Bortezomib in recurrent and/or refractory multiple myeloma

• Published in: Cancer 2005-03, Vol.103 (6), p.1195-1200
• Main Authors: Jagannath, Sundar, Barlogie, Bart, Berenson, James R., Singhal, Seema, Alexanian, Raymond, Srkalovic, Gordan, Orlowski, Robert Z., Richardson, Paul G., Anderson, Jessica, Nix, Darrell, Esseltine, Dixie L., Anderson, Kenneth C.
• Format: Article
• Language: eng ; jpn
• Subjects: bortezomib; myeloma; proteasome; renal failure
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.20888

BACKGROUND Bortezomib is a potent, reversible proteasome inhibitor that has been approved for the treatment of recurrent and/or refractory multiple myeloma, but its activity in patients with renal impairment has not been studied to date. METHODS Response rates, safety, and 20S proteasome activity were assessed in relation to baseline creatinine clearance (CrCl) among patients with recurrent and/or refractory myeloma (n = 256 patients) who were treated with bortezomib in 2 Phase II trials. Bortezomib was administered by intravenous bolus on Days 1, 4, 8, and 11 of a 21‐day cycle at 2 doses, 1.0 mg/m2 (n = 28 patients) and 1.3 mg/m2 (n = 228 patients). RESULTS Of 10 patients with CrCl ≤ 30 mL/minute, 7 patients completed the protocol‐specified 8 cycles of treatment; 4 patients received the 1.3 mg/m2 bortezomib dose, and 3 patients received the 1.0 mg/m2 bortezomib dose. Using the European Group for Blood and Marrow Transplantation criteria, responses were assigned by an independent committee to 3 of the 10 patients (2 partial responses and 1 minimal response), a response rate similar to that of the overall treated population. Patients with CrCl > 80 mL/minute (n = 105 patients), 51–80 mL/minute (n = 99 patients), and ≤ 50 mL/minute (n = 52 patients) had similar rates of discontinuation and similar adverse event profiles. Renal function did not appear to affect the 1‐hour postdose proteasome inhibition or its recovery. CONCLUSIONS Clinical experience in a limited number of patients with impaired renal function suggests that bortezomib provides clinical benefit with manageable toxicities in this high‐risk population. Cancer 2005. © 2005 American Cancer Society. Clinical experience in a limited number of patients with multiple myeloma and severely impaired renal function suggested that the proteasome inhibitor bortezomib provides clinical benefit with manageable toxicity in this high‐risk population. Although the inhibition and recovery of proteasome activity in whole blood, as measured in an ex vivo assay, was independent of baseline creatinine clearance, formal pharmacokinetic and pharmacodynamic studies are needed.