Abstract: Multiple myeloma (MM) is a plasma cell malignancy characterized by bone pain, renal insufficiency, hypercalcemia, anemia, and recurrent infections. The advent of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibodies, chimeric antigen receptor T-cell immunotherapy (CAR-T), and other novel drugs has significantly improved the survival and prognosis of patients with MM. However, a definitive cure remains elusive. CAR-T cell therapy offers a promising approach for relapsed and refractory MM by specifically targeting and eliminating MM cells through antigen recognition. Despite significant advancements in treatment, nearly all MM patients eventually relapse due to drug resistance. This article reviews the mechanisms of resistance and strategies to optimize CAR-T cell therapy for MM.