Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial.
Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial.
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DOI：
10.1016/s0140-6736(16)31594-x
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发表时间：
2017-02-04
期刊：
影响因子：
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通讯作者：
Dispenzieri A
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文献类型：
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作者：
Durie BGM;Hoering A;Abidi MH;Rajkumar SV;Epstein J;Kahanic SP;Thakuri M;Reu F;Reynolds CM;Sexton R;Orlowski RZ;Barlogie B;Dispenzieri A
来那度胺加地塞米松是新诊断的骨髓瘤患者的参考治疗。蛋白酶体抑制剂硼替佐米联合来那度胺和地塞米松治疗新诊断的骨髓瘤有显著疗效。我们的目的是研究来那度胺和地塞米松联合使用硼替佐米是否会改善先前未经治疗且未计划立即进行自体干细胞移植的多发性骨髓瘤患者的无进展生存期，并提供更好的应答率。在这项随机、开放标签的3期试验中，我们招募了来自西南肿瘤集团（SWOG）和国家临床试验网络（NCTN）机构（包括住院和门诊）的18岁及以上新诊断的多发性骨髓瘤患者。主要纳入标准为存在CRAB （C=钙升高，R=肾损害，A=贫血，B=骨受累），伴有可测量疾病的标准（通过评估游离轻链来测量），东方肿瘤合作组（ECOG）性能状态0-3，血红蛋白浓度9 g/dL或更高，绝对中性粒细胞计数1 × 103细胞/ mm3；或更高，血小板计数80000 /mm3或更高。我们随机分配（1:1）患者接受来那度胺和地塞米松的硼替佐米初始治疗（VRd组）或来那度胺和地塞米松单独治疗（Rd组）。随机化根据国际分期系统分期（I、II或III）和移植意向（是或否）进行分层。VRd方案为8个21天周期。在第1、4、8、11天给予硼替佐米1·3 mg/m2静脉滴注，联合来那度胺25 mg/天口服（1 - 14天）和地塞米松20 mg/天口服（1、2、4、5、8、9、11、12天）。Rd方案为6个28天周期。标准Rd方案包括25 mg口服来那度胺，每天一次，持续第1 - 21天，加上40 mg口服地塞米松，每天一次，持续第1、8、15和22天。主要终点为无进展生存期，采用预先指定的单侧分层对数秩检验，显著性水平为0.02。分析是为了治疗。该试验已在ClinicalTrials.gov注册，编号NCT00644228。在2008年4月至2012年2月期间，我们在139个参与机构随机分配了525名患者（264名到VRd， 261名到Rd）。在随机分配的患者中，21名VRd组患者和31名Rd组患者被认为不符合条件，主要基于缺失、不充分或早期或晚期基线实验室数据。VRd组的中位无进展生存期显著提高（Rd组为43个月，Rd组为30个月；分层风险比[HR] 0.712, 96% CI 0.56 ~ 0.906；单侧p值0.0018）。VRd组的中位总生存期也显著提高（75个月vs Rd组64个月，HR 0.709, 95% CI 0.524 - 0.959；双侧p值0.025）。VRd组的总缓解率（部分缓解或更好）为82% (176/216)，Rd组为72%(153/214)，分别有16%（34/216）和8%（18/214）的可评估缓解的患者在这两组中有完全缓解或更好。VRd组241例患者中有198例（82%）和Rd组226例患者中有169例（75%）报告了3级或以上不良事件；分别有55例（23%）和22例（10%）患者因不良事件而停止诱导治疗。Rd组无治疗相关死亡，VRd组2例。在新诊断的骨髓瘤患者中，来那度胺和地塞米松联合使用硼替佐米可显著改善无进展和总生存期，并具有可接受的风险-收益概况。NIH， NCI， NCTN, Millennium Pharmaceuticals， Takeda Oncology Company和Celgene Corporation。
Lenalidomide plus dexamethasone is a reference treatment for patients with newly diagnosed myeloma. The combination of the proteasome inhibitor bortezomib with lenalidomide and dexamethasone has shown significant efficacy in the setting of newly diagnosed myeloma. We aimed to study whether the addition of bortezomib to lenalidomide and dexamethasone would improve progression-free survival and provide better response rates in patients with previously untreated multiple myeloma who were not planned for immediate autologous stem-cell transplant. In this randomised, open-label, phase 3 trial, we recruited patients with newly diagnosed multiple myeloma aged 18 years and older from participating Southwest Oncology Group (SWOG) and National Clinical Trial Network (NCTN) institutions (both inpatient and outpatient settings). Key inclusion criteria were presence of CRAB (C=calcium elevation; R=renal impairment; A=anaemia; B=bone involvement) criteria with measurable disease (measured by assessment of free light chains), Eastern Cooperative Oncology Group (ECOG) performance status of 0–3, haemoglobin concentration 9 g/dL or higher, absolute neutrophil count 1 × 103 cells per mm3; or higher, and a platelet count of 80 000/mm3 or higher. We randomly assigned (1:1) patients to receive either an initial treatment of bortezomib with lenalidomide and dexamethasone (VRd group) or lenalidomide and dexamethasone alone (Rd group). Randomisation was stratified based on International Staging System stage (I, II, or III) and intent to transplant (yes vs no). The VRd regimen was given as eight 21-day cycles. Bortezomib was given at 1·3 mg/m2 intravenously on days 1, 4, 8, and 11, combined with oral lenalidomide 25 mg daily on days 1–14 plus oral dexamethasone 20 mg daily on days 1, 2, 4, 5, 8, 9, 11, and 12. The Rd regimen was given as six 28-day cycles. The standard Rd regimen consisted of 25 mg oral lenalidomide once a day for days 1–21 plus 40 mg oral dexamethasone once a day on days 1, 8, 15, and 22. The primary endpoint was progression-free survival using a prespecified one-sided stratified log rank test at a significance level of 0·02. Analyses were intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00644228. Between April, 2008, and February, 2012, we randomly assigned 525 patients at 139 participating institutions (264 to VRd and 261 to Rd). In the randomly assigned patients, 21 patients in the VRd group and 31 in the Rd group were deemed ineligible based mainly on missing, insufficient, or early or late baseline laboratory data. Median progression-free survival was significantly improved in the VRd group (43 months vs 30 months in the Rd group; stratified hazard ratio [HR] 0·712, 96% CI 0·56–0·906; one-sided p value 0·0018). The median overall survival was also significantly improved in the VRd group (75 months vs 64 months in the Rd group, HR 0·709, 95% CI 0·524–0·959; two-sided p value 0·025). The rates of overall response (partial response or better) were 82% (176/216) in the VRd group and 72% (153/214) in the Rd group, and 16% (34/216) and 8% (18/214) of patients who were assessable for response in these respective groups had a complete response or better. Adverse events of grade 3 or higher were reported in 198 (82%) of 241 patients in the VRd group and 169 (75%) of 226 patients in the Rd group; 55 (23%) and 22 (10%) patients discontinued induction treatment because of adverse events, respectively. There were no treatment-related deaths in the Rd group, and two in the VRd group. In patients with newly diagnosed myeloma, the addition of bortezomib to lenalidomide and dexamethasone resulted in significantly improved progression-free and overall survival and had an acceptable risk-benefit profile. NIH, NCI, NCTN, Millennium Pharmaceuticals, Takeda Oncology Company, and Celgene Corporation.