Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial
Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial
复制标题
DOI：
10.1016/s0140-6736(20)32292-3
复制
发表时间：
2020-11-14
期刊：
影响因子：
168.9
通讯作者：
Delimpasi, Sosana
中科院分区：
文献类型：
--
作者：
Grosicki, Sebastian;Simonova, Maryana;Delimpasi, Sosana
背景Selinexor联合地塞米松在重度预治疗的多发性骨髓瘤患者中显示出活性。在一项1b/2期研究中，口服赛林克斯与硼替佐米（一种蛋白酶体抑制剂）和地塞米松联合治疗诱导了高缓解率，周围神经病变（硼替佐米的主要剂量限制性毒性）发生率较低。我们的目的是评估临床效益每周赛林克斯，硼替佐米，地塞米松与标准硼替佐米和地塞米松治疗多发性myeloma.Methods这3期，随机，开放标签试验在21个国家的123个网站。年龄≥ 18岁的多发性骨髓瘤患者，既往接受过1 - 3线治疗（包括蛋白酶体抑制剂），随机分配（1：1）接受赛林克斯（100 mg，每周1次）、硼替佐米（1.3 mg/m2，每周1次）和地塞米松（20 mg，每周2次），或硼替佐米（1.3 mg/m2，前24周每周2次，此后每周1次）和地塞米松（20 mg，前24周每周4次，此后每周2次）。使用交互式应答技术进行随机化，并按既往蛋白酶体抑制剂治疗、治疗线和多发性骨髓瘤分期分层。主要终点是意向治疗人群的无进展生存期。接受至少一剂研究治疗的患者被纳入安全性人群。本试验注册于ClinicalTrials.gov，NCT 03110562。该试验正在进行中，截至2020年2月20日，仍有55名患者接受随机治疗。结果在筛选合格性的457名患者中，402名患者被随机分配-195名（49%）被分配到selinexor，bortezalide和地塞米松组，207名（51%）被分配到bortezalide和地塞米松组-并且在2017年6月6日之间给予第一剂研究药物，2019年2月5日赛林克斯、硼替佐米和地塞米松组的中位随访持续时间为13.2个月[IQR 6.2-19.8]，硼替佐米和地塞米松组为16.5个月[9.4-19.8]。司林克斯、硼替佐米和地塞米松组的中位无进展生存期为13.93个月（95% CI 11.73-不可评估），硼替佐米和地塞米松组为9.46个月（8.11-10.78）（风险比0.70 [95% CI 0.53-0.93]，p=0.0075）。最常见的3-4级不良事件是血小板减少症（赛林克斯、硼替佐米和地塞米松组195例患者中的77例[39%] vs硼替佐米和地塞米松组204例患者中的35例[17%]）、疲乏（26例[13%] vs 2例[1%]）、贫血（31例[16%] vs 20例[10%]）和肺炎（22例[11%] vs 22例[11%]）。与硼替佐米和地塞米松组（70例[34%]患者;比值比0.50 [95%CI 0.32-0.79]，p=0.0013）相比，使用赛林克斯、硼替佐米和地塞米松组（41例[21%]患者）发生2级或以上周围神经病变的频率较低。赛林克斯、硼替佐米和地塞米松组中47例（24%）患者和硼替佐米和地塞米松组中62例（30%）患者死亡。解释赛林克斯、硼替佐米和地塞米松每周一次给药方案是一种新颖、有效和方便的治疗选择，适用于既往接受过一到三线治疗的多发性骨髓瘤患者。版权所有（c）2020 Elsevier Ltd.保留所有权利。
Background Selinexor combined with dexamethasone has shown activity in patients with heavily pre-treated multiple myeloma. In a phase 1b/2 study, the combination of oral selinexor with bortezomib (a proteasome inhibitor) and dexamethasone induced high response rates with low rates of peripheral neuropathy, the main dose-limiting toxicity of bortezomib. We aimed to evaluate the clinical benefit of weekly selinexor, bortezomib, and dexamethasone versus standard bortezomib and dexamethasone in patients with previously treated multiple myeloma.Methods This phase 3, randomised, open-label trial was done at 123 sites in 21 countries. Patients aged 18 years or older, who had multiple myeloma, and who had previously been treated with one to three lines of therapy, including proteasome inhibitors, were randomly allocated (1:1) to receive selinexor (100 mg once per week), bortezomib (1.3 mg/m(2) once per week), and dexamethasone (20 mg twice per week), or bortezomib (1.3 mg/m(2) twice per week for the first 24 weeks and once per week thereafter) and dexamethasone (20 mg four times per week for the first 24 weeks and twice per week thereafter). Randomisation was done using interactive response technology and stratified by previous proteasome inhibitor therapy, lines of treatment, and multiple myeloma stage. The primary endpoint was progression-free survival in the intention-to-treat population. Patients who received at least one dose of study treatment were included in the safety population. This trial is registered at ClinicalTrials.gov, NCT03110562. The trial is ongoing, with 55 patients remaining on randomised therapy as of Feb 20, 2020.Findings Of 457 patients screened for eligibility, 402 were randomly allocated-195 (49%) to the selinexor, bortezomib, and dexamethasone group and 207 (51%) to the bortezomib and dexamethasone group-and the first dose of study medication was given between June 6, 2017, and Feb 5, 2019. Median follow-up durations were 13.2 months [IQR 6.2-19.8] for the selinexor, bortezomib, and dexamethasone group and 16.5 months [9.4-19.8] for the bortezomib and dexamethasone group. Median progression-free survival was 13.93 months (95% CI 11.73-not evaluable) with selinexor, bortezomib, and dexamethasone and 9.46 months (8.11-10.78) with bortezomib and dexamethasone (hazard ratio 0.70 [95% CI 0.53-0.93], p=0.0075). The most frequent grade 3-4 adverse events were thrombocytopenia (77 [39%] of 195 patients in the selinexor, bortezomib, and dexamethasone group vs 35 [17%] of 204 in the bortezomib and dexamethasone group), fatigue (26 [13%] vs two [1%]), anaemia (31 [16%] vs 20 [10%]), and pneumonia (22 [11%] vs 22 [11%]). Peripheral neuropathy of grade 2 or above was less frequent with selinexor, bortezomib, and dexamethasone (41 [21%] patients) than with bortezomib and dexamethasone (70 [34%] patients; odds ratio 0.50 [95% CI 0.32-0.79], p=0.0013). 47 (24%) patients in the selinexor, bortezomib, and dexamethasone group and 62 (30%) in the bortezomib and dexamethasone group died.Interpretation A once-per-week regimen of selinexor, bortezomib, and dexamethasone is a novel, effective, and convenient treatment option for patients with multiple myeloma who have received one to three previous lines of therapy. Copyright (c) 2020 Elsevier Ltd. All rights reserved.