Prevalence of monoclonal gammopathies and clinical outcomes in a high-risk US population screened by mass spectrometry: a multicentre cohort study

Summary

Background

Prevalence estimates for monoclonal gammopathy of undetermined significance (MGUS) are based on predominantly White study populations screened by serum protein electrophoresis supplemented with immunofixation electrophoresis. A prevalence of 3% is reported for MGUS in the general population of European ancestry aged 50 years or older. MGUS prevalence is two times higher in individuals of African descent or with a family history of conditions related to multiple myeloma. We aimed to evaluate the prevalence and clinical implications of monoclonal gammopathies in a high-risk US population screened by quantitative mass spectrometry.

Methods

We used quantitative matrix-assisted laser desorption ionisation-time of flight (MALDI-TOF) mass spectrometry and EXENT-iQ software to screen for and quantify monoclonal gammopathies in serum from 7622 individuals who consented to the PROMISE screening study between Feb 26, 2019, and Nov 4, 2021, and the Mass General Brigham Biobank (MGBB) between July 28, 2010, and July 1, 2021. M-protein concentrations at the monoclonal gammopathy of indeterminate potential (MGIP) level were confirmed by liquid chromatography mass spectrometry testing. 6305 (83%; 2211 from PROMISE, 4094 from MGBB) of 7622 participants in the cohorts were at high risk for developing a monoclonal gammopathy on the basis of Black race or a family history of haematological malignancies and fell within the eligible high-risk age range (30 years or older for PROMISE cohort and 18 years or older for MGBB cohort); those over 18 years were also eligible if they had two or more family members with a blood cancer (PROMISE cohort). Participants with a plasma cell malignancy diagnosed before screening were excluded. Longitudinal clinical data were available for MGBB participants with a median follow-up time from serum sample screening of 4·5 years (IQR 2·4–6·7). The PROMISE study is registered with ClinicalTrials.gov, NCT03689595.

Findings

The median age at time of screening was 56·0 years (IQR 46·8–64·1). 5013 (66%) of 7622 participants were female, 2570 (34%) male, and 39 (<1%) unknown. 2439 (32%) self-identified as Black, 4986 (65%) as White, 119 (2%) as other, and 78 (1%) unknown. Using serum protein electrophoresis with immunofixation electrophoresis, the MGUS prevalence was 6% (101 of 1714) in high-risk individuals aged 50 years or older. Using mass spectrometry, we observed a total prevalence of monoclonal gammopathies of 43% (1788 of 4207) in this group. We termed monoclonal gammopathies below the clinical immunofixation electrophoresis detection level (<0·2 g/L) MGIPs, to differentiate them from those with higher concentrations, termed mass-spectrometry MGUS, which had a 13% (592 of 4207) prevalence by mass spectrometry in high-risk individuals aged 50 years or older. MGIP was predominantly of immunoglobulin M isotype, and its prevalence increased with age (19% [488 of 2564] for individuals aged <50 years, 29% [1464 of 5058] for those aged ≥50 years, and 37% [347 of 946] for those aged ≥70 years). Mass-spectrometry MGUS prevalence increased with age (5% [127 of 2564] for individuals aged <50 years, 13% [678 of 5058] for those aged ≥50 years, and 18% [173 of 946] for those aged ≥70 years) and was higher in men (314 [12%] of 2570) compared with women (485 [10%] 5013; p=0·0002), whereas MGIP prevalence did not differ significantly by gender. In those aged 50 years or older, the prevalence of mass spectrometry was significantly higher in Black participants (224 [17%] of 1356) compared with the controls (p=0·0012) but not in those with family history (368 [13%] of 2851) compared with the controls (p=0·1008). Screen-detected monoclonal gammopathies correlated with increased all-cause mortality in MGBB participants (hazard ratio 1·55, 95% CI 1·16–2·08; p=0·0035). All monoclonal gammopathies were associated with an increased likelihood of comorbidities, including myocardial infarction (odds ratio 1·60, 95% CI 1·26–2·02; p=0·00016 for MGIP-high and 1·39, 1·07–1·80; p=0·015 for mass-spectrometry MGUS).

Interpretation

We detected a high prevalence of monoclonal gammopathies, including age-associated MGIP, and made more precise estimates of mass-spectrometry MGUS compared with conventional gel-based methods. The use of mass spectrometry also highlighted the potential hidden clinical significance of MGIP. Our study suggests the association of monoclonal gammopathies with a variety of clinical phenotypes and decreased overall survival.

Funding

Stand Up To Cancer Dream Team, the Multiple Myeloma Research Foundation, and National Institutes of Health.

Introduction

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal expansion of plasma cells.1, 2 The condition is defined as the presence of a serum monoclonal protein (M protein) concentration of less than 30 g/L, less than 10% clonal plasma cells in the bone marrow, and the absence of myeloma-defining events. MGUS carries a 1% per year risk of progression to multiple myeloma and confers susceptibility to other lymphoproliferative disorders, amyloidosis, or light-chain deposition disease.1, 2, 3

The first studies evaluating the prevalence of MGUS originated in Sweden more than 50 years ago and estimated a prevalence of 3·1% in individuals older than 70 years.4, 5 A large prospective screening study in Olmsted County, MA, USA, subsequently estimated a prevalence of 3% in individuals older than 50 years and 5·3% in those older than 70 years.⁴ These studies, however, were done in majority White populations and did not consider that MGUS prevalence is two to three times higher in Black individuals than in White individuals,6, 7, 8 with more pronounced differences at younger ages.⁹ MGUS and multiple myeloma appear to be two times more prevalent in individuals who have a first-degree relative diagnosed with a multiple myeloma-related disorder or other lymphoproliferative disease.10, 11, 12, 13 These data suggest that race and family history are risk factors in MGUS development and help identify at-risk individuals.

All MGUS prevalence studies to date have relied on serum protein electrophoresis supplemented by immunofixation to identify M proteins. These conventional methods, however, have limited sensitivity in detecting lower-level monoclonal gammopathies, in which the M protein fades into the polyclonal background. The serum free light-chain assay led to improvements in the detection of light-chain MGUS, which has an estimated 0·8% prevalence in the general population.¹⁴ Later, mass spectrometry emerged as a more sensitive approach to measure M protein, enabling detection of low disease burden, including minimal residual disease following therapy.15, 16 Analyses based on stratified quantification of M protein for early disease stages of monoclonal gammopathies have not yet been reported.

Our study evaluated the prevalence and association with clinical outcomes of screen-detected monoclonal gammopathies in individuals at higher-than-average risk for multiple myeloma on the basis of race and family history using a high-throughput quantitative mass-spectrometry approach.