This study investigates the role of nuclear factor (NF)-κB in the therapeutic activity of specific NF-κB inhibitors against multiple myeloma (MM). The authors used an IκB kinase (IKK) inhibitor, PS-1145, to block NF-κB activation in MM cells. They found that PS-1145 and PS-341 (a proteasome inhibitor) inhibited TNFα-induced NF-κB activation in a dose- and time-dependent manner by inhibiting IκBα phosphorylation and degradation, respectively. Dexamethasone (Dex), which up-regulates IκBα, enhanced the inhibitory effect of PS-1145 on NF-κB activation. PS-1145 also blocked the protective effect of IL-6 against Dex-induced apoptosis and inhibited TNFα-induced expression of intracellular adhesion molecule (ICAM-1) on MM cells. Additionally, PS-1145 reduced IL-6 secretion from bone marrow stromal cells (BMSCs) triggered by MM cell adhesion and proliferation. However, PS-1145 only partially inhibited MM cell proliferation, suggesting that NF-κB blockade cannot account for all the anti-MM activity of PS-341. Importantly, TNFα-induced MM cell toxicity was observed in the presence of PS-1145. These findings demonstrate that specific targeting of NF-κB can overcome the growth and survival advantages conferred by tumor cell binding to BMSCs and cytokine secretion in the BM microenvironment. The study provides a framework for clinical evaluation of novel MM therapies based on targeting NF-κB.This study investigates the role of nuclear factor (NF)-κB in the therapeutic activity of specific NF-κB inhibitors against multiple myeloma (MM). The authors used an IκB kinase (IKK) inhibitor, PS-1145, to block NF-κB activation in MM cells. They found that PS-1145 and PS-341 (a proteasome inhibitor) inhibited TNFα-induced NF-κB activation in a dose- and time-dependent manner by inhibiting IκBα phosphorylation and degradation, respectively. Dexamethasone (Dex), which up-regulates IκBα, enhanced the inhibitory effect of PS-1145 on NF-κB activation. PS-1145 also blocked the protective effect of IL-6 against Dex-induced apoptosis and inhibited TNFα-induced expression of intracellular adhesion molecule (ICAM-1) on MM cells. Additionally, PS-1145 reduced IL-6 secretion from bone marrow stromal cells (BMSCs) triggered by MM cell adhesion and proliferation. However, PS-1145 only partially inhibited MM cell proliferation, suggesting that NF-κB blockade cannot account for all the anti-MM activity of PS-341. Importantly, TNFα-induced MM cell toxicity was observed in the presence of PS-1145. These findings demonstrate that specific targeting of NF-κB can overcome the growth and survival advantages conferred by tumor cell binding to BMSCs and cytokine secretion in the BM microenvironment. The study provides a framework for clinical evaluation of novel MM therapies based on targeting NF-κB.