Despite no monoclonal antibody (mAb)-based targeted therapy approved to treat patients with multiple myeloma (MM), many mAbs targeting different antigens have been pre-clinically and clinically evaluated. One of my research focuses is to identify new MM target antigens and evaluate therapeutic potential of their mAbs against MM. For the past few years, following promising preclinical results of my studies on elotuzumab targeting a new MM antigen SLAMF7/CS1, encouraging activity was subsequently reported in derived clinical trials when combined with lenalidomide/dexamethasone or bortezomib. Another mAb currently in phase I/II clinical development for MM, daratumumab targeting CD38 also shows an acceptable safety profile with signs of single agent activity in refractory MM. These preliminary results have further stimulated development of 2 other therapeutic anti-CD38 mAb for the treatment of other CD38-expressing blood cancers. However, these antigens still lack specificity and are also expressed in other normal tissues including NK or other effectors, which could limit their clinical utility. Therefore, novel therapeutic mAbs to achieve improved MM selectivity and simultaneously targeting cytotoxic drugs to MM cells are urgently needed. Most recently, I showed that B cell maturation antigen (BCMA) is universally expressed on the MM cell surface and determined specific anti-MM activity of a novel humanized and afucosylated antagonistic anti-BCMA antibody-drug conjugate via a noncleavable linker. Excitingly, these studies clearly demonstrate more potent and selective myeloma cell killing without systemic cytotoxicity via multiple cytotoxic mechanisms, thus providing a promising next-generation immunotherapeutic in this cancer. We are further defining molecular mechanisms regulating APRIL-BCMA pathway in MM and devising novel immuno-oncological approaches to simultaneously kill myeloma cells and harness immune effectors. We also characterized other novel cancer pathways, i.e., BTK and CRM1/XPO1, to block the interaction of osteoclasts and myeloma cells in the bone marrow microenvironment. We continue to develop novel therapeutic strategy that effectively targets specific molecules on myeloma cells and also potentially overcomes tumor microenvironment-mediated drug resistance and the downstream effects of genetic instability.