Race-related molecular differences in SLAMF7 expression drive disparities in multiple myeloma outcomes

Abstract Background: African Americans (AA) experience earlier onset and a 2-3 fold higher incidence of multiple myeloma (MM) compared to Whites, with disproportionately poor outcomes that persist despite therapeutic advances. We previously demonstrated that AA patients with t(11;14) MM show inferior clinical outcomes compared to White patients even after adjusting for treatment factors, transplant rates, and socioeconomic variables. SLAMF7 is critical for myeloma tumorigenicity and serves as the target for elotuzumab, an FDA-approved monoclonal antibody. Single nucleotide polymorphisms (SNPs) can be associated with ancestry and contribute to racial disparities in disease risk and treatment outcomes. We investigated the molecular basis for racial disparities in MM outcomes. Methods: We performed comprehensive molecular profiling using NanoString's GeoMx™ Digital Spatial Profiler on archived bone marrow biopsies from AA (n=2) and White (n=1) patients with t(11;14) MM, analyzing >1,800 genes across >100 pathways. SLAMF7 protein expression was identified on molecular profiling and validated by Western blot and immunohistochemistry in MM cell lines and patient samples. To investigate mechanisms of expression; we performed mechanistic studies that included chromatin immunoprecipitation (ChIP) assays to assess Blimp-1/PRDM1 binding to SLAMF7 promoter regions, luciferase reporter assays to measure transcriptional activity, and site-directed mutagenesis to evaluate the functional impact of the A>G polymorphism at position -742 in the Blimp-1 binding motif. We genotyped this polymorphism in 88 MM patients (40 AA, 48 White) using tetra-primer ARMS-PCR and correlated findings with cell line sensitivity to SLAMF7 crosslinking antibodies. Results: Spatial transcriptomic analysis revealed significantly higher SLAMF7 expression in AA patients with t(11;14) MM compared to White patients. Principal component analysis demonstrated distinct gene expression patterns between racial groups, with enrichment of antigen presentation and Toll-like receptor pathways in AA patients. SLAMF7 protein expression was markedly elevated in MM cell lines derived from AA patients (MM1R, MM1S) compared to those from White patients (U266), correlating with differential sensitivity to SLAMF7 antibody treatment. SLAMF7 knockdown significantly inhibited growth specifically in AA-derived cell lines with high SLAMF7 expression. Mechanistic studies revealed that Blimp-1/PRDM1 bound effectively to SLAMF7 promoter regions in AA-derived cell lines (MM1R, MM1S) but showed minimal binding in White-derived cell lines (U266). The SLAMF7 promoter region (-833 to -726) from AA-derived cells demonstrated robust transcriptional activity that was enhanced by IL-6 treatment, while the same region from White-derived cells showed minimal activity. Critically, introduction of a single A>G point mutation at position -742 completely abrogated SLAMF7 transcriptional activity in AA-derived cell lines. Genotyping revealed striking racial differences in the distribution of this functional polymorphism: 50% of AA patients were A homozygotes and 42.5% were A/G heterozygotes (only 7.5% G homozygotes), while 48% of White patients were G homozygotes and 37.5% were A/G heterozygotes (only 14.5% A homozygotes; p<0.001). The A allele, associated with higher SLAMF7 expression, was significantly more prevalent in AA patients across both t(11;14) and cytogenetically normal MM subgroups. Conclusions: We identified a novel molecular mechanism underlying racial disparities in MM outcomes. AA patients demonstrate significantly higher SLAMF7 expression driven by differential Blimp-1-mediated transcriptional regulation due to a functional A>G polymorphism at position -742 of the SLAMF7 promoter. This polymorphism shows striking racial distribution differences, with AA patients predominantly carrying the A allele associated with increased SLAMF7 expression and potentially more aggressive disease. These findings provide a mechanistic rationale for personalized treatment approaches, particularly suggesting that AA patients with high SLAMF7 expression may benefit preferentially from elotuzumab-based therapy. Our results establish the foundation for developing this polymorphism as a predictive biomarker and support larger population studies to validate its clinical utility in reducing racial disparities in MM treatment outcomes.