Multiple myeloma (MM) is a genetically heterogenous disease and remains mostly incurable with a small group of patients achieving long-term disease remission. The past decade witnessed enormous efforts to break the circulus vitiosus of tumor-induced immunosuppression and to re-engage the immune system to fight cancer. The first-in-class anti-CD38 monoclonal antibody, daratumumab, has shown unprecedented responses especially in combination with other novel agents in both newly diagnosed and relapsed MM. There has been great interest in harnessing the power of T cells with bispecific antibodies and chimeric antigen receptor T-cell therapies in hematologic malignancies including MM. These immune-based approaches have shown notable antimyeloma effects with deeper, durable responses in early clinical trials of heavily pretreated patients with MM with limited therapeutic options. Several trials are underway investigating both single and combinatorial immune therapies at different stages with a hope to bring major transformation in MM. In the current review, we summarize how an immunologic approach offers promise for the treatment of MM and is setting the stage for second major paradigm shift 2 decades after the emergence of thalidomide and novel therapeutics.