This study investigates the role of NF-κB as a therapeutic target in multiple myeloma (MM). Thalidomide (Thal) and its derivatives (IMiDs), proteasome inhibitor PS-341, and arsenic trioxide (As₂O₃) act directly on MM cells and in the bone marrow (BM) to overcome drug resistance. These agents inhibit NF-κB activation but also have other effects. The study focuses on the role of NF-κB blockade in mediating anti-MM activity. Using an IKK inhibitor (PS-1145), the study shows that PS-1145 and PS-341 block TNFα-induced NF-κB activation in MM cells by inhibiting IκBα phosphorylation and degradation. Dexamethasone (Dex) enhances this effect. PS-1145 also blocks the protective effect of IL-6 against Dex-induced apoptosis. TNFα-induced ICAM-1 expression on MM cells is inhibited by PS-1145. PS-1145 also inhibits IL-6 secretion from BMSCs and MM cell proliferation. However, PS-1145 only partially inhibits MM cell proliferation, suggesting that NF-κB blockade cannot account for all of the anti-MM activity of PS-341. Importantly, TNFα induces MM cell toxicity in the presence of PS-1145. These studies demonstrate that specific targeting of NF-κB can overcome the growth and survival advantage conferred by tumor cell binding to BMSCs and cytokine secretion in the BM milieu. The study also provides a framework for clinical evaluation of novel MM therapies targeting NF-κB. NF-κB activation is involved in various cellular processes, including growth, survival, and apoptosis. In MM, NF-κB is constitutively activated, and its inhibition blocks MM cell growth. The study shows that MM cell adhesion to BMSCs induces NF-κB-dependent up-regulation of IL-6, a growth and anti-apoptotic factor in MM. TNFα secreted by MM cells activates NF-κB in BMSCs and MM cells, leading to increased adhesion molecule expression and MM cell to BMSC binding. IL-6 is the major growth and survival factor in MM cells, and adherence to fibronectin confers resistance to drug-induced apoptosis. Specific blockade of NF-κB signaling may represent a novel therapeutic strategy in MM. The study also shows that PS-1145 inhibits NF-κB activation and blocks the protective effect of IL-6 against apoptosis. These findings suggest that targeting NF-κB could be a promising approach for treating MM.This study investigates the role of NF-κB as a therapeutic target in multiple myeloma (MM). Thalidomide (Thal) and its derivatives (IMiDs), proteasome inhibitor PS-341, and arsenic trioxide (As₂O₃) act directly on MM cells and in the bone marrow (BM) to overcome drug resistance. These agents inhibit NF-κB activation but also have other effects. The study focuses on the role of NF-κB blockade in mediating anti-MM activity. Using an IKK inhibitor (PS-1145), the study shows that PS-1145 and PS-341 block TNFα-induced NF-κB activation in MM cells by inhibiting IκBα phosphorylation and degradation. Dexamethasone (Dex) enhances this effect. PS-1145 also blocks the protective effect of IL-6 against Dex-induced apoptosis. TNFα-induced ICAM-1 expression on MM cells is inhibited by PS-1145. PS-1145 also inhibits IL-6 secretion from BMSCs and MM cell proliferation. However, PS-1145 only partially inhibits MM cell proliferation, suggesting that NF-κB blockade cannot account for all of the anti-MM activity of PS-341. Importantly, TNFα induces MM cell toxicity in the presence of PS-1145. These studies demonstrate that specific targeting of NF-κB can overcome the growth and survival advantage conferred by tumor cell binding to BMSCs and cytokine secretion in the BM milieu. The study also provides a framework for clinical evaluation of novel MM therapies targeting NF-κB. NF-κB activation is involved in various cellular processes, including growth, survival, and apoptosis. In MM, NF-κB is constitutively activated, and its inhibition blocks MM cell growth. The study shows that MM cell adhesion to BMSCs induces NF-κB-dependent up-regulation of IL-6, a growth and anti-apoptotic factor in MM. TNFα secreted by MM cells activates NF-κB in BMSCs and MM cells, leading to increased adhesion molecule expression and MM cell to BMSC binding. IL-6 is the major growth and survival factor in MM cells, and adherence to fibronectin confers resistance to drug-induced apoptosis. Specific blockade of NF-κB signaling may represent a novel therapeutic strategy in MM. The study also shows that PS-1145 inhibits NF-κB activation and blocks the protective effect of IL-6 against apoptosis. These findings suggest that targeting NF-κB could be a promising approach for treating MM.