Multiple myeloma (MM) shows constitutive activation of canonical and non-canonical nuclear factor-ĸB (NF-ĸB) signaling through genetic mutations or stimuli from the tumour microenvironment (TME). A subset of MM cell lines showed dependency for cell growth and survival on the canonical NF-ĸB transcription factor RELA alone, suggesting a critical role for a RELA-mediated biological program in MM pathogenesis. Here, we determined the RELA-dependent transcriptional program in MM cell lines and found the expression of the cell surface molecules IL-27 receptor-α (IL-27Rα) and the adhesion molecule JAM2 to be responsive to RELA at the mRNA and protein levels. IL-27Rα and JAM2 were expressed on primary MM cells at higher levels than on normal long-lived plasma cells (PCs) in the bone marrow. IL-27 activated STAT1, and to a lesser extent STAT3, in MM cell lines and in PCs generated from memory B-cells in an IL-21-dependent in vitro PC-differentiation assay. Concomitant activity of IL-21 and IL-27 enhanced differentiation into PCs and increased cell-surface expression of the known STAT target gene CD38. In accordance, a subset of MM cell lines and primary MM cells cultured with IL-27 upregulated CD38 cell-surface expression, a finding with potential implications for enhancing the efficacy of CD38-directed monoclonal antibody (mAb) therapies by increasing CD38-expression on tumour cells. The elevated expression of IL-27Rα and JAM2 on MM cells compared to normal PCs may be exploited for the development of targeted therapeutic strategies that modulate the interaction of MM cells with the TME.