Multiple myeloma is an incurable disease characterized by unregulated growth of malignant plasma cells in the bone marrow (BM). Tumor-induced dysfunction of T-cells may be responsible for immune evasion and failure of immunotherapy. Therefore, a better understanding of the phenotype of T-cells at the tumor site is needed. We assessed the expression of immune regulatory receptors on T-cell subsets from peripheral blood (PB) and BM using multicolor flow cytometry. Paired PB and BM samples were collected from newly diagnosed, treatment-naïve myeloma patients (n = 19) and patients progressing during treatment with the CD38 monoclonal antibody daratumumab alone or in combination with other anti-myeloma drugs (n = 39). We observed that CD4 + T-cells from both PB and BM of patients relapsing on daratumumab have a higher expression of the costimulatory checkpoint receptor DNAM-1. The potential role of DNAM-1 +CD4 + T-cells in the development of resistance to daratumumab needs further exploration. We also observed that the inhibitory checkpoint receptor TIGIT is more frequently expressed by BM CD8 + T-cells from myeloma patients than PD-1 and CTLA-4, which supports the hypothesis that TIGIT may play a central role in the immune escape of the malignant plasma cells.