Abstract 6881: Investigating the role of post-transplant bone marrow immune dysregulation in multiple myeloma

Abstract Multiple myeloma (MM) is a cancer of bone marrow plasma cells (BMPCs), which to date remains incurable. Standard of care for qualifying patients involves high-dose chemotherapy followed by autologous stem cell transplant (ASCT), after which minimal residual disease (MRD) testing is used to assess the degree of tumor clearance. Though strongly associated with better survival, MRD-negativity is an imperfect predictor for patient outcomes and fails to account for the pro-tumorigenic BM dysregulation often found in MM patients. As the post-transplant BM milieu in MM is not well understood, we conducted 3' single-cell RNA sequencing (scRNAseq) of 49 newly diagnosed (NDMM) and 79 day-100 post-ASCT whole-BM aspirates to investigate how immunosuppressive microenvironmental signatures may persist or develop following ASCT to influence patient outcomes. 68 of 79 post-ASCT samples come from uniformly-treated clinical trial enrollees with progression-free survival (PFS) ranging from 10 months to over 7 years, with both MRD- and MRD+ cases at either PFS extreme. We observe that although post-ASCT samples have uniformly lower PC count than NDMM samples, only erythroblasts and B cells appear relatively depleted in NDMM samples to compensate for higher PC proportions. T/NK cells and myeloid lineages, though similar in percentage across samples, exhibit clear subtype bias between the two timepoints. Post-ASCT samples are significantly enriched for GZMH+ CD8+ T and NK cells, HIF1A+ hypoxia-responsive monocytes, and depleted for S100A8/9-high CD14+ monocytes. NDMM samples are also enriched for SPINK2+, CDK6+, and AVP+ neutrophils, which are rare in post-ASCT samples. Notably, higher HIF1A expression in myeloid cells post-ASCT is further associated with longer PFS. Regardless of MRD status, NFKBIA, FOS, and GNLY upregulation and GZMK downregulation in post-ASCT T cells are associated with worse PFS. Conversely, enrichment of CD16+ IFN-responsive monocytes and depletion of ARG1+/FUT4+/CEACAM8+ myeloid-derived suppressor cells (MDSCs) are associated with longer PFS. Beyond such general trends, we observe MRD-dependent PFS-association of several CD8+ T cell subsets. Overall, this study enhances our understanding of how post-transplant BM repopulation and immune interaction may impact treatment response in MM. Citation Format: Julia T. Wang, Mark Fiala, Kazuhito Sato, Julie Fortier, Ravi Vij, Li Ding. Investigating the role of post-transplant bone marrow immune dysregulation in multiple myeloma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6881.