美国纽约西奈山伊坎医学院Sundar Jagannath课题组近日取得一项新成果。他们研究发现口服selinexor联合地塞米松可治疗难治性多发性骨髓瘤。2019年8月22日出版的《新英格兰医学杂志》发表了这项成果。

美国和欧洲共有122名患者被纳入改良意向治疗人群，123名患者被纳入安全人群。中位年龄为65岁，既往治疗方案的中位数量为7个，53%的患者存在高危细胞遗传学异常。研究小组每周两次给骨髓瘤患者口服selinexor 80 mg和地塞米松20 mg，这些患者之前曾接受硼替佐米、卡非佐米、来那度胺、泊马度胺、达拉木单抗和烷基化剂治疗，且至少对一种蛋白酶体抑制剂、一种免疫调节剂和达拉木单抗耐药。

26%的患者至少获得部分缓解，包括两例完全缓解；39%的患者至少获得最小缓解。缓解的中位持续时间为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。 常见不良反应为疲劳、恶心和食欲下降，通常为1级或2级（多达25%的患者出现3级不良反应，未出现4级不良反应）。 73%的患者发生血小板减少（25%为3级不良反应，33%为4级不良反应）。 血小板减少导致6例患者发生3级以上出血事件。

综上，selinexor联合地塞米松对目前治疗方法无效的难治性骨髓瘤有一定疗效。

研究人员介绍，Selinexor是一种选择性的核输出化合物抑制剂，可阻断输出蛋白1（XPO1），迫使肿瘤抑制蛋白在核内聚集并激活，抑制核转录因子κB，并减少肿瘤蛋白信使RNA翻译，是一种治疗难治性骨髓瘤的新方法，且对目前的治疗方案不敏感。

Title: Oral Selinexor–Dexamethasone for Triple-Class Refractory Multiple Myeloma

Author: Ajai Chari, M.D., Dan T. Vogl, M.D., Maria Gavriatopoulou, M.D., Ajay K. Nooka, M.D., Andrew J. Yee, M.D., Carol A. Huff, M.D., Philippe Moreau, M.D., David Dingli, M.D., Ph.D., Craig Cole, M.D., Sagar Lonial, M.D., Meletios Dimopoulos, M.D., A. Keith Stewart, M.B., Ch.B., et al

Issue&Volume: Vol 381 No 7, 22 August 2019

Abstract: 

BACKGROUND
Selinexor, 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 κB, and reduces oncoprotein messenger RNA translation, is a potential novel treatment for myeloma that is refractory to current therapeutic options.

METHODS
We 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.

RESULTS
A 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.

CONCLUSIONS
Selinexor–dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies.

DOI: 10.1056/NEJMoa1903455

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1903455