Multiple myeloma (MM) is a plasma cell malignancy that is still largely incurable, despite considerable progress in recent years. NF-κB is a well-established therapeutic target in MM, but none of the currently available treatment options offer direct, specific pharmacological targeting of NF-κB transcriptional activity. Thus, we designed a novel direct NF-κB inhibitor (IT848) as a drug candidate with strong potential for clinical translation and conducted comprehensive in vitro and in vivo mechanistic studies in MM cell lines, primary MM cells, xenograft models and immunocompetent mouse models of MM. Here we show that IT848 inhibits NF-κB activity through inhibition of DNA binding of all five NF-κB subunits. IT848 treatment of MM cell lines and patient samples inhibited proliferation and induced caspase-dependent and independent apoptosis. In addition to direct NF-κB inhibitory effects, IT848 treatment altered the redox homeostasis of MM cells through depletion of the reduced glutathione pool, selectively inducing oxidative stress in MM but not in healthy cells. MM xenograft studies confirmed the efficacy of IT848 as single agent and in combination with bortezomib. Furthermore, IT848 significantly improved survival when combined with PD-1 inhibition, and correlative immune studies revealed that this clinical benefit was associated with suppression of regulatory T cell infiltration of the bone marrow microenvironment. In conclusion, IT848 is a potent direct NF-κB inhibitor and inducer of oxidative stress specifically in tumor cells, displaying significant activity against MM cells in vitro and in vivo, both as monotherapy as well as in combination with bortezomib or immune checkpoint blockade.