Abstract

Although recent advances have improved the management of multiple myeloma, it remains an incurable malignancy. We now demonstrate that anti-CD138 genetically fused to interferon alpha14 (IFNα14) synergizes with the approved therapeutic lenalidomide in arresting the proliferation of the human multiple myeloma cell line NCIH929 both in vitro and in vivo. This synergism is the consequence of the combined effects of multiple, complementary anti-tumor activities including potentiated activation of STAT1 and downregulation of c-Myc, interferon regulatory factor 4 (IRF4) and poly(ADP-ribose) polymerase 1 (PARP-1). Caspase activation and glucose utilization also play a role in the induction of apoptosis by lenalidomide+anti-CD138-IFNα14 as inhibition of caspase activation, glycolysis or oxidative phosphorylation (OXPHOS) decreased but did not eliminate the apoptosis seen following treatment. Treatment with lenalidomide+anti-CD138-IFNα14 results in replicative stress resulting from increased accumulation of reactive oxygen species (ROS). Unexpectedly, we observed that the cellular stress elicited by treatment with lenalidomide or lenalidomide+anti-CD138-IFNα14 results in the degradation of Chk1, the Ser/Thr kinase central to the genome surveillance pathways of the DNA damage response and cell cycle checkpoints. Using an in vivo xenograft model we found that treatment with anti-CD138-IFNα14+lenalidomide was much more effective than either treatment alone with approximately 40% (9/24) of the animals with established tumors cured. Based on our findings, clinical testing of combination therapy with lenalidomide and anti-CD138-IFN fusion proteins for the treatment of multiple myeloma may be merited.

Keywords: Antibody immunotherapy; Interferon-α; Lenalidomide; Multiple myeloma