Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom macroglobulinemia
Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom macroglobulinemia
复制标题
DOI：
10.1182/blood-2017-08-797886
复制
发表时间：
2018-02-22
期刊：
影响因子：
20.3
通讯作者：
Reece, Donna
中科院分区：
文献类型：
--
作者：
Chen, Christine;Siegel, David;Reece, Donna
复发性或难治性多发性骨髓瘤（MM）患者需要新的治疗方法。我们在晚期恶性血液病中进行了一项多中心、I期研究，以评估口服赛林克斯（一种核输出蛋白XPO 1的选择性抑制剂）的安全性、疗效和推荐II期剂量（RP 2D）。在剂量递增阶段，25例重度预治疗MM（22例）或Waldenstrom巨球蛋白血症（3例）患者接受了selinexor（3-60 mg/m2）给药，每28天为1周期，分8或10次给药。在剂量扩展阶段，59例MM患者接受45或60 mg/m2的赛林克斯联合20 mg地塞米松，每周两次，28天为一个周期，或21天为一个周期，赛林克斯（40或60 mg固定剂量）不含皮质类固醇。最常见的非血液学不良事件（AE）为恶心（75%）、疲乏（70%）、厌食（64%）、呕吐（43%）、体重减轻（32%）和腹泻（32%），主要为1级或2级。最常见的3级或4级AE为血液学，特别是血小板减少症（45%）。单药赛林克斯显示出适度的疗效，客观缓解率（ORR）为4%，临床获益率为21%。相比之下，添加地塞米松增加了ORR，在45 mg/m2司林克斯+20 mg地塞米松每周两次队列中发生了>=部分缓解的所有缓解（ORR 550%）。此外，46%的患者显示MM标志物较基线降低。基于这些发现，我们得出结论，司林克斯联合地塞米松对重度预治疗的MM有效，并建议RP 2D为45 mg/m2（80 mg）加20 mg地塞米松，每周两次。
Novel therapies are needed for patients with relapsed or refractory multiple myeloma (MM). We conducted a multicenter, phase 1 study in advanced hematological malignancies to assess the safety, efficacy, and recommended phase 2 dose (RP2D) of oral selinexor, a selective inhibitor of the nuclear export protein XPO1. In the dose-escalation phase, 25 patients with heavily pretreated MM (22) or Waldenstrom macroglobulinemia (3) were administered selinexor (3-60 mg/m(2)) in 8 or 10 doses per 28-day cycle. In the dose-expansion phase, 59 patients with MM received selinexor at 45 or 60 mg/m(2) with 20 mg dexamethasone, twice weekly in 28-day cycles, or selinexor (40 or 60 mg flat dose) without corticosteroids in 21-day cycles. The most common nonhematologic adverse events (AEs) were nausea (75%), fatigue (70%), anorexia (64%), vomiting (43%), weight loss (32%), and diarrhea (32%), which were primarily grade 1 or 2. The most common grade 3 or 4 AEs were hematologic, particularly thrombocytopenia (45%). Single-agent selinexor showed modest efficacy with an objective response rate (ORR) of 4% and clinical benefit rate of 21%. In contrast, the addition of dexamethasone increased the ORR with all responses of >= partial response occurring in the 45 mg/m(2) selinexor plus 20 mg dexamethasone twice weekly cohort (ORR550%). Furthermore, 46% of all patients showed a reduction in MM markers from baseline. Based on these findings, we conclude that selinexor in combination with dexamethasone is active in heavily pretreated MM and propose a RP2D of 45 mg/m(2) (80 mg) plus 20 mg dexamethasone given twice weekly.