Division of Hematology, Mayo Clinic, Rochester, MN, USA.
Clinical Hematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia.
Lancet Oncol. 2020 Dec;21(12):1630-1642. doi: 10.1016/S1470-2045(20)30525-8. Epub 2020 Oct 29.
Venetoclax is a highly selective, potent, oral BCL-2 inhibitor, which induces apoptosis in multiple myeloma cells. Venetoclax plus bortezomib and dexamethasone has shown encouraging clinical efficacy with acceptable safety and tolerability in a phase 1 trial. The aim of this study was to evaluate venetoclax plus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma.
In this randomised, double-blind, multicentre, phase 3 trial, patients aged 18 years or older with relapsed or refractory multiple myeloma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received one to three previous therapies were enrolled from 90 hospitals in 16 countries. Eligible patients were randomly assigned (2:1) centrally using an interactive response technology system and a block size of three to receive venetoclax (800 mg per day orally) or placebo with bortezomib (1·3 mg/m subcutaneously or intravenously and dexamethasone (20 mg orally). Treatment was given in 21-day cycles for the first eight cycles and 35-day cycles from the ninth cycle until disease progression, unacceptable toxicity, or patient withdrawal. Randomisation was stratified by previous exposure to a proteasome inhibitor and the number of previous therapies. Sponsors, investigators, study site personnel, and patients were masked to the treatment allocation throughout the study. The primary endpoint was independent review committee-assessed progression-free survival in the intention-to-treat population. Safety analyses were done in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT02755597.
Between July 19, 2016, and Oct 31, 2017, 291 patients were randomly assigned to receive venetoclax (n=194) or placebo (n=97). With a median follow-up of 18·7 months (IQR 16·6-21·0), median progression-free survival according to independent review committee was 22·4 months (95% CI 15·3-not estimable) with venetoclax versus 11·5 months (9·6-15·0) with placebo (hazard ratio [HR] 0·63 [95% CI 0·44-0·90]; p=0·010). The most common grade 3 or worse treatment-emergent adverse events were neutropenia (35 [18%] of 193 patients in the venetoclax group vs seven [7%] of 96 patients in the placebo group), pneumonia (30 [16%] vs nine [9%]), thrombocytopenia (28 [15%] vs 29 [30%]), anaemia (28 [15%] vs 14 [15%]), and diarrhoea (28 [15%] vs 11 [11%]). Serious treatment-emergent adverse events occurred in 93 (48%) patients in the venetoclax group and 48 (50%) patients in the placebo group, with eight (4%) treatment-emergent fatal infections reported in the venetoclax group and none reported in the placebo group. Three deaths in the venetoclax group (two from pneumonia and one from septic shock) were considered treatment-related; no deaths in the placebo group were treatment-related.
The primary endpoint was met with a significant improvement in independent review committee-assessed progression-free survival with venetoclax versus placebo plus bortezomib and dexamethasone. However, increased mortality was seen in the venetoclax group, mostly because of an increased rate of infections, highlighting the importance of appropriate selection of patients for this treatment option.
AbbVie and Genentech.
Venetoclax 是一种高选择性、强效的口服 BCL-2 抑制剂，可诱导多发性骨髓瘤细胞凋亡。在 1 期试验中， Venetoclax 联合硼替佐米和地塞米松显示出令人鼓舞的临床疗效，且安全性和耐受性可接受。本研究旨在评估 Venetoclax 联合硼替佐米和地塞米松在复发性或难治性多发性骨髓瘤患者中的疗效。
这是一项随机、双盲、多中心、3 期临床试验，纳入了来自 16 个国家的 90 家医院的年龄在 18 岁及以上、东部肿瘤协作组体能状态为 2 级或更低、接受过 1 至 3 种既往治疗的复发性或难治性多发性骨髓瘤患者。符合条件的患者采用中央交互式反应技术系统和三的块大小进行随机分组（2:1），接受 Venetoclax（每天 800mg 口服）或安慰剂联合硼替佐米（1.3mg/m 皮下或静脉注射和地塞米松（20mg 口服）。在前 8 个周期中，每 21 天治疗一次，从第 9 个周期开始，每 35 天治疗一次，直至疾病进展、不可接受的毒性或患者退出。随机分组按既往接受蛋白酶体抑制剂的情况和既往治疗次数进行分层。在整个研究过程中，赞助商、研究者、研究现场工作人员和患者对治疗分配均不知情。主要终点是在意向治疗人群中由独立审查委员会评估的无进展生存期。在至少接受一剂研究药物的患者中进行安全性分析。这项研究在 ClinicalTrials.gov 注册，NCT02755597。
2016 年 7 月 19 日至 2017 年 10 月 31 日期间，共 291 名患者被随机分配接受 Venetoclax（n=194）或安慰剂（n=97）。中位随访 18.7 个月（IQR 16.6-21.0），独立审查委员会评估的中位无进展生存期为 Venetoclax 组 22.4 个月（95%CI 15.3-不可估计），安慰剂组 11.5 个月（9.6-15.0）（风险比[HR]0.63 [95%CI 0.44-0.90]；p=0.010）。最常见的 3 级或更严重的治疗相关不良事件为中性粒细胞减少症（Venetoclax 组 193 例患者中有 35 例[18%]，安慰剂组 96 例患者中有 7 例[7%]）、肺炎（30 例[16%] vs 9 例[9%]）、血小板减少症（28 例[15%] vs 29 例[30%]）、贫血（28 例[15%] vs 14 例[15%]）和腹泻（28 例[15%] vs 11 例[11%]）。Venetoclax 组 93 例（48%）患者和安慰剂组 48 例（50%）患者发生严重治疗相关不良事件，Venetoclax 组报告 8 例（4%）治疗相关致命感染，安慰剂组无报告。Venetoclax 组有 3 例死亡（2 例死于肺炎，1 例死于感染性休克）被认为与治疗相关，安慰剂组无死亡与治疗相关。
主要终点达到，独立审查委员会评估的 Venetoclax 联合硼替佐米和地塞米松治疗组的无进展生存期显著改善。然而，Venetoclax 组的死亡率增加，主要是由于感染率增加，这突出了适当选择患者进行这种治疗方案的重要性。
AbbVie 和 Genentech。
