Background: Multiple myeloma (MM) remains incurable despite novel therapies, highlighting the need for further identification of factors mediating disease progression and resistance. We showed that plasmacytoid dendritic cells (pDCs) in the MM bone marrow promote MM cell growth (Chauhan et al., Cancer Cell 2009, 16:309-323). pDC-MM interactions trigger secretion of interleukin-3 (IL-3), which in turn, induces MM cell growth, and pDCs survival. Additionally, IL-3 contributes to the progression of osteolytic bone disease in MM. Here, we examined the effect of SL-401, a novel targeted therapy directed to IL-3R, on pDC-induced MM cell growth and osteoclast (OCL) formation. Methods: Patient MM cells, pDCs, and MNCs were obtained from normal donors or MM patients. Cell growth/viability was analyzed using MTT assays. OCL function and bone resorption was measured using the OsteoAssays and TRAP staining. Results: SL-401 decreased the viability of pDCs even at low concentrations (IC₅₀: 0.83 ng/ml; 14.6 pM). SL-401 decreased the viability of MM cells at clinically achievable doses without significantly affecting the viability of normal PBMCs. Co-culture of MM patient-derived pDCs triggered proliferation of MM cell lines and primary MM cells; and importantly, SL-401 inhibited pDC-triggered MM cell growth (P < 0.005). Moreover, 3 of 5 samples were obtained from patients whose disease was progressing while on bortezomib, dexamethasone, and lenalidomide therapies. SL-401 blocked pDC-induced growth of dexamethasone-, doxorubicin- or melphalan-resistant MM cells.Combination of SL-401 with bortezomib, melphalan, lenalidomide, or pomalidomide showed synergistic anti-MM activity. Finally, SL-401 inhibited monocyte-derived osteoclast formation in a dose-dependent manner as well as stabilized MM patient BM-derived osteoblast formation. Conclusions: Our study provides the basis for directly targeting pDCs and inhibiting the pDC-MM interaction, as well as targeting osteolytic bone disease, in novel therapeutic strategies with SL-401 to enhance MM cytotoxicity, overcome drug-resistance, and improve patient outcome.