Division of Medical Oncology, Hematology and Infectious Diseases, Department of Medicine, Fukuoka University, Fukuoka, 814-0180, Japan.
Int J Hematol. 2010 Oct;92(3):503-9. doi: 10.1007/s12185-010-0673-y. Epub 2010 Sep 8.
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.
硼替佐米与阿霉素体外协同作用于骨髓瘤细胞。我们进行了硼替佐米联合阿霉素和中剂量地塞米松（iPAD 治疗）治疗复发性或难治性骨髓瘤患者的剂量探索研究。硼替佐米在第 1、4、8 和 11 天分别以 1.0 和 1.3 mg/m²的剂量给药，在第 1 和 2 队列中分别给药。第 1-4 天快速静脉输注阿霉素 9 mg/m²，第 1-2、4-5、8-9 和 11-12 天给予地塞米松 20 mg。每 3 周重复治疗，并评估剂量限制性毒性（DLT），定义为持续超过 5 天的 4 级血液学毒性和/或 3 级或更高级别的非血液学毒性。在第 1 队列中，6 例患者中有 2 例发生 DLT，包括 4 级低钠血症和适当中性粒细胞计数的 3 级感染。其余 4 例患者未观察到 DLT，表明该剂量可耐受。在第 2 队列中，5 例患者中有 3 例发生 DLT，包括持续超过 5 天的 4 级血小板减少症、3 级肝转氨酶升高和 3 级肠梗阻，表明该剂量不可耐受。结论是硼替佐米 1.0 mg/m²剂量与阿霉素和中剂量地塞米松联合使用是推荐的。
