MGUS Monitoring

Multiple myeloma (MM) is frequently associated with diagnostic delay, despite earlier detection improving clinical outcomes. MM is consistently preceded by Monoclonal Gammopathy of Undetermined Significance (MGUS). The high prevalence of MGUS (~4.5% of individuals >40 years) and low risk of malignant progression (~1%) make longitudinal monitoring unlikely to be cost-effective or sustainable. Improved diagnostics and identification of novel biomarkers are essential to refine risk stratification and optimise resource allocation. Preliminary data from the Mayo Clinic suggests glycosylation of monoclonal light chains (LCs) is a promising biomarker for MGUS progression, associated with a five-fold increased risk of MM and AL amyloidosis progression, beyond current risk stratification models. This study aims to characterise the frequency and stability of monoclonal LC glycosylation in an incidental MGUS cohort, evaluating its potential as a predictive biomarker for malignant progression.

Methods:   

This pilot study included 124 MGUS patients incidentally diagnosed between 2020-2024 at Oxford University Hospital. A trust audit (ID 8776) granted access to 158 serum samples which were evaluated for LC glycosylation by EXENT Quantitative Immunoprecipitation Mass Spectrometry (QIP-MS). The mass spectra were acquired over 10,000-30,000 m/z. Prevalence of glycosylated LCs were compared with previously reported screened cohort data. Stability of glycosylation was assessed using sequential samples.

Results:   

Of 124 incidental MGUS patients analysed, 18 (15%) had glycosylated LCs, a significantly higher proportion than 6% previously reported in the screened cohort (P=0.0013). Demographics and current MGUS risk stratification were comparable between the groups, though the incidental cohort had a greater proportion of non-IgG isotypes (50%) compared to the screened cohort (20%).  

In the 18 incidental MGUS patients with glycosylation, 14 (78%) involved the primary clone and 4 a non-clonal isotype. 11 of the clonal group had follow-up samples available. Glycosylation remained stable in all 11 over a mean of 29 months (5-52 months), whilst none of the non-clonal glycosylation persisted.

Characteristics of Glycosylated MGUS Cohorts ^a

^a Screened cohort analysed by MASS-FIX (Dispenzieri et al. 2020), incidental cohort analysed by EXENT QIP-MS.

Conclusions:   

This pilot study demonstrates a higher prevalence of glycosylated monoclonal LCs in incidentally identified MGUS patients compared to previously reported screened cohorts. The observed stability of glycosylation within primary MGUS clones highlights its potential as a predictive biomarker for malignant progression, warranting further evaluation for its use in MGUS risk stratification models.