The proteasome inhibitor CEP‐18770 enhances the anti‐myeloma activity of bortezomib and melphalan

The anti‐multiple myeloma (MM) efficacy of bortezomib has led to the development of other proteasome inhibitors (PI), including CEP‐18770 which has shown anti‐MM effects in preclinical studies. However, the efficacy of orally (PO) or intravenously (IV) administered CEP‐18770 in multiple MM models and in combination with conventional anti‐MM therapies has not been evaluated. Herein, we show that CEP‐18770 combined with melphalan or bortezomib induces synergistic inhibition of MM cell viability in vitro. In MM xenograft models, the addition of CEP‐18770 IV to melphalan completely prevented the growth of both melphalan‐sensitive and melphalan‐resistant tumours. The combination of CEP‐18770 IV and bortezomib induced complete regression of bortezomib‐sensitive tumours and markedly delayed progression of bortezomib‐resistant tumours compared to treatment with either agent alone. Single agent CEP‐18770 PO also showed marked anti‐MM effects in these xenograft models. These studies provide strong preclinical rationale for further development of this novel PI in the treatment of MM as a monotherapy as well as combined with either melphalan or bortezomib.