Plasma Proteomic Profiles Among White and African American Individuals With Monoclonal Gammopathy of Unknown Significance (MGUS) and Multiple Myeloma (MM).

Abstract

Background: Compared to Non-Hispanic Whites, African American (AA) individuals have a 2-fold higher incidence of MGUS and MM. Understanding the molecular mechanisms that drive progression from MGUS to MM is crucial, but few studies have explored whether there are differences in protein expression patterns in the progression of MGUS to MM by race. Here, we used mass-spectrometry to compare proteomic profiles between AA and White individuals with MGUS and MM. We hypothesized that biological differences between MGUS and MM could be captured by measuring protein presence and abundance. The primary aim was to identify protein pathways distinguishing these 2 stages.

Methods: In this study, we conducted untargeted serum protein profiling using data-independent acquisition mass spectrometry proteomics, quantifying over 1550 proteins in 30 MGUS and 30 newly diagnosed, treatment-naive MM samples. Samples were evenly split by self-reported race and matched for age and sex. Linear and logistic regression models were used to test for association between protein abundance or presence and MGUS/ MM status, adjusting for sex, age, BMI, batch, and race as covariates. Missing values in logistic regression were imputed as 0, with all other values set to 1. Proteins with unadjusted P < .05 were selected for pathway and network analysis.

Results: No significant differences were observed between AA and White patients with MM in M-spike level (P = .644), light chain involvement (P = .122), or plasmacytosis (P = .877). Proteomic analysis identified 26 proteins that significantly differed in detection or in abundance between MGUS and MM samples in a race agnostic manner (P < .05), with 15 showing increased abundance in MM and 11 varying in detection rates (presence or absence). Among these, ICAM-3, HSP90B1, ORM2, MAN1A1, OSCAR, PRKDC, and cDNA-FLJ-41552 (interaction P < .05) were particularly notable. Two proteins, PRKDC and cDNA FLJ41552 were decreased exclusively in AA patients with MM (interaction P < .05), suggesting population specific differences. Notably, 16 proteins showed changes between MGUS and MM exclusively in White patients (interaction P < .05), with the most significant being SERPIND1, C4B, CPN1, CNDP1 in abundance, and SERPINE1, CA2, CD109 in detection.

Conclusion: While the exact roles of these molecular pathways in the progression from MGUS to MM remain unclear, the identified protein differences may serve as biomarkers and therapeutic targets, warranting further validation and functional studies for clinical application. In addition, the differential expression of PRKDC in AA patients suggests potential population-specific vulnerabilities. Validation of these findings in additional cohorts will help assess the potential usefulness of these biomarkers in predicting transition from MGUS to MM.