Originally published as JCO Early Release 10.1200/JCO.2007.14.2372 on July 21 2008

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Phase I-II Trial of Bortezomib Plus Oral Cyclophosphamide and Prednisone in Relapsed and Refractory Multiple Myeloma

Donna E. Reece, Giovanni Piza Rodriguez, Christine Chen, Suzanne Trudel, Vishal Kukreti, Joseph Mikhael, Mariela Pantoja, Wei Xu, A. Keith Stewart

From the Department of Medical Oncology and Hematology and Department of Biostatistics, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada; and the Mayo Clinic, Scottsdale, AZ

Corresponding author: Donna E. Reece, MD, Princess Margaret Hospital, 610 University Ave, Suite 5-207, Toronto, Ontario, M5G 2M9 Canada; e-mail: donna.reece{at}uhn.on.ca

Purpose The combination of oral weekly cyclophosphamide and alternate day prednisone is a convenient regimen for relapsed/refractory multiple myeloma (MM), and we sought to improve its efficacy by adding bortezomib, a proteasome inhibitor with proven antimyeloma activity.

Patients and Methods We conducted a phase I-II trial evaluating six dose levels to define the maximum tolerated dose (MTD) of this combination in relapsed/refractory MM. An additional 10 patients were evaluated at the highest dose level reached.

Results Thirty-seven patients were treated on this study. The MTD was not defined. Both of the highest dose levels of bortezomib tested (1.3 mg/m² on days 1, 4, 8, and 11 and 1.5 mg/m² on days 1, 8, and 15, each on a 28-day cycle) could be safely given with cyclophosphamide 300 mg/m² per week and prednisone. At these dose levels, the overall response rate was 95% (complete responses [CR] plus partial response plus minimal response), with CR observed in more than 50% of patients. The weekly bortezomib regimen resulted in fewer instances of grade 3 thrombocytopenia and grade 1 to 2 peripheral neuropathy; the 1-year progression-free and overall survival probabilities with this dose level were 83% (95% CI, 73% to 96%) and 100%, respectively.

Conclusion Weekly bortezomib 1.5 mg/m² plus oral cyclophosphamide and prednisone produces an unprecedented response rate and encouraging 1-year survival in relapsed/refractory patients with MM. Further evaluation of this promising regimen is warranted both in relapsed and newly diagnosed disease.

published online ahead of print at www.jco.org on July 21, 2008

Supported by Ortho Biotech Canada.

Presented in part at the 47th Annual Meeting of the American Society of Hematology, Atlanta, GA, December 10-13, 2005; the 48th Annual Meeting of the American Society of Hematology, Orlando, FL, December 9-12, 2006; and the XIth International Myeloma Workshop, Kos Island, Greece, June 25-30, 2007.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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