Abstract B-cell activating factor (BAFF), a member of the TNF superfamily, has been reported to play a role in the growth and survival of B-cell malignancies. However, the effect of inhibiting BAFF in vivo on tumor growth has not been fully determined. Additionally, studies so far have not addressed relative contributions of BAFF vs. APRIL towards cancer growth as the inhibitors used, such as TACI-Ig and BCMA-Ig, inhibit both BAFF and APRIL ligands. In the present study, we examined the potential therapeutic utility of a BAFF inhibitor, AMG 523, for treating B-cell malignancies in murine multiple myeloma in vivo models. AMG 523 is a peptibody that is a potent BAFF antagonist as a result of its high affinity binding to BAFF (KD of 1 pM). It inhibits BAFF-mediated increases in human and mouse B cell proliferation (IC50 of 0.1 nM at 0.2 nM BAFF). To determine the in vivo efficacy of AMG 523 in myeloma cells, we used the 5T series of murine models of myeloma. The 5T murine models of myeloma are myelomas that arose spontaneously in an inbred substrain of C57 black mice (C57BL/KaLwRij substrain). Several of the 5T myeloma lines closely mimic myeloma disease in humans. AMG 523 was first evaluated in a 5TGM1 syngeneic in vivo myeloma model. 5TGM1 was injected into the C57BL/KaLwRij mice and mice were treated with 5 or 20mg/kg of AMG 523 three times a week for four weeks. Tumor burden was determined by measuring the serum level of IgG2b, a paraprotein secreted by 5TGM1 myeloma cells. AMG 523 decreased serum IgG2b levels at early time points (day 8 and 15) but not at late time points (day 22 and 27) compared to the control. AMG 523 was also tested in two bone microenvironment dependent murine myeloma in vivo models: 5T33MMvv and 5T2MM. Both 5T33MMvv and 5T2MM cell lines express TACI receptor but not BCMA. BAFF increased survival of 5T2MM cells ex vivo, but inhibiting the activity of BAFF in vivo with AMG 523 had no effect on tumor burden, measured by proportion of bone marrow occupied by 5TMM cells, in both 5T33MMvv and 5T2MM models. Taken together, our data suggests that the BAFF inhibitor AMG 523 lacks efficacy in murine multiple myeloma in vivo tumor models.