Abstract
Bortezomib and doxorubicin have synergistic activity against myeloma cells in vitro. We underwent a dose finding study of bortezomib in combination with a fixed dose of doxorubicin and intermediate-dose dexamethasone (iPAD therapy) in patients with relapsed or refractory myeloma. Bortezomib was administered on days 1, 4, 8 and 11 at a dose of 1.0 and 1.3 mg/m2 in cohorts 1 and 2, respectively. Doxorubicin 9 mg/m2 was given by rapid intravenous infusion on days 1–4, and dexamethasone 20 mg on days 1–2, 4–5, 8–9 and 11–12. Treatment was repeated at a 3-week interval and the dose-limiting toxicity (DLT), defined as grade 4 hematological toxicity lasting more than 5 days and/or grade 3 or higher non-hematological toxicity, was evaluated. In cohort 1, 2 of 6 patients developed DLTs including grade 4 hyponatremia and grade 3 infection with appropriate neutrophil counts. No DLT was observed in the remaining 4 patients, indicating this dose was tolerable. In cohort 2, 3 of 5 patients developed DLTs including grade 4 thrombocytopenia lasting more than 5 days, grade 3 hepatic transaminase elevation and grade 3 ileus, indicating this dose was intolerable. It is concluded that bortezomib at the dose of 1.0 mg/m2 is recommended in combination with doxorubicin and intermediate-dose dexamethasone.
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Acknowledgments
This clinical study was registered in University hospital Medical Information Network (UMIN) (registration number; UMIN000001210), and was supported by the non-profit organization of Clinical Hematology/Oncology Treatment Study Group (CHOT-SG). There was no financial disclosure from any authors. We thank project managers Ms. Y. Ito and N. Gushima, and secretaries Ms. E. Kumakawa and N. Ikoma for valuable assistance in conducting the present study, and the medical staff of the following institutions for participating in this study; T. Toyota, Y. Ikari, H. Sasaki, K. Ishitsuka (Fukuoka University), T. Ochi, Y. Meguri (Okayama Medical Center), S. Murakami, M. Kugimiya (Kumamoto University), Y. Mori, Y. Abe, T. Miyamoto, T. Teshima (Kyushu University), N. Uike (Kyushu Cancer Center), K. Aoki (Kyushu Kosei-nenkin Hospital), D. Nakamura (Kagoshima University), M. Miki (Kanazawa Medical University), J. Suzumiya (Shimane University), J. Tsukada (University of Occupational and Environmental Health), T. Okamura, K. Yakushiji (Kumure University), T. Eto, K. Takase (Hamanomachi Hospital), Y. Imamura (St. Mary’s Hospital), F. Taguchi, Y. Tachikawa, Y. Nakashima (Iizuka Hospital), S. Makino (Toranomon Hospital), and S. Aoki (Niigata University).
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Takamatsu, Y., Sunami, K., Hata, H. et al. A phase I study of bortezomib in combination with doxorubicin and intermediate-dose dexamethasone (iPAD therapy) for relapsed or refractory multiple myeloma. Int J Hematol 92, 503–509 (2010). https://doi.org/10.1007/s12185-010-0673-y
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DOI: https://doi.org/10.1007/s12185-010-0673-y