Monoclonal light chain glycosylation is associated with evolution of incidental MGUS

Abstract Introduction: Diagnostic delay remains a challenge in Multiple myeloma (MM), despite evidence that early detection improves clinical outcomes. Monoclonal gammopathy of undetermined significance (MGUS) is a consistent precursor to MM. However, the high prevalence of MGUS (~4.5% of individuals >40 years), combined with the low annual risk of malignant progression (~1%) as estimated by current risk stratification models, renders longitudinal surveillance unlikely to be cost-effective or sustainable. Advancements in diagnostics and refined risk stratification criteria are essential to enable the accurate identification of individuals at elevated risk of malignant progression, thereby supporting effective resource allocation and optimisation of MGUS surveillance strategies. Preliminary data from the Mayo Clinic has highlighted glycosylation of monoclonal light chains as a potential biomarker for inclusion in MGUS risk stratification. Screened MGUS patients with glycosylated monoclonal light chains (6%) showed a five-fold increased risk of progression to MM and/or AL amyloidosis, independent of current progression risk models (Dispenzieri et al,. 2020). This study aims to investigate monoclonal light chain glycosylation and MGUS evolution within an incidental MGUS cohort. Methods: This study included 155 MGUS patients incidentally diagnosed between 2020-2024 at Oxford University Hospital. Serum samples were evaluated for light chain glycosylation by EXENT Quantitative Immunoprecipitation Mass Spectrometry (QIP-MS). The mass spectra were acquired over 10,000-30,000 m/z. Evolution was defined as three consecutive increases in annual monitoring of monoclonal protein or involved immunoglobulin level, as described by the Mayo clinic (Rosiñol et al,. 2007). Participants with less than three years of follow-up, inconsistent follow-up data, or light-chain only disease were excluded from the MGUS evolution analysis. Risk stratification was conducted using the Mayo Clinic criteria, with light chain ratio adjusted for age and eGFR, in line with iSTOPMM recommendations. Results: Among the 155 MGUS patients analysed by EXENT QIP-MS, 21 (13.55%) were found to have light chain glycosylation. Of the glycosylated MGUS cohort, 16 (76%) showed glycosylation in a primary clone and 5 had glycosylation of a non-clonal isotype. Of the 21 glycosylated patients, 12 underwent MGUS evolution analysis and 5 (41.67%) were defined as evolving. All 5 evolving MGUS patients in the glycosylated group exhibited glycosylation of the primary clone. A total of 9 patients were excluded from evolution analysis, mostly due to having less than 3 years of follow-up data. Of the 134 non-glycosylated MGUS patients, 66 were eligible for evolution analysis and 12 (18.2%) were defined as evolving. A total of 68 were excluded, predominantly due to missing or incomplete data. Among the MGUS patients eligible for evolution analysis, demographic characteristics (including median age and proportion of males) were comparable between the glycosylated and non-glycosylated cohorts. Both groups had a similar proportion of IgG isotype MGUS patients. All of the patients in both the glycosylated and non-glycosylated cohorts were classified as low or intermediate risk MGUS according to the Mayo risk stratification criteria. The glycosylated MGUS cohort demonstrated a higher proportion of evolving MGUS cases compared to the non-glycosylated cohort (41.67% vs. 18.2%), although this difference did not reach statistical significance (p = 0.12), possibly due to the small sample size. Conclusions: This pilot study suggests a possible association between monoclonal light chain glycosylation and MGUS evolution, independent of current MGUS risk stratification models. Larger prospective studies are necessary to further evaluate the utility of monoclonal light chain glycosylation as a potential biomarker within MGUS surveillance strategies, to support earlier detection of MM in clinical practice.