Monoclonal antibody (MoAb)-based immunotherapies have significantly improved the prognosis of the patients with multiple myeloma (MM) in the recent years. When combined with immunomodulatory drugs (IMiDs) or proteasome inhibitors (PIs), these new classes of drugs target malignant plasma cells (PCs) and modulate the immune microenvironment, leading to prolonged anti-MM responses. However, MM remains an incurable cancer for most patients, there continues to be a need to identify new tumor target molecules and develop alternative cellular and molecular approaches using gene therapeutic strategies and novel treatment mechanisms. My research group continues to focus on improving existing immunotherapies and identifying ideal partners for combinational treatment strategies for MM and related-hematological diseases. We study molecular and cellular components critical for tumor-induced immunosuppressive bone marrow (BM) microenvironment using various in vitro, ex vivo, and in vivo models. Besides the field utilizing SLAMF7/CS1 and CD38 targeting MoAbs, B cell maturation antigen (BCMA)-targeting T-, NK-, and dendritic cell-based immunotherapies have remained one of our researches to further improve impressive responses in heavily-treated MM patients and define resistance mechanisms. BCMA, as a most specific MM target antigen thus far, has stimulated much basic and clinical researches using next generation immunotherapeutic platforms, i.e., antibody-drug conjugate (ADC), CAR T/NK, bi-/tri-specific T-/NK- cell engagers, as well as vaccination approaches. Our ongoing efforts also include defining and understanding various subsets of immune regulators in the MM development and treatment resistance. Built upon BCMA/SLAMF7/CD38/CD138-related pathways as study models for promising anti-MM immunotherapies, all these studies will ultimately help to inform best treatment regimens/strategies to restore and permit full anti-MM immunity. In terms of basic researches, we characterized novel druggable cancer pathways, i.e., BTK, CRM1/XPO1, APRIL, immuno-checkpoint proteins (both membrane and soluble forms), B7-related family, EZH2/PRC/PHF19-related epigenetic regulators, as well as components critical in DNA damage and repair responses, in MM cells via the bi-directional interactions with non-myeloma BM accessory cells, i.e., bone cells, mesenchymal stem cells, myeloid-derived suppressive cells, with myeloma cells. The goal is to utilizing novel insight in regulating multifaceted immune microenvironment and maximize effectiveness of next generation immunotherapies to simultaneously kill tumor cells, modulate immune inhibitory cells, and harness immune effectors to cure cancer.