Results of the promise study from ~30,000 individuals screened for monoclonal gammopathies

Abstract Background Monoclonal gammopathy (MG) of undetermined significance (MGUS) affects 3–5% of individuals aged 50 and older, as reported by the Olmsted County screening study (1995) and the iStopMM study. However, these primarily included white individuals. Prior work has shown that MGUS is three times more prevalent in Black populations and twice as common in individuals with a family history of hematologic malignancies (FH-HM). The PROMISE study is the first nationwide, prospective screening effort in the United States (US) to assess the prevalence of (MG) in high-risk populations using highly sensitive mass spectrometry (MS). Methods The PROMISE study (NCT03689595), launched in 2019, enrolls individuals at high risk for MG, including: (1) those aged ≥30 years identifying as Black or African American (Black/AA) and/or with a first-degree relative with a blood cancer; or (2) those aged ≥18 years with a strong FH-HM (two or more 1st- or 2nd-degree relatives affected). Subsequent phases expanded to include participants from South Africa, Israel, and Greece, as well as non–high-risk individuals consented to national biobanks such as the Mass General Brigham Biobank (MGBB) and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Genetic ancestry was inferred from genotype array data using a k-Nearest Neighbors classifier for MGB and principal component analysis for PLCO. Screening was performed using MALDI-TOF MS and Optilite free light-chain assay. MGUS and light chain MGUS (LC-MGUS) were identified by a heavy chain peak ≥0.2 g/L or an abnormal free light chain ratio based on race-specific reference ranges. For comparison with other studies, MG above the electrophoresis detection threshold (0.2g/L) is collectively reported as MGUS. Results As of August,a total of 30,133 individuals were screened, including 15,500 high-risk participants. The median age at sample was 56 years (IQR:44-64), 60% were females, 28% Black/AA, and 24% Non-Black with FH-HM. The overall prevalence of MGUS was 12.6% (n= 3,793; 95CI 12.2 - 13%), with LC-MGUS accounting for 1.6%. In high-risk populations aged ≥50 years, MGUS prevalence was higher in Black/AA individuals (17.8%) compared to Non-Black individuals with FH-HM (14.8%, p<0.001). Multivariable regression identified age (per 10-year increase) as the strongest predictor of MGUS, followed by Black race (OR 1.29, 95CI 1.06–1.57; p=0.01), male sex (OR 1.22, 95CI 1.09–1.36; p<0.001), and FH-HM (OR 1.16, 95CI 1.003-1.33; p=0.046). BMI (per 5-unit change) and sample origin were not significant predictors. Subgroup analysis revealed that within individuals with FH-HM, race remained significantly associated with MGUS prevalence (OR 1.27, 95CI 1.12-1.44; p<0.001), while FH-HM was not a factor among self-identified Black individuals. Additionally, BMI demonstrated a unique association with MGUS prevalence in Black individuals (OR 1.12, 95CI 1.02-1.21; p=0.008), while age and sex remained significant predictors across groups. Examining genetic ancestry in the multivariable model showed significant association between African ancestry and MGUS (OR 1.21; 95CI 1.07-1.38; p=0.003), suggesting a genetic contribution to the observed racial disparity. After adjusting for age and sex, no significant difference in MGUS prevalence was found between Black/AA individuals residing in South Africa and those residing in the US. When comparing isotypes across groups, IgM MGUS prevalence was significantly lower in Black/AAs compared to the non-high-risk group (6% vs.17%; p<0.001), while IgG MGUS and IgA MGUS were more common (77% vs. 72%, p=0.016 and 17% vs. 11%, p<0.001). Among Non-Black individuals, only IgA MGUS prevalence was significantly higher in those with a FH-HM compared to those without (16% vs. 11%, p=0.002). In addition, significant differences in concentration were observed for IgM and IgG between risk groups, with a higher concentration of IgG MGUS in Black/AA compared to Non-Black risk groups (p<0.001). Conclusion As efforts grow to evaluate population-level screening, this study in a racially diverse population refines risk stratification, identifying subgroups most likely to benefit while minimizing false positives. The higher prevalence in individuals of Black race and African ancestry, along with distinct age-related patterns, provides a foundation to assess the implications of targeted screening strategies and inform future screening guidelines.