Survival in multiple myeloma (MM) has improved due to the ongoing revolution of therapeutic approaches. Nevertheless, many patients relapse, and additional novel approaches are required to prolong remissions and prevent disease progression. Considering the success of monoclonal antibodies (mAbs) against CD38 and SLAMF7 in relapsed/refractory MM (R/R MM), additional antigens expressed on malignant plasma cells are being investigated as treatment targets. Among these, many trials are focusing on B cell maturation antigen (BCMA), using either antibody-drug conjugates (ADCs), bispecific T cell engagers (TCE), or chimeric antigen receptor T cells (CAR-T). Other potential targets include the myeloma markers CD138, GPRC5D, FcRH5, the plasma cell differentiating factors APRIL, TACI and BAFF, and the immune checkpoint proteins CD47 and TIGIT. Additionally, novel immunomodulatory Cereblon E3 Ligase Modulators (CELMoDs) offer the potential to overcome resistance to conventional immunomodulatory agents. Based upon PubMed and abstract searches primarily from the past 4 years, here we review the data supporting novel immunotherapies for R/R MM. Overcoming disease resistance remains a challenge in R/R MM. Novel therapeutic approaches targeting MM antigens and/or enhancing immune cell function offer the potential to prolong survival and are actively being investigated in clinical trials.