Hispanic or Latin American Ancestry Is Associated with a Similar Genomic Profile and a Trend Toward Inferior Outcomes in Newly Diagnosed Multiple Myeloma As Compared to Non-Hispanic White Patients in the Multiple Myeloma Research Foundation (MMRF) CoMMpassstudy

Introduction

Large clinical data sets suggest that the natural history and prognosis of newly diagnosed multiple myeloma (NDMM) differs between patients of European and African ancestry, with the latter group exhibiting an earlier age at onset and poorer overall prognosis in some studies. The use of next generation sequencing (NGS) to characterize the genomic landscape of multiple myeloma (MM) suggests that the observed phenotypic differences between these groups of patients may reflect distinct underlying genomic profiles and mutational processes. Thus far, characterizations of this type have focused principally on patients of African ancestry (AA). Here, we characterize the genomic features and outcomes of a large series of patients of Hispanic or Latin American ancestry (HL) as compared to their Non-Hispanic white (NHW) counterparts.

Methods

Subjects were selected from the MMRF CoMMpass ^SM trial, a study that includes 1,154 patients with updated outcome data as of March, 2020. Within this data set, 760 patients had information on race and ethnicity. Among these, 55 HL patients and 478 NHW patients possessed complete clinical and genomic information.

We analyzed baseline whole exome sequencing (WES) and long insert whole genome sequencing (WGS) as previously described (Walker, et al. Blood 2019). Our analysis focused on 63 known driver mutations in multiple myeloma and 39 sites of common copy number variation across the study population. Complex structural variants and tumor telomere length were called using previously described bioinformatic tools (Boyle et al. Leukemia 2021). Survival analysis was undertaken using the Kaplan-Meier method with hazard ratios determined by the Cox proportional hazards model.

Results

In a comparison of clinical features between the Hispanic and NHW population, we did not identify any differences in age of onset, gender, presenting cytogenetics, International Staging System Score (ISS), and IMWG Risk Category. The proportion of patients undergoing autologous stem cell transplantation was similar between groups. We identified no statistically significant differences in the presence of characteristic translocations involving IgH locus or in hyperdiploidy status. No statistically significant differences in tumor mutational burden or loss-of-heterozygosity percentage emerged between HL and NHW patients.

We examined non-synonymous variations (NSV) and copy number variations at the loci of known MM driver genes and encountered no statistically significant differences in NSV, copy number, or biallelic status. We further categorized genes into pathways relevant to the pathogenesis of MM and discovered no difference in the proportions of patients harboring mutations in genes related to the MEK/ERK and NF-κB pathways, cell cycle regulation, and epigenetic modification. We were unable to the distinguish either population based on the presence of chromothripsis or in the overall preponderance of an APOBEC mutational signature. Tumor telomere length was not significantly different between the populations.

An analysis of overall and progression free survival (PFS) with a median duration of follow up of 44 months revealed a trend toward poorer outcomes among the HL population that did not reach statistical significance. Median PFS was 24 months in HL patients and 35 months in the NHW population (p = 0.19). Median OS was not reached in either ethnic subgroup. In terms of overall survival, age, ISS score, overall number of driver mutations, and the presence of chromothripsis emerged with a negative impact on outcome (Figures 1a, 1b). These variables with the exception of chromothripsis retained their significant impact on progression free survival (Figure 2a, 2b).

Conclusion

The correlation between Hispanic or Latin American ancestry and underlying disease biology in MM has yet to be fully elucidated. In our analysis, which was based on self-declared ancestry as opposed to admixture, no obvious differences in significant measures of genomic variation known to impact prognosis in MM emerged between HL and NHW patients. These results may help to inform the future large-scale studies to ascertain the impact of genomics, disease biology and socioeconomic factors on outcomes in this heterogeneous patient population.

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