Medical University of Silesia, Katowice, Poland.
Institute of Blood Pathology and Transfusion Medicine, National Academy of Medical Sciences of Ukraine, Lviv, Ukraine.
Lancet. 2020 Nov 14;396(10262):1563-1573. doi: 10.1016/S0140-6736(20)32292-3.
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.
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 once per week), and dexamethasone (20 mg twice per week), or bortezomib (1·3 mg/m 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.
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.
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.
Karyopharm Therapeutics.
塞来昔布联合地塞米松在经过大量预处理的多发性骨髓瘤患者中显示出疗效。在一项 1b/2 期研究中，口服塞来昔布联合硼替佐米（蛋白酶体抑制剂）和地塞米松诱导了高缓解率，外周神经病变的发生率较低，这是硼替佐米的主要剂量限制毒性。我们旨在评估每周塞来昔布、硼替佐米和地塞米松与标准硼替佐米和地塞米松在先前治疗过的多发性骨髓瘤患者中的临床获益。
这是一项在 21 个国家的 123 个地点进行的 3 期、随机、开放标签试验。年龄在 18 岁及以上、患有多发性骨髓瘤且已接受过一线至三线治疗（包括蛋白酶体抑制剂）的患者，按 1:1 比例随机分配（1:1）接受塞来昔布（每周一次，100mg）、硼替佐米（每周一次，1.3mg/m）和地塞米松（每周两次，20mg），或硼替佐米（前 24 周每周两次，此后每周一次，1.3mg/m）和地塞米松（前 24 周每周四次，此后每周两次，20mg）。随机分配使用交互式反应技术，并根据先前的蛋白酶体抑制剂治疗、治疗线数和多发性骨髓瘤分期进行分层。主要终点是在意向治疗人群中的无进展生存期。至少接受一剂研究治疗的患者被纳入安全性人群。这项试验在 ClinicalTrials.gov 注册，NCT03110562。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。
在 402 名筛选合格的患者中，有 402 名被随机分配（49%）至塞来昔布、硼替佐米和地塞米松组，207 名（51%）被分配至硼替佐米和地塞米松组，并且在 2017 年 6 月 6 日至 2019 年 2 月 5 日之间给予了第一次研究药物治疗。塞来昔布、硼替佐米和地塞米松组的中位随访时间为 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）。塞来昔布、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）（危险比 0.70[95%CI 0.53-0.93]，p=0.0075）。最常见的 3-4 级不良事件为血小板减少症（塞来昔布、硼替佐米和地塞米松组 195 名患者中有 77 名[39%]，硼替佐米和地塞米松组 204 名患者中有 35 名[17%]）、疲劳（塞来昔布、硼替佐米和地塞米松组 26 名[13%]，硼替佐米和地塞米松组 2 名[1%]）、贫血（塞来昔布、硼替佐米和地塞米松组 31 名[16%]，硼替佐米和地塞米松组 20 名[10%]）和肺炎（塞来昔布、硼替佐米和地塞米松组 22 名[11%]，硼替佐米和地塞米松组 22 名[11%]）。与硼替佐米和地塞米松组相比，塞来昔布、硼替佐米和地塞米松组的外周神经病变 2 级或更高级别发生率较低（塞来昔布、硼替佐米和地塞米松组 41 名[21%]患者，硼替佐米和地塞米松组 70 名[34%]患者；比值比 0.50[95%CI 0.32-0.79]，p=0.0013）。塞来昔布、硼替佐米和地塞米松组有 47 名（24%）患者死亡，硼替佐米和地塞米松组有 62 名（30%）患者死亡。
每周一次的塞来昔布、硼替佐米和地塞米松方案是一种新的、有效且方便的多发性骨髓瘤治疗选择，适用于已接受一线至三线治疗（包括蛋白酶体抑制剂）的患者。
Karyopharm Therapeutics。
