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VRd induction therapy is a common approach to treat newly diagnosed multiple myeloma (MM) patients. Although in vitro studies of bortezomib (Velcade, V), lenalidomide (Revlimid, R), and dexamethasone (d) reveal mechanisms of these individual drugs, VRd therapy induced immune cell phenotype changes in vivo are unknown. We have utilized multimodal single cell methods to elucidate novel mechanisms of induction therapy response in human immune cells over time as a longitudinal study: pre-treatment (pretrt), after 2-cycles of VRd therapy (post-induction; pi) and after the end of 4-6 additional cycles of VRd therapy (end induction; ei). Protein measurements in plasma demonstrate significantly increased levels of IL-15 and IL-18 only at pi compared to pretrt but IL-2 and IFN-γ are progressively reduced from pretrt to ei. Both flow cytometry and single cell RNA -seq reveal that the proportion of NK cells (NK) significantly increased in PBMC only at pi compared to pretrt. NK subsets with strong dexamethasone effect emerge at pi; In contrast, memory like NK subsets (CD56dimCD16+NKG2A+CD94+) become the major NK in PBMC and bone marrow (BM) at ei. In addition, single cell ATAC-seq suggests that RUNX-family transcription factors may mediate lenalidomide to up-regulate NK cytotoxic gene expression during VRd therapy. In summary, comprehensive immune profiling of newly diagnosed MM patients suggests that transient increase of IL-15 and IL-18 may mediate the generation of memory like NK cells, which may play important roles in controlling MM growth and/or reducing risk of infection during VRd induction therapy. Citation Format: Tao Peng, Emma Kuan, Anthony Cicalo, Qiuyu Gong, Troy Torgerson, Xiaojun Li. Vrd induction therapy drives memory like NK cell development in newly diagnosed multiple myeloma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3280.

Chromatin architecture, a key regulator of gene expression, can be inferred using chromatin contact data from chromosome conformation capture, or Hi-C. However, classical Hi-C does not preserve multi-way contacts. Here we use long sequencing reads to map genome-wide multi-way contacts and investigate higher order chromatin organization in the human genome. We use hypergraph theory for data representation and analysis, and quantify higher order structures in neonatal fibroblasts, biopsied adult fibroblasts, and B lymphocytes. By integrating multi-way contacts with chromatin accessibility, gene expression, and transcription factor binding, we introduce a data-driven method to identify cell type-specific transcription clusters. We provide transcription factor-mediated functional building blocks for cell identity that serve as a global signature for cell types.