(PA-254) Ancestry-Associated Dysregulation of the Bone Marrow T Cell Compartment in Multiple Myeloma Revealed via scRNA-seq and CyTOF Profiling

Multiple Myeloma (MM) disproportionately affects Black individuals in the U.S., with an incidence nearly double that of other groups. Although differences in the frequencies of cytogenetic events and age of onset have been observed, the immune microenvironment (IME) in Black patients with MM has not yet been investigated. Given the critical role of the IME in response toward current MM therapies, we examined ancestry associated differences in IME and outcomes.

Methods:

ScRNA-seq data of 337 newly diagnosed MM (NDMM) patients with >1.4 million cells from the MMRF Immune Atlas (IA) was used for this analysis. Ancestry was estimated from blood whole exome sequencing data. Ancestry associated alterations in immune composition or expression were assessed adjusting for sex, age, ISS stage, and BMI. To validate our findings, we generated an independent cohort (Mayo Clinic) of 94 BM aspirates using CyTOF. Of these, 41 patients had a precursor condition, 28 had NDMM, 37 had treated MM (TrMM) and 39 were Black, and 55 were White.

Results:

In the 337 NDMM patients of the Immune Atlas, 63 self-reported as ‘Black’, while 257 self-reported as ‘White’. Fewer high risk cytogenetic events, such as del(17p13), were observed with high African ancestry (AA), though triplet therapy and ASCT were significantly underutilized. PFS and OS were similar across race when matched for therapy.

T, NK, and Myeloid compartments showed significant alterations with ancestry. In T cells, AA significantly correlated with higher cytotoxicity (PRF1, FGFBP2, GNLY, p< 0.05), and enrichment of cytotoxic CD4⁺ and CD8⁺ cells (p< 0.001). Naive CD8⁺ T cells showed significant enrichment with high AA, while Naïve CD4⁺ T cells showed significant reduction (p< 0.04). High AA showed depletion of MAITs (p< 0.05, SLC4A10, ZBTB16, KLRB1), an MR1 responsive effector population with innate-like properties. In NK cells, higher AA was associated with adaptive NK markers (KLRC2⁺, FCER1G^-, p< 0.001), a memory-like, cytotoxic NK population which has been associated with chronic viral infections. Lastly, AA ancestry showed significant enrichment of CD16⁺ non-classical monocytes (nCM, p< 0.05). Differential expression across cellular clusters showed significant upregulation of RPS26 with AA. Differences in expression were associated with the C allele for the rs1131017 germline variant, which strongly associated with AA (p< 0.001).

In the independent CyTOF cohort, NDMM AA patients displayed similar enrichment of terminal effector T cell populations (p< 0.05). T cells alterations across race were specific to NDMM and TrMM groups. In the healthy cohort, AA patients were enriched in CD57⁺, Adaptive NK cells.

Conclusions:

High African ancestry MM patients exhibit significant dysregulation in T and NK cell compartments, which are strongly associated with outcomes. Given the central role of the immune landscape in determining therapeutic response, it is imperative to ensure adequate representation of underrepresented minorities in clinical trials.