Monoclonal antibody (mAb)-based targeted therapy has become available as a novel treatment strategy for patients with multiple myeloma (MM) following over a decade of evaluating many mAbs targeting various antigens, pre-clinically and clinically. This is one of my research focuses to both identify new MM target antigens and develop more effective targeted immunotherapy to treat this malignancy. We continue to study and provide new cellular and molecular insights to improve current immunotherapies for MM using various in vitro, ex vivo, and in vivo models. In addition to elotuzumab which targets SLAMF7/CS1 and daratumumab or isatuximab which target CD38, our preclinical studies have confirmed that B cell maturation antigen (BCMA) is universally expressed on the MM cell surface and even selective MM antigen than SLAMF7 and CD38. Our group has contributed to multiple major forms of adoptive and active I mmunotherapies targeting BCMA in recent 3 years. Importantly, based on our preclinical studies, the first antibody-drug conjugate (ADC) and bispecific T cell engager (BiTE) targeting BCMA have been successfully translated into clinics for MM patients. We also explore BCMA targeting using CAR-T and vaccination approaches. Our ongoing efforts are to identify immune suppressive regulators in the MM bone marrow micro environment in order to permit full anti-MM immunity based on BCMA and APRIL pathways, alone and in combination with various immune modulators and chemoreagents with diverse mechanisms of action. The goal is to improve next generation immunotherapies to simultaneously kill myeloma cells and harness immune effectors to cure this cancer. In parallel, we characterize other novel cancer pathways, i.e., BTK and CRM1/XPO1, APRIL, immuno-checkpoint proteins, B7-related family, EZH2/PRC-related epigenetic regulators, and DNA damage responses, in the interaction and suppression of osteoclasts or various immune cells with myeloma cells in the bone marrow microenvironment. We continue to identify mechanisms for drug resistance and further develop novel therapies to overcome tumor microenvironment-mediated drug resistance and the downstream effects of genetic instability.