Association of Immune Marker Changes With Progression of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma

This cohort study investigates the association of prediagnostic serum immune markers with the subsequent diagnosis of stable monoclonal gammopathy of undetermined significance vs progression to multiple myeloma. Key PointsQuestionAre changes in serum immune marker results associated with disease progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma? FindingsIn this cohort study of 685 individuals with a diagnosis of progressing or stable MGUS, in longitudinal analysis of individuals with serial samples prior to progression, 23 of 43 (53%) had high-risk MGUS before progression, and 16 of these 23 (70%) experienced conversion from low-risk or intermediate-risk MGUS to multiple myeloma within 5 years; similar results were found for light-chain MGUS. Evolving monoclonal proteins, serum-free light chains, and immunosuppression were associated with disease progression. MeaningThese findings support annual blood testing and risk assessment for all individuals with MGUS or light-chain MGUS. ImportanceMultiple myeloma is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS). Risk models that estimate the risk of progression from MGUS to multiple myeloma use data from a single time point, usually the initial workup. ObjectiveTo longitudinally investigate the alterations of serum immune markers with stable vs progressive MGUS. Design, Setting, and ParticipantsThis prospective cross-sectional cohort study included 77469 adult participants aged 55 to 74 years in the screening arm of the National Cancer Institute Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial who had a diagnosis of progressing MGUS (n=187) or stable MGUS (n=498), including light-chain subtype, from November 1993, through December 2011. For each participant, all available serially stored prediagnostic serum samples (N=3266) were obtained. Data analysis was performed from April 2018, to December 2018. Main Outcomes and MeasuresSerum protein and monoclonal immunoglobulin levels, serum free light chains, and serum light chains within each immunoglobulin class were measured. ResultsOf 685 individuals included in the study, 461 (67.3%) were men; the mean (SD) age was 69.1 (5.6) years. In cross-sectional modeling, risk factors associated with progressive MGUS were IgA isotype (adjusted odds ratio [OR], 1.80; 95% CI, 1.03-3.13; P=.04), 15 g/L or more monoclonal spike (adjusted OR, 23.5; 95% CI, 8.9-61.9; P<.001), skewed (<0.1 or >10) serum free light chains ratio (adjusted OR, 46.4; 95% CI, 18.4-117.0; P<.001), and severe immunoparesis (<greater than or equal to>2 suppressed uninvolved immunoglobulins) (adjusted OR, 19.1; 95% Cl, 7.5-48.3; P<.001). Risk factors associated with progressive light-chain MGUS were skewed serum free light chains ratio (adjusted OR, 44.0; 95% CI, 14.2-136.3; P<.001) and severe immunoparesis (adjusted OR, 48.6; 95% CI, 9.5-248.2; P<.001). In longitudinal analysis of participants with serial samples prior to progression, 23 of 43 participants (53%) had high-risk MGUS before progression; 16 of these 23 (70%) experienced conversion from low-risk or intermediate-risk MGUS within 5 years. Similar results were found for light-chain MGUS. Conclusions and RelevanceThe findings of evolving risk patterns support annual blood testing and risk assessment for patients with MGUS or light-chain MGUS.