(PA-161) Assessing the Clinical Implications and Prognostic Value of Light-chain N-glycosylation in 781 Multiple Myeloma Patients at Diagnosis

Light-chain (LC) N-glycosylation, a post-translational modification where glycans bind to monoclonal LC, is detectable by mass spectrometry. While associated with an increased risk of progression in monoclonal gammopathy of uncertain significance (MGUS) its clinical implications in newly diagnosed multiple myeloma (MM) are mostly unknown.

Objective: To investigate the clinical associations and prognostic impact of LC N-glycosylation at diagnosis in MM and high-risk smoldering MM (SMM) patients included in 3 clinical trials of the Spanish Myeloma Group.

 

Methods:

A total of 781 baseline serum samples obtained from patients enrolled in the GEM2012MENOS65 (n=336), GEM2017FIT (n=368) and GEMCESAR (n=77) trials were analyzed. LC N-glycosylation was assessed using Quantitative Immunoprecipitation Mass Spectrometry with anti-IgG/A/M, total κ, and total λ beads via the EXENT® system. High-risk cytogenetic abnormalities (HRCA) were defined as the presence of t(4;14), t(14;16) and/or del17p. Measurable residual disease (MRD) was assessed by flow cytometry following EuroFlow guidelines.

Results:

LC N-glycosylation was present in 70 patients (9.0%) and was more frequent in those older than 75 years (21.4% vs. 12.4%; P=0.036), with kappa isotype (74.3% vs. 64.8%; P=0.081), hypoalbuminemia (< 3.5 mg/dL: 44.1% vs. 30.7%; P=0.025) and HRCA (41.3% vs. 27.4%, P=0.049). No association was observed with ISS or bone marrow infiltration. In the multivariate analysis, age > 75 years and HRCA were independently associated with LC N-glycosylation (P=0.035 and P=0.043, respectively).

In terms of prognostic value, after a median follow-up of 52 months (range, 3-291), no significant differences in progression-free survival (PFS) or overall survival were seen between patients with and without LC N-glycosylation, either in the overall cohort or stratified by age.

Interestingly, among patients with undetectable disease by next-generation flow, those with LC N-glycosylation showed a significantly lower rate of complete response (59.5% vs. 75.0%; P=0.032). Given that PFS was similar regardless of immunofixation status, these findings suggest that glycosylation may interfere with monoclonal protein (MP) clearance or impact the interpretation of the immunofixation.

Conclusions:

LC N-glycosylation was observed in 8–9% of newly diagnosed MM patients, more frequently in older individuals, those with kappa isotype, and HRCA. Glycosylation was not associated with treatment response or progression-free survival. Its higher prevalence among MRD-negative but immunofixation-positive cases suggests interference with MP clearance or assay interpretation and deserves further investigation.