Pharmacodynamic and efficacy studies of the novel proteasome inhibitor NPI‐0052 (marizomib) in a human plasmacytoma xenograft murine model

Summary Our previous study showed that the novel proteasome inhibitor NPI‐0052 induces apoptosis in multiple myeloma (MM) cells resistant to conventional and bortezomib (Velcade™, Takeda, Boston, MA, USA) therapies. In vivo studies using human MM‐xenografts demonstrated that NPI‐0052 is well tolerated, prolongs survival, and reduces tumour recurrence. These preclinical studies provided the basis for an ongoing phase‐1 clinical trial of NPI‐0052 in relapsed/refractory MM patients. Here we performed pharmacodynamic (PD) studies of NPI‐0052 using human MM xenograft murine model. Our results showed that NPI‐0052: (i) rapidly left the vascular compartment in an active form after intravenous (i.v.) administration, (ii) inhibited 20S proteasome chymotrypsin‐like (CT‐L, β5), trypsin‐like (T‐L, β2), and caspase‐like (C‐L, β1) activities in extra‐vascular tumours, packed whole blood (PWB), lung, liver, spleen, and kidney, but not brain and (iii) triggered a more sustained (>24 h) proteasome inhibition in tumours and PWB than in other organs (