Telomere Length Variation by Ancestry in Multiple Myeloma: Insights into Racial Differences in Disease Presentation and Prognosis

Introduction

Telomere shortening, a marker of genomic instability, has been observed in multiple myeloma (MM) and is thought to contribute to disease progression (Dratwa et al., 2023). Interestingly, longer leukocyte telomere length (LTL) has been associated with an increased risk of MM, suggesting that inherited telomere biology may influence disease susceptibility (Campa et al., 2014). Large clinical datasets indicate that the natural history and prognosis of newly diagnosed MM (NDMM) differ by ancestry, with patients of African ancestry (AA) often presenting at a younger age and, in some studies, experiencing worse outcomes. Although next-generation sequencing (NGS) has revealed ancestry-related genomic differences in MM, most studies have focused on patients of European descent. Notably, Black individuals generally exhibit longer LTL in healthy states, potentially reflecting germline variation in telomere regulation (Zhu et al., 2010). These inherited differences, along with varying telomere attrition under disease stress, may contribute to ancestry-specific MM biology. Here, we investigate the genomic features and outcomes of a large cohort of Black and White MM patients, with a focus on LTL and total telomere length (TTL).

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 our study, we observed a statistically significant difference in leukocyte telomere length (LTL) between Black and White individuals (F = 4.13, p = 0.042), indicating ancestry-related variation in baseline telomere length. More strikingly, a highly significant difference was found in total telomere length (TTL) between the two groups (F = 80.99, p = 2.42 × 10⁻¹⁸). Black individuals exhibited substantially shorter average TTL (mean = 2.40, variance = 29.67) compared to White individuals (mean = 6.86, variance = 21.12) in this cohort. This significant difference suggests distinct telomere biology across ancestral groups, which may contribute to disparities in multiple myeloma pathogenesis and clinical outcomes. The magnitude of the TTL difference highlights the critical need for further investigation into ancestry-specific telomere maintenance mechanisms in multiple myeloma to better understand how these variations may influence disease progression and treatment response.

Conclusions

Our findings demonstrate significant ancestry-related differences in telomere length among patients with multiple myeloma, with Black individuals exhibiting shorter total telomere length compared to White individuals. These disparities in telomere biology may play a crucial role in disease pathogenesis and contribute to observed clinical differences. Further research into the mechanisms of telomere maintenance across ancestral groups is warranted to inform tailored therapeutic strategies and improve outcomes in multiple myeloma.