Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma
Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma
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DOI：
10.1056/nejmoa1903455
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发表时间：
2019-08-22
影响因子：
158.5
通讯作者：
Jagannath, Sundar
中科院分区：
文献类型：
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作者：
Chari, Ajai;Vogl, Dan T.;Jagannath, Sundar
selinexor是一种核输出化合物的选择性抑制剂，可阻断输出蛋白1 (XPO1)，促进核积累和肿瘤抑制蛋白的激活，抑制核因子κ B，减少癌蛋白信使RNA的翻译，是一种潜在的治疗骨髓瘤的新方法，目前的治疗方案是难耐的。方法：对既往暴露于硼替佐米、卡非佐米、来那度胺、泊马度胺、达拉图单抗和一种烷化剂，且对至少一种蛋白酶体抑制剂、一种免疫调节剂和达拉图单抗（三级难治）难治性疾病的骨髓瘤患者，每周两次口服selinexor （80mg）加地塞米松（20mg）。主要终点是总体反应，定义为部分反应或更好，反应由独立审查委员会评估。临床获益，定义为最小反应或更好，是次要终点。结果美国和欧洲共有122例患者被纳入修改意向治疗人群（初步分析），123例患者被纳入安全人群。年龄中位数为65岁，既往治疗次数中位数为7次；53%的患者有高危细胞遗传学异常。26%的患者出现部分缓解或更好的缓解（95%可信区间，19 - 35），包括两个严格的完全缓解；39%的患者有最小或更好的反应。中位缓解期为4.4个月，中位无进展生存期为3.7个月，中位总生存期为8.6个月。疲劳、恶心和食欲下降是常见的，通常为1级或2级（高达25%的患者出现3级事件，没有4级事件的报道）。73%的患者发生血小板减少症（3级为25%，4级为33%）。6例患者血小板减少导致3级或以上的出血事件。结论selinexor -地塞米松对现有治疗方法难治的骨髓瘤患者有客观的治疗反应。（由Karyopharm Therapeutics资助；STORM ClinicalTrials.gov号码，NCT02336815。）Selinexor是一种抑制肿瘤抑制蛋白核输出的药物，在一项2期试验中对骨髓瘤患者进行了测试，这些患者尽管接受了蛋白酶体抑制剂、免疫调节剂、烷基化剂和单克隆抗体的治疗，但病情仍在恶化。26%的患者部分缓解或更好，中位总生存期为8.6个月。
BackgroundSelinexor, a selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1) and forces nuclear accumulation and activation of tumor suppressor proteins, inhibits nuclear factor kappa B, and reduces oncoprotein messenger RNA translation, is a potential novel treatment for myeloma that is refractory to current therapeutic options.MethodsWe administered oral selinexor (80 mg) plus dexamethasone (20 mg) twice weekly to patients with myeloma who had previous exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent and had disease refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab (triple-class refractory). The primary end point was overall response, defined as a partial response or better, with response assessed by an independent review committee. Clinical benefit, defined as a minimal response or better, was a secondary end point.ResultsA total of 122 patients in the United States and Europe were included in the modified intention-to-treat population (primary analysis), and 123 were included in the safety population. The median age was 65 years, and the median number of previous regimens was 7; a total of 53% of the patients had high-risk cytogenetic abnormalities. A partial response or better was observed in 26% of patients (95% confidence interval, 19 to 35), including two stringent complete responses; 39% of patients had a minimal response or better. The median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival was 8.6 months. Fatigue, nausea, and decreased appetite were common and were typically grade 1 or 2 (grade 3 events were noted in up to 25% of patients, and no grade 4 events were reported). Thrombocytopenia occurred in 73% of the patients (grade 3 in 25% and grade 4 in 33%). Thrombocytopenia led to bleeding events of grade 3 or higher in 6 patients.ConclusionsSelinexor-dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies. (Funded by Karyopharm Therapeutics; STORM ClinicalTrials.gov number, NCT02336815.)Selinexor, a drug that inhibits nuclear export of tumor suppressor proteins, was tested in a phase 2 trial involving patients with myeloma whose disease had progressed despite treatment with proteasome inhibitors, immunomodulatory agents, alkylating agents, and monoclonal antibodies. A partial response or better was observed in 26% of patients, and the median overall survival was 8.6 months.