Deciphering N‑Glycosylation Dynamics of Serum Monoclonal Immunoglobulins in Multiple Myeloma via EThcD-sceHCD-MS/MS

Serum glycoprotein glycosylation changes can indicate disease onset and progression. However, the site-specific N-glycosylation of monoclonal immunoglobulins (M-proteins) in multiple myeloma (MM) and its clinical implications are unclear. In this study, we isolated pathogenic micromonoclonal IgA or IgG (approximately 2 μg) from IgA-MM patients (n = 22) and IgG-MM patients (n = 30), and normal polyclonal IgA and IgG from healthy controls (HCs) (n = 16). Using EThcD-sceHCD-MS/MS, the N-glycosylation dynamics of serum M-proteins in MM were determined. Compared with polyclonal IgA1 from HCs, monoclonal IgA1 from IgA-MM patients had higher fucosylation (58.1% vs 32.1%, p p = 0.011), and mannosylation (1.5% vs 0.3%, p p r = −0.363, p = 0.049) and estimated glomerular filtration rate (r = −0.433, p = 0.017); and HexNAc4Hex5 was associated with therapeutic prognosis. In conclusion, monoclonal IgA1 and IgG1 in MM patients and their polyclonal isotypes in HCs have distinct N-glycosylation profiles, and specific N-glycans of M-proteins are associated with MM characteristics and therapeutic prognosis.