Signalling through the interleukin (IL)-6 pathway induces proliferation and drug 
resistance of multiple myeloma cells. We therefore sought to determine whether 
the IL-6-neutralizing monoclonal antibody siltuximab, formerly CNTO 328, could 
enhance the activity of melphalan, and to examine some of the mechanisms 
underlying this interaction. Siltuximab increased the cytotoxicity of melphalan 
in KAS-6/1, INA-6, ANBL-6, and RPMI 8226 human myeloma cell lines (HMCLs) in an 
additive-to-synergistic manner, and sensitized resistant RPMI 8226.LR5 cells to 
melphalan. These anti-proliferative effects were accompanied by enhanced 
activation of drug-specific apoptosis in HMCLs grown in suspension, and in HMCLs 
co-cultured with a human-derived stromal cell line. Siltuximab with melphalan 
enhanced activation of caspase-8, caspase-9, and the downstream effector 
caspase-3 compared with either of the single agents. This increased induction of 
cell death occurred in association with enhanced Bak activation. Neutralization 
of IL-6 also suppressed signalling through the phosphoinositide 3-kinase/Akt 
pathway, as evidenced by decreased phosphorylation of Akt, p70 S6 kinase and 
4E-BP1. Importantly, the siltuximab/melphalan regimen demonstrated enhanced 
anti-proliferative effects against primary plasma cells derived from patients 
with myeloma, monoclonal gammopathy of undetermined significance, and 
amyloidosis. These studies provide a rationale for translation of siltuximab 
into the clinic in combination with melphalan-based therapies.