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 and daratumumab targeting CD38, encouraging clinical activities when combined with lenalidomide/dexamethasone have quickly moved these two Abs into multiple phase III clnical trials in MM. Specifically, daratumumab shows an acceptable safety profile with signs of single agent activity in relapsed and refractory (R/R) MM. We further identified novel mechanisms of action for the second therapeutic anti-CD38 mAb SAR650984 (SAR) to directly kill MM cells mainly via lysosomal activation and reactive oxygen species. Although caspase 3/7-dependent apoptosis plays a minor role in SAR-induced myeloma cell death, it is synergistically activated when SAR is combined with Pomalidomide, strongly supporting ongoing combination trials in R/R MM and other CD38-expressing blood cancers. However, these antigens still lack specificity since they also expressed in other normal tissues including NK and T effectors, which might limit their clinical utilities. 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. These studies clearly demonstrate more potent and selective myeloma cell killing without systemic cytotoxicity via multiple cytotoxic mechanisms in two mice models, 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, APRIL, and other immuno-checkpoint proteins to block the interaction and suppression of osteoclasts or various immune cells with myeloma cells in the bone marrow microenvironment. We continue to develop novel immunotherapeutics that effectively targets specific molecules on myeloma cells and also potentially overcomes tumor microenvironment-mediated drug resistance and the downstream effects of genetic instability.