title: A phase I study of bortezomib in combination with doxorubicin and intermediate-dose dexamethasone (iPAD therapy) for relapsed or refractory multiple myeloma.
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.
authors.affiliation: Division of Medical Oncology, Hematology and Infectious Diseases, Department of Medicine, Fukuoka University, Fukuoka, 814-0180, Japan. yasushi@fukuoka-u.ac.jp
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Takamatsu
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Sunami
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hata
authors.forename: Koji
authors.initials: K
authors.lastname: Nagafuji
authors.forename: Ilseung
authors.initials: I
authors.lastname: Choi
authors.forename: Masakazu
authors.initials: M
authors.lastname: Higuchi
authors.forename: Kimiharu
authors.initials: K
authors.lastname: Uozumi
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Masaki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tamura
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000069286:Bortezomib; D003907:Dexamethasone / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000517:prevention & control*; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012008:Recurrence
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D003907:Dexamethasone; D004317:Doxorubicin
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