Background: Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant condition characterized by the presence of monoclonal immunoglobulin (M-protein) in serum, with a lifelong risk of progression to multiple myeloma and other plasma cell disorders. The intact M-protein Screening-Light Chain Assay (iMS-LC Assay) is a novel MALDI-TOF mass spectrometry (MS)-based method for detecting M-proteins in serum, offering high sensitivity, high throughput, and cost-effectiveness without requiring antibody enrichment. This study aimed to evaluate the feasibility and advantages of applying iMS-LC Assay for M-protein screening in individuals undergoing physical examinations and to compare its performance with conventional serum protein electrophoresis (SPE).

Methods: We prospectively enrolled 15,068 consecutive individuals aged ≥30 years undergoing physical examinations at Peking Union Medical College Hospital between December 2, 2024, and April 10, 2025. Residual serum samples from SPE testing were subjected to automated iMS-LC Assay screening. Samples positive by either MS or SPE underwent further verification by serum immunofixation electrophoresis (IFE), free light chain (FLC) analysis, and MS isotyping. A true M-protein gammopathy was defined as positivity by any of these three confirmatory methods.

Results: MS screening identified 201 positive cases, significantly exceeding the 71 cases detected by SPE (P < 0.0001). Notably, all SPE-positive samples were also detected by MS, demonstrating its superior sensitivity. After confirmatory testing, 181 samples (1.19%, 95% CI: 1.03–1.37%) were confirmed as true monoclonal gammopathy. Age- and gender-specific MS positivity rates increased with age: males 30–39y (0.44%), 40–49y (1.23%), 50–59y (1.90%), 60–69y (2.51%), 70–79y (7.56%), ≥80y (10.7%); females 30–39y (0.44%), 40–49y (1.10%), 50–59y (1.55%), 60–69y (2.46%), 70–79y (3.92%), ≥80y (8.00%). MS demonstrated consistently higher detection rates across all age groups and identified over three times as many positive cases as SPE among individuals under 60 years. MS detection in younger age groups exceeded the SPE positive rate in individuals two decades older, suggesting that MS may detect M-proteins approximately 20 years earlier than SPE, thereby enabling earlier diagnosis and clinical monitoring. Isotype analysis of the 179 MS-isotyped positive samples revealed IgG subtypes as the most common (IgGλ 31.3%, IgGκ 27.9%), followed by IgA (IgAλ 16.8%, IgAκ 8.4%), IgM (IgMλ 4.5%, IgMκ 3.9%), and IgDλ (0.6%). MS additionally detected light chain glycosylation in 5 cases (3 IgGκ, 2 IgAκ), a feature undetectable by standard clinical assays. Biclonal M-proteins was identified in 6.1% of MS-isotyped cases, exceeding the 3.4% detected by IFE. However, it is notable that certain reactive immunoglobulins associated with infections or inflammatory conditions may be classified as clonal by MS, necessitating cautious interpretation in clinical practice.

Conclusion: The iMS-LC Assay demonstrated superior sensitivity compared to SPE for M-protein screening, particularly in younger individuals, with the potential to detect M-proteins up to two decades earlier than conventional methods. Its high throughput, automation, and cost-effectiveness support its use as a scalable screening tool for early diagnosis and risk stratification of monoclonal gammopathies in general populations.

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2025
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