Multiple myeloma (MM) is a haematological malignancy characterized by the clonal expansion of plasma cells within the bone marrow, thus resulting in the overproduction of monoclonal immunoglobulins. Despite the availability of various immunotherapeutic strategies, patient survival rates remain disappointingly low, thus underscoring the need for innovative immunotherapies to improve outcomes. Leukocyte Ig-like receptor subfamily B (LILRB1), which is a recently identified immune checkpoint, has an undefined role and molecular mechanism in MM. Herein, we demonstrated that LILRB1 was significantly upregulated in MM patients and MM cell lines and was negatively correlated with patient survival. The knockdown of LILRB1 promoted apoptosis in MM cells, enhanced sensitivity to bortezomib and diminished tumourigenicity in a subcutaneous mouse model. Mechanistically, LILRB1 triggers downstream GATA Binding Protein 2 (GATA2) and sustains MM cell proliferation via the GATA2-Sarcoma Antigen 1 (SAGE1) signalling pathway. Consequently, the targeting of LILRB1 may represent a promising therapeutic approach for MM.© 2025 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.