Multimodality targeting of MM in the context of the BM microenvironment. In the center is the MMC (in light pink), with nuclear clumped chromatin and endoplasmic reticulum (ER). The surrounding 5 sections each represent a different modality of anti-MM therapy, with investigational agents outlined in red. In section A is the UPS, closely interacting with the aggresome pathway. Deubiquitinating enzymes USP7 and USP14/UCHL5 are symbolized by a scissors and the 19S ubiquitin (Ub) receptor RPN13 as a receptor associated with the proteasome cap. Section B contains the monoclonal antibodies mAbs) daratumumab (DARA) and SAR650984 (SAR), targeting CD38, as well as elotuzumab (ELO), targeting SLAMF-7, which mediate CDC, direct cytotoxicity from cross-linking, and ADCC. The antibody-drug conjugates (ADCs) indatuximab ravtansine (BT062) and J6M0-mcMMAF (J6M0) target CD138 and BCMA, respectively. Both toxins cause mitotic arrest and apoptosis after being released intracellularly upon internalization of the ADC–target complex and lysosomal lysis. Section C represents several strategies for modulation of cytotoxic immunity. In red is an anti-BCMA CAR-T cell; in orange is an MM-specific cytotoxic T cell activated via direct interaction with MM-DC vaccine or with autologous DC presenting peptides from the PVX-140 vaccine. Two different strategies to modulate epigenetic control of oncosuppressor and oncogene expression are outlined in section D. Nucleosomes are represented as spheres (histones) wrapped in a black thread (DNA). Open nucleosomes with acetylated (Ac) sites are green, whereas closed chromatin structure is pink. The BET bromodomain 4 protein (BRD4) is represented as a red trapezoid, binding to acetylated nucleosomes and inducing Myc transcription. Section E contains a representation of immune checkpoint blockade, with cytotoxic T and NK-T cells represented in green and blue, respectively. PD-1 and its ligand PD-L1 are represented as complementary transmembrane structures on effector cells and target cells (MMCs, myeloid-derived suppressor cells [MDSCs], and pDCs), respectively. Cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and killer cell immunoglobulin-like receptor (KIR) are also pictured on effector cells. Outside the sections, TH-302 hypoxia–activated alkylating agent and NOX-A12 CXCL12 inhibitor are represented. In the 4 corners are key cellular and noncellular elements of the BM niche that contribute to MM pathogenesis: excess of osteoclasts (OC) compared to osteoblasts (OB; upper left corner); increased neoangiogenesis (upper right corner); tumor-tolerant immune system (lower right corner); and cancer-associated fibroblasts (CAF) responsible for the secretion of a pro-MM extracellular matrix (ECM), and MM-associated BM stromal cells (BMSC; lower left corner). Relevant cytokines in the BM milieu are represented as orange ovals. FcR, Fc receptor; HATs, histone acetylases; HGF, hepatocyte growth factor; MIP-1α, macrophage inflammatory protein 1α; PD-L1, programmed cell death ligand 1; RANKL, receptor activator of NF-κB ligand; RBC, red blood cell; TCR, T-cell receptor; TGFβ, transforming growth factor β; TH17, T helper 17 cells; TNFα, tumor necrosis factor α; Treg, regulatory T cell; VEGFA, vascular endothelial growth factor A.