Cell-type–specific effects of GSI on gene expression and chromatin accessibility. (A) Volcano plot depicting differentially expressed genes from bone marrow samples of patients before and after GSI treatment. Genes encoding proteins that are known substrates of γ-secretase are highlighted. (B) Dot plot of the log-fold change and FDR of genes encoding γ-secretase subunits after GSI exposure in each cell type. (C-D) Gene set enrichment analysis (GSEA) of Reactome pathways using log2 fold change of differentially expressed genes (C) and gene activity scores between pre- and post-GSI exposure samples (D). (E) IL-10 and TNF-α levels in MM cell lines (H292, U266, and MOLP8) cocultured with or without allogeneic classical or nonclassical monocytes isolated from healthy donor peripheral blood mononuclear cells (PBMCs). Error bars represent standard error from 3 independent experiments using 3 MM cell lines and 3 donor PBMCs. P values from Wilcoxon rank-sum tests indicate significant differences. (F) Significantly differentially detected circulating cytokines in clinical trial participants before and after GSI exposure (n = 10). P values from Wilcoxon signed-rank tests are shown. CCL, chemokine (C-C motif) ligand; CSF, colony stimulating factor; DC2, dendritic cell type 2; DVL, disheveled; GPCR, G protein-coupled receptor; GTPase, guanosine triphosphatase; LTA, lymphotoxin-α; NES, normalized enrichment score; NGF, nerve growth factor; NCSTN, nicastrin; PCP, planar cell polarity; PTEN, phosphatase and tensin homolog; PSEN, presenilin; RAF, rapidly accelerated fibrosarcoma; RHOF, Ras homolog family member F; TGF, transforming growth factor; WNT, wingless-INT.