Richardson Paul G, Weller Edie, Jagannath Sundar, Avigan David E, Alsina Melissa, Schlossman Robert L, Mazumder Amitabha, Munshi Nikhil C, Ghobrial Irene M, Doss Deborah, Warren Diane L, Lunde Laura E, McKenney Mary, Delaney Carol, Mitsiades Constantine S, Hideshima Teru, Dalton William, Knight Robert, Esseltine Dixie-Lee, Anderson Kenneth C
Dana-Farber Cancer Institute, Boston, MA 02115, USA.
J Clin Oncol. 2009 Dec 1;27(34):5713-9. doi: 10.1200/JCO.2009.22.2679. Epub 2009 Sep 28.
Lenalidomide and bortezomib are active in relapsed and relapsed/refractory multiple myeloma (MM). In preclinical studies, lenalidomide sensitized MM cells to bortezomib and dexamethasone. This phase I, dose-escalation study (ie, NCT00153933) evaluated safety and determined the maximum-tolerated dose (MTD) of lenalidomide plus bortezomib in patients with relapsed or with relapsed and refractory MM.
Patients received lenalidomide 5, 10, or 15 mg/d on days 1 through 14 and received bortezomib 1.0 or 1.3 mg/m(2) on days 1, 4, 8, and 11 of 21-day cycles. Dexamethasone (20mg or 40 mg on days 1, 2, 4, 5, 8, 9, 11, and 12) was added for progressive disease after two cycles. Primary end points were safety and MTD determination.
Thirty-eight patients were enrolled across six dose cohorts. The MTD was lenalidomide 15 mg/d plus bortezomib 1.0 mg/m(2). Dose-limiting toxicities (n = 1 for each) were grade 3 hyponatremia and herpes zoster reactivation and grade 4 neutropenia. The most common treatment-related, grades 3 to 4 toxicities included reversible neutropenia, thrombocytopenia, anemia, and leukopenia. Among 36 response-evaluable patients, 61% (90% CI, 46% to 75%) achieved minimal response or better. Among 18 patients who had dexamethasone added, 83% (90% CI, 62% to 95%) achieved stable disease or better. Median overall survival was 37 months.
Lenalidomide plus bortezomib was well tolerated and showed promising activity with durable responses in patients with relapsed and relapsed/refractory MM, including patients previously treated with lenalidomide, bortezomib, and/or thalidomide. The combination of lenalidomide, bortezomib, and dexamethasone is being investigated in a phase II study in this setting and in newly diagnosed MM.
来那度胺和硼替佐米对复发及复发/难治性多发性骨髓瘤（MM）有效。临床前研究显示，来那度胺可使MM细胞对硼替佐米和地塞米松敏感。此项I期剂量递增研究（即NCT00153933）评估了复发或复发/难治性MM患者中来那度胺联合硼替佐米的安全性并确定其最大耐受剂量（MTD）。
患者在第1至14天接受来那度胺5、10或15mg/日治疗，并在21天周期的第1、4、8和11天接受硼替佐米1.0或1.3mg/m²治疗。两个周期后疾病进展时加用地塞米松（第1、2、4、5、8、9、11和12天20mg或40mg）。主要终点为安全性和MTD的确定。
38例患者入组6个剂量组。MTD为来那度胺15mg/日加硼替佐米1.0mg/m²。剂量限制性毒性（各1例）为3级低钠血症和带状疱疹再激活以及4级中性粒细胞减少。最常见的3至4级治疗相关毒性包括可逆性中性粒细胞减少、血小板减少、贫血和白细胞减少。在36例可评估反应的患者中，61%（90%CI，范围46%至75%）达到最小反应或更好反应。在18例加用地塞米松的患者中，83%（90%CI，范围62%至95%）达到疾病稳定或更好状态。中位总生存期为37个月。
来那度胺联合硼替佐米耐受性良好，在复发及复发/难治性MM患者中显示出有前景的活性及持久反应，包括既往接受过来那度胺、硼替佐米和/或沙利度胺治疗的患者。来那度胺、硼替佐米和地塞米松的联合方案正在此项背景下的II期研究以及新诊断MM中进行研究。
