Multiple myeloma (MM) is an incurable B-cell malignancy, characterized by the proliferation of malignant plasma cells. B-cell-activating factor (BAFF, also known as BlyS or B-lymphocyte stimulator) and a proliferation-inducing ligand (APRIL), the two members of the tumor necrosis factor ligand superfamily, enhance the production of antibodies and regulate and promote proliferation and survival. Both BAFF and APRIL have an important role in B cell lymphoma and chronic lymphocytic leukemia cell survival. This study evaluates the expression of BAFF, APRIL, and their three receptors in two human MM cell lines (KM3 and PRMI 8226) and ten primary MM cell lines, and their effects on the growth of MM cells in vivo. MM cells were found to express BAFF, APRIL, and their three receptor genes both at the gene and protein levels. ELISA found high concentrations of BAFF and APRIL in the supernatants of these cultured cells. Treatment with PS-341 decreased the concentration of BAFF and APRIL. The WST-1 analysis of growth found that BAFF and APRIL stimulated the proliferation of MM cells. PS-341 inhibited this enhanced proliferation and induced apoptosis. Making use of the rhTACI-Fc to block the BAFF- and APRIL-induced activation of NF-kappaB2, we demonstrated that the NF-kappaB2-p52/RelB signal contributes to MM cell survival. In summary, PS-341 was shown to block this pathway. PS-341 inhibits the autocrine secretion of BAFF and APRIL and thereby MM cell proliferation by the alterative NF-kappaB2 pathway. BAFF and APRIL appear to be the targets of PS-341.