In the current treatment paradigm, the use of anti-CD38 monoclonal antibodies (mAbs) in frontline has notably increased, for both transplant-ineligible and transplant-eligible patients with newly diagnosed multiple myeloma (NDMM) patients. As a result, patients with multiple myeloma (MM) are frequently exposed to or develop resistance to anti-CD38 mAb therapy during the initial stages of treatment. Here, we review second-line (first relapse) and some third-line (second relapse) therapies for patients with MM with disease progression after exposure to anti-CD38 mAb-based therapy. We discuss therapies including B-cell maturation antigen (BCMA)-targeted and non-BCMA-targeted therapeutic options in the setting of prior anti-CD38 mAb exposure/refractoriness.