Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study
Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study
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DOI：
10.1016/s1470-2045(11)70081-x
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发表时间：
2011-05-01
期刊：
影响因子：
51.1
通讯作者：
Harousseau, Jean-Luc
中科院分区：
文献类型：
--
作者：
Moreau, Philippe;Pylypenko, Halyna;Harousseau, Jean-Luc
背景静脉注射是硼替佐米的标准给药途径；然而，皮下给药是一种重要的替代方法。我们比较了复发性多发性骨髓瘤患者皮下注射和静脉注射硼替佐米的疗效和安全性，批准剂量为1.3 mg/m(2)，每周两次。方法：这项随机iii期研究在欧洲、亚洲和南美10个国家的53个中心进行。年龄在18岁及以上的多发性骨髓瘤患者在先前的一到三条治疗线后复发，随机分配接受至多8个21天周期的硼替佐米1.3 mg/m(2)，分别在第1、4、8和11天皮下注射或静脉输注。随机化是通过基于计算机生成的随机化时间表的交互式语音应答系统进行的，根据之前的线路数量和疾病阶段进行分层。患者和治疗医生不受治疗分配的影响。主要目的是在所有诊断为可测量的分泌性多发性骨髓瘤并接受一剂或多剂药物（可评估反应的人群）的患者中，显示在四个周期后，皮下注射与静脉注射硼替佐米在总缓解率（ORR）方面的非劣性。非劣效性定义为保持60%的静脉治疗效果。该研究已在ClinicalTrials.gov注册，编号NCT00722566，并正在进行长期随访。结果222例患者随机分配接受皮下注射（n=148）或静脉注射（n=74）硼替佐米。可评估反应的人群包括145名皮下注射组和73名静脉注射组。两组患者均接受了中位数为8个周期（范围从1到10）的治疗。两组4个周期后的ORR均为42%（皮下组61例，静脉组31例；ORR差-0.4%,95% CI -14.3 ~ 13.5），无劣效性（p=0.002）。在中位随访中，皮下组为11.8个月（IQR 7.9-16-8），静脉组为12.0个月（8.1-15.6），在进展时间（中位10.4个月，95% CI 8.5-11.7, vs 9.4个月，7.6-10.6;p=0.387）和1年总生存率（72.6%,95% CI 63.1-80.0, vs 76.7%, 64.1-85-4; p=0.504）方面，皮下组和静脉组没有显著差异。皮下注射组有84例（57%）患者报告了3级或更严重的不良事件，静脉注射组有52例（70%）；最常见的是血小板减少症（19例[13%]对14例[19%]）、中性粒细胞减少症（26例[18%]对13例[18%]）和贫血（18例[12%]对6例[8%]）。任何级别的周围神经病变（56[38%]对39 [53%]，p=0.044）， 2级或更严重（35[24%]对30 [41%]，p=0.012）， 3级或更严重（9[6%]对12 [16%]，p=0.026），皮下给药明显少于静脉给药。局部皮下给药耐受性良好。解释：与标准静脉给药相比，皮下硼替佐米的疗效不差，安全性也有所提高。
Background Intravenous injection is the standard administration route of bortezomib; however, subcutaneous administration is an important alternative. We compared the efficacy and safety of subcutaneous versus intravenous bortezomib at the approved 1.3 mg/m(2) dose and twice per week schedule in patients with relapsed multiple myeloma.Methods This randomised, phase 3 study was undertaken at 53 centres in ten countries in Europe, Asia, and South America. Patients aged 18 years and older with relapsed multiple myeloma after one to three previous lines of therapy were randomly assigned to receive up to eight 21-day cycles of bortezomib 1.3 mg/m(2), on days 1,4,8, and 11, by subcutaneous injection or intravenous infusion. Randomisation was by an interactive voice response system based on a computer-generated randomisation schedule, stratified by number of previous lines and disease stage. Patients and treating physicians were not masked to treatment allocation. The primary objective was to show non-inferiority of subcutaneous versus intravenous bortezomib in terms of overall response rate (ORR) after four cycles in all patients with a diagnosis of measurable, secretory multiple myeloma who received one or more dose of drug (response-evaluable population). Non-inferiority was defined as retaining 60% of the intravenous treatment effect. This study is registered with ClinicalTrials.gov, number NCT00722566, and is ongoing for long-term follow-up.Findings 222 patients were randomly assigned to receive subcutaneous (n=148) or intravenous (n=74) bortezomib. The response-evaluable population consisted of 145 patients in the subcutaneous group and 73 in the intravenous group. Patients received a median of eight cycles (range one to ten) in both groups. ORR after four cycles was 42% in both groups (61 patients in subcutaneous group and 31 in intravenous group; ORR difference -0.4%, 95% CI -14.3 to 13.5), showing non-inferiority (p=0.002). After a median follow-up of 11.8 months (IQR 7.9-16-8) in the subcutaneous group and 12.0 months (8.1-15.6) in the intravenous group, there were no significant differences in time to progression (median 10.4 months, 95% CI 8.5-11.7, vs 9.4 months, 7.6-10.6; p=0.387) and 1-year overall survival (72.6%, 95% CI 63.1-80.0, vs 76.7%, 64.1-85-4; p=0.504) with subcutaneous versus intravenous bortezomib. Grade 3 or worse adverse events were reported in 84 (57%) patients in the subcutaneous group versus 52 (70%) in the intravenous group; the most common were thrombocytopenia (19 [13%] vs 14 [19%]), neutropenia (26 [18%] vs 13 [18%]), and anaemia (18 [12%] vs six [8%]). Peripheral neuropathy of any grade (56 [38%] vs 39 [53%]; p=0.044), grade 2 or worse (35 [24%] vs 30 [41%]; p=0.012), and grade 3 or worse (nine [6%] vs 12 [16%]; p=0.026) was significantly less common with subcutaneous than with intravenous administration. Subcutaneous administration was locally well tolerated.Interpretation Subcutaneous bortezomib offers non-inferior efficacy to standard intravenous administration, with an improved safety profile.