Monoclonal antibody (mAb)-based targeted therapy will 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 MM. Following promising pre-clinical 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 MM with diverse heterogenecity. Most recently, we further identified that the second therapeutic anti-CD38 mAb SAR650984 (SAR) directly kills p53-mutated MM cells, which represent high-risk patient subgroup, via lysosomal activation and reactive oxygen species. This is the first therapeutic mAb inducing direct tumor cell death without immune effector cells. 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 resistant MM and other CD38-expressing blood cancers. However, these antigens still lack tumor specificity since they also expressed in other normal tissues including NK and T effectors, which could limit their clinical utilities. Therefore, novel therapeutic mAbs to achieve improved MM selectivity and simultaneously targeting cytotoxic drugs to MM cells are urgently needed. Very encouragingly, I reported that B cell maturation antigen (BCMA) is universally expressed on the MM cell surface which was further translated to elicit specific anti-MM activity by a novel humanized and afucosylated antagonistic anti-BCMA antibody-drug conjugate via a noncleavable linker. These studies demonstrate more potent and selective myeloma cell killing without affecting surrounding BCMA-null bone marrow cells via multiple cytotoxic mechanisms even in two mice models, thus providing a promising next-generation immunotherapeutics in this cancer. We are further defining molecular mechanisms regulating this signaling pathway in MM and continuing to devise improved immunotherapies to simultaneously kill myeloma cells and harness immune effectors. We also characterize other novel cancer pathways, i.e., BTK and CRM1/XPO1, APRIL, and immuno-checkpoint proteins in the interaction and suppression of osteoclasts or various immune cells with myeloma cells in the bone marrow microenvironment. We also continue to develop novel immunotherapeutics that potentially overcome tumor microenvironment-mediated drug resistance and the downstream effects of genetic instability.