Mayo Clinic, Rochester, MN, USA.
ECOG-ACRIN Biostatistics Center, Dana-Farber Cancer Institute, Boston, MA, USA.
Lancet Oncol. 2020 Oct;21(10):1317-1330. doi: 10.1016/S1470-2045(20)30452-6. Epub 2020 Aug 28.
Bortezomib, lenalidomide, and dexamethasone (VRd) is a standard therapy for newly diagnosed multiple myeloma. Carfilzomib, a next-generation proteasome inhibitor, in combination with lenalidomide and dexamethasone (KRd), has shown promising efficacy in phase 2 trials and might improve outcomes compared with VRd. We aimed to assess whether the KRd regimen is superior to the VRd regimen in the treatment of newly diagnosed multiple myeloma in patients who were not being considered for immediate autologous stem-cell transplantation (ASCT).
In this multicentre, open-label, phase 3, randomised controlled trial (the ENDURANCE trial; E1A11), we recruited patients aged 18 years or older with newly diagnosed multiple myeloma who were ineligible for, or did not intend to have, immediate ASCT. Participants were recruited from 272 community oncology practices or academic medical centres in the USA. Key inclusion criteria were the absence of high-risk multiple myeloma and an Eastern Cooperative Oncology Group performance status of 0-2. Enrolled patients were randomly assigned (1:1) centrally by use of permuted blocks to receive induction therapy with either the VRd regimen or the KRd regimen for 36 weeks. Patients who completed induction therapy were then randomly assigned (1:1) a second time to either indefinite maintenance or 2 years of maintenance with lenalidomide. Randomisation was stratified by intent for ASCT at disease progression for the first randomisation and by the induction therapy received for the second randomisation. Allocation was not masked to investigators or patients. For 12 cycles of 3 weeks, patients in the VRd group received 1·3 mg/m of bortezomib subcutaneously or intravenously on days 1, 4, 8, and 11 of cycles 1-8, and day 1 and day 8 of cycles nine to twelve, 25 mg of oral lenalidomide on days 1-14, and 20 mg of oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. For nine cycles of 4 weeks, patients in the KRd group received 36 mg/m of intravenous carfilzomib on days 1, 2, 8, 9, 15, and 16, 25 mg of oral lenalidomide on days 1-21, and 40 mg of oral dexamethasone on days 1, 8, 15, and 22. The coprimary endpoints were progression-free survival in the induction phase, and overall survival in the maintenance phase. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who received at least one dose of their assigned treatment. The trial is registered with ClinicalTrials.gov, NCT01863550. Study recruitment is complete, and follow-up of the maintenance phase is ongoing.
Between Dec 6, 2013, and Feb 6, 2019, 1087 patients were enrolled and randomly assigned to either the VRd regimen (n=542) or the KRd regimen (n=545). At a median follow-up of 9 months (IQR 5-23), at a second planned interim analysis, the median progression-free survival was 34·6 months (95% CI 28·8-37·8) in the KRd group and 34·4 months (30·1-not estimable) in the VRd group (hazard ratio [HR] 1·04, 95% CI 0·83-1·31; p=0·74). Median overall survival has not been reached in either group. The most common grade 3-4 treatment-related non-haematological adverse events included fatigue (34 [6%] of 527 patients in the VRd group vs 29 [6%] of 526 in the KRd group), hyperglycaemia (23 [4%] vs 34 [6%]), diarrhoea (23 [5%] vs 16 [3%]), peripheral neuropathy (44 [8%] vs four [<1%]), dyspnoea (nine [2%] vs 38 [7%]), and thromboembolic events (11 [2%] vs 26 [5%]). Treatment-related deaths occurred in two patients (<1%) in the VRd group (one cardiotoxicity and one secondary cancer) and 11 (2%) in the KRd group (four cardiotoxicity, two acute kidney failure, one liver toxicity, two respiratory failure, one thromboembolic event, and one sudden death).
The KRd regimen did not improve progression-free survival compared with the VRd regimen in patients with newly diagnosed multiple myeloma, and had more toxicity. The VRd triplet regimen remains the standard of care for induction therapy for patients with standard-risk and intermediate-risk newly diagnosed multiple myeloma, and is a suitable treatment backbone for the development of combinations of four drugs.
US National Institutes of Health, National Cancer Institute, and Amgen.
硼替佐米、来那度胺和地塞米松（VRd）是新诊断多发性骨髓瘤的标准治疗方法。卡非佐米是一种下一代蛋白酶体抑制剂，与来那度胺和地塞米松（KRd）联合使用，在 2 期试验中显示出良好的疗效，与 VRd 相比可能改善疗效。我们旨在评估在不考虑立即进行自体干细胞移植（ASCT）的新诊断多发性骨髓瘤患者中，KRd 方案是否优于 VRd 方案。
在这项多中心、开放标签、3 期、随机对照试验（ENDURANCE 试验；E1A11）中，我们招募了年龄在 18 岁或以上、不适合或不打算进行 ASCT 的新诊断多发性骨髓瘤患者。参与者来自美国 272 个社区肿瘤学诊所或学术医学中心。主要纳入标准是无高危多发性骨髓瘤和东部肿瘤协作组表现状态 0-2。入组患者通过中心随机化（使用置换块）按 1:1 比例随机分配接受 VRd 方案或 KRd 方案治疗 36 周的诱导治疗。完成诱导治疗的患者随后按 1:1 再次随机分配接受无期限维持治疗或 2 年的来那度胺维持治疗。第一次随机化按疾病进展时是否有 ASCT 的意向分层，第二次随机化按接受的诱导治疗分层。对研究人员和患者不设盲法。对于 3 周 12 个周期的治疗，VRd 组患者在第 1、4、8 和 11 周期的第 1-8 周期和第 9-12 周期的第 1 和第 8 天接受 1·3 mg/m 的皮下或静脉注射硼替佐米，第 1-14 天口服来那度胺 25 mg，第 1、2、4、5、8、9、11 和 12 天口服地塞米松 20 mg。在 4 周 9 个周期的治疗中，KRd 组患者在第 1、2、8、9、15 和 16 天接受静脉注射卡非佐米 36 mg/m，第 1-21 天口服来那度胺 25 mg，第 1、8、15 和 22 天口服地塞米松 40 mg。主要终点是诱导期无进展生存期和维持期总生存期。主要分析在意向治疗人群中进行，安全性在接受至少一剂指定治疗的患者中进行评估。该试验在 ClinicalTrials.gov 上注册，编号为 NCT01863550。研究招募已完成，维持阶段的随访正在进行中。
在 2013 年 12 月 6 日至 2019 年 2 月 6 日期间，共纳入 1087 名患者并随机分配至 VRd 组（n=542）或 KRd 组（n=545）。在中位随访 9 个月（IQR 5-23）时，在第二次计划的中期分析中，KRd 组的中位无进展生存期为 34·6 个月（95%CI 28·8-37·8），VRd 组为 34·4 个月（30·1-未估计）（HR 1·04，95%CI 0·83-1·31；p=0·74）。两组均未达到中位总生存期。最常见的 3-4 级治疗相关非血液学不良事件包括疲劳（VRd 组 527 名患者中有 34 名[6%]，KRd 组 526 名患者中有 29 名[6%]）、高血糖（23 名[4%]比 34 名[6%]）、腹泻（23 名[5%]比 16 名[3%]）、周围神经病变（44 名[8%]比 4 名[<1%]）、呼吸困难（9 名[2%]比 38 名[7%]）和血栓栓塞事件（11 名[2%]比 26 名[5%]）。VRd 组有 2 名患者（<1%）发生治疗相关死亡（1 例为心脏毒性，1 例为继发性癌症），KRd 组有 11 名患者（2%）发生治疗相关死亡（4 例为心脏毒性，2 例为急性肾衰竭，1 例为肝毒性，2 例为呼吸衰竭，1 例为血栓栓塞事件，1 例为猝死）。
与 VRd 方案相比，KRd 方案在新诊断多发性骨髓瘤患者中并未改善无进展生存期，且毒性更大。VRd 三联疗法仍然是新诊断多发性骨髓瘤标准风险和中危风险患者的诱导治疗标准，也是开发四种药物联合方案的合适治疗基础。
美国国立卫生研究院、美国国家癌症研究所和安进公司。
