Multiple myeloma (MM) is a hematologic malignancy characterized by high heterogeneity in both its clinical presentation and biological behavior. The prognosis for patients with MM is closely related to the presence or absence of high-risk cytogenetic abnormalities (HRCAs). In recent years, although the widespread application of proteasome inhibitors and immunomodulatory drugs in MM has significantly improved survival, high-risk patients with HRCAs continue to face challenges such as drug resistance, early disease progression, and poor prognosis. The exploration and optimization of treatment strategies for these patients remain a clinical challenge. In the relapsed or refractory disease state, the choice of subsequent treatment is crucial for high-risk patients. With the advent of the immunotherapy era in MM treatment, the continuous emergence of new drugs has brought hope to patients. This article focuses on patients with relapsed or refractory MM accompanied by HRCAs, reviewing the efficacy of monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, and chimeric antigen receptor T-cells in these patients, aiming to explore optimal treatment strategies and provide guidance for clinical decision-making.