A phase I study of bortezomib in combination with doxorubicin and intermediate-dose dexamethasone (iPAD therapy) for relapsed or refractory multiple myeloma |
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Authors: | Yasushi Takamatsu Kazutaka Sunami Hiroyuki Hata Koji Nagafuji Ilseung Choi Masakazu Higuchi Kimiharu Uozumi Yasufumi Masaki Kazuo Tamura |
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Affiliation: | 1. Division of Medical Oncology, Hematology and Infectious Diseases, Department of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan 2. Department of Hematology, National Hospital Organization Okayama Medical Center, Okayama, Japan 3. Department of Hematology, Kumamoto University of Medicine, Kumamoto, Japan 4. Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan 5. Department of Hematology, National Kyushu Cancer Center, Fukuoka, Japan 6. Department of Internal Medicine, Kyushu Kosei-Nenkin Hospital, Kitakyushu, Japan 7. Department of Hematology and Immunology, Kagoshima University, Kagoshima, Japan 8. Department of Hematology and Immunology, Kanazawa Medical University, Kanazawa, Japan
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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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