Multiple myeloma genetic alterations have distinct repertoires and prognostic implications in African and european ancestries

Abstract Introduction: Multiple Myeloma (MM) disproportionately affects Black individuals, where it is 2-3 times more prevalent than in White populations. Prior studies have identified distinct germline risk alleles between Black and White individuals; however, somatic mutational differences remain limited with research suggesting Black patients exhibit lower mutational burdens of TP53 and IRF4. It remains unclear if the repertoire of genomic structural variants is similar between Black and White individuals or if they carry distinct prognostic implications. Methods: Institutionaldata from 977 patients uniformly treated with lenalidomide, bortezomib, and dexamethasone (hereafter RVD1000) were obtained from Joseph et al., 2020 and analyzed using self-identified race and cytogenetic FISH results. Whole Genome Sequencing (WGS) data from the MMRF CoMMpass were utilized. Germline variants were determined using HaplotypeCaller (v4.3.0.0) and phased using SHAPEIT (v5) before assessing global and local ancestry using RFMix (v2) with the 1000 Genomes project as a reference. Somatic mutations were determined with Mutect2 based on exome data and translocations were determined with Manta based on WGS. Copy number alterations were provided by TGen. Differences in somatic genetic events were determined using Fisher's exact test. Outcome analysis used Kaplan-Meier survival analysis and differences in prognostic impact used a Cox proportional hazards model considering the interaction of ancestry. Results: Of 977 RVD1000 patients with self-identified race, 36.7% (N=359) were Black, with no difference in PFS or OS observed between White and Black patients. The only significant differences were in age, 1q gain and del17p loss and all favored Black patients. Similarly, no differences in PFS or OS was observed between newly-diagnosed self-identified White (N=620) and Black (N=135) patients in CoMMpass. Genetic ancestry analysis of CoMMpass was concordant with self-identified race with all self-identified Black patients categorized as having primarily African (AFR) ancestry and only 7/620 self-identified White patients being categorized as having African ancestry. Analysis of somatic mutations in CoMMpass between AFR and European (EUR) patients indicated AFR patients had a lower overall mutational burden (P = 0.035) and lower number of non-synonymous mutations (P = 0.016). Analysis of gene mutations indicated a similar frequency in the most commonly mutated genes such as KRAS, NRAS, DIS3, and BRAF. However, consistent with previous reports AFR patients had fewer mutations in TP53 as well as DST and PABPC1 (P 0.05), but were not significant after multiple hypothesis correction. Common copy number alterations (CNAs) were similar between AFR and EUR MM patients, although AFR trended to have a lower frequency of CNAs and this was significant for del(6q25) (FDR 0.01). Consistently, analysis of structural variants (SVs) found AFR MM patients were less likely to have deletions (P = 0.0014). The total number of other SVs including duplications, deletions, and translocations between AFR and EUR were similar as were the most common translocations including both primary translocations t(11;14), t(4;14), t(14;16) and secondary events such as t(MYC) and t(IgL). Finally, we looked to see if common SVs conferred a similar prognosis in AFR and EUR patients. Surprisingly, we found several secondary translocations conferred a worse prognosis in AFR patients than those of EUR ancestry. These included t(8;22) and t(MAP3K14) where AFR patients with these translocations had a worse OS and PFS (P 0.05; t(8;22) HR 3.07 PFS, 5.83 OS, t(MAPK3K14) HR 8.05 PFS, 4.52 OS) as compared to EUR patients with the same events. Conclusion: Our analyses indicate that White and Black MM patients have similar overall outcomes, despite Black patients have a lower mutational burden and fewer copy number deletions. This is somewhat surprising given Black patients tend to be diagnosed at a younger age and less commonly have TP53 loss as observed in RVD1000 which typically confer a worse prognosis. Specific secondary translocations were associated with significantly worse outcomes in patients of African ancestry, suggesting the influence of ancestry-specific genetic modifiers on disease progression. These findings indicate that risk markers may have different implications in White and Black MM patients.