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联合用药可显著延长新诊断的多发性骨髓瘤生存率
作者:小柯机器人 发布时间:2019/12/16 17:49:33

近日,西班牙萨拉曼卡大学医院Maria-Victoria Mateos及其研究组研究了达雷木单抗+硼替佐米+美法仑+泼尼松治疗新诊断的多发性骨髓瘤的效果。该项研究成果发表在2019年12月10日出版的《柳叶刀》上。

新诊断的多发性骨髓瘤患者的治疗标准包括不符合自体干细胞移植条件的患者进行联合治疗。在ALCYONE临床3期试验中,达雷木单抗+硼替佐米+美法仑+泼尼松(D-VMP)治疗不适宜移植的新诊断多发性骨髓瘤患者,其无进展生存期明显高于硼替佐米+美法仑+泼尼松(VMP)。

ALCYONE是一项多中心、随机、开放标签、主动控制的临床3期试验,2015年2月9日至2016年7月14日,研究组在北美、南美、欧洲和亚太地区的25个国家中的162个地点招募了706名新诊断的多发性骨髓瘤患者,均由于年龄较大或实质性共病而不适宜进行自体干细胞移植。按1:1将这些患者随机分组,其中350名接受D-VMP方案进行治疗,356名接受VMP方案进行治疗。

中位随访40.1个月后,D-VMP组的总生存率显著提高。与VMP组相比,D-VMP组的死亡风险比为0.60。D-VMP组36个月的总生存率为78.0%,而VMP组为67.9%。D-VMP组的无进展生存率显著高于VMP组。D-VMP组中最常见的不良反应是呼吸道感染,其中上呼吸道感染、支气管炎和病毒性上呼吸道感染的发生率分别为19%、15%和12%;咳嗽和腹泻的发生率分别为12%和10%。

总之,D-VMP延长了新诊断的不适宜干细胞移植的多发性骨髓瘤患者的总生存率。经过3年多的随访,D-VMP的无进展生存率持续改善,且未出现新的安全问题。

附:英文原文

Title: Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial

Author: Maria-Victoria Mateos, Michele Cavo, Joan Blade, Meletios A Dimopoulos, Kenshi Suzuki, Andrzej Jakubowiak, Stefan Knop, Chantal Doyen, Paulo Lucio, Zsolt Nagy, Ludek Pour, Mark Cook, Sebastian Grosicki, Andre Crepaldi, Anna Marina Liberati, Philip Campbell, Tatiana Shelekhova, Sung-Soo Yoon, Genadi Iosava, Tomoaki Fujisaki, Mamta Garg, Maria Krevvata, Ying Chen, Jianping Wang, Anupa Kudva, Jon Ukropec, Susan Wroblewski, Ming Qi, Rachel Kobos, Jesus San-Miguel

Issue&Volume: December 10, 2019

Abstract:

Background

Standard-of-care treatment for patients with newly diagnosed multiple myeloma includes combination therapies for patients who are not eligible for autologous stem-cell transplantation. At the primary analysis for progression-free survival of the phase 3 ALCYONE trial, progression-free survival was significantly longer with daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) alone in patients with transplant-ineligible, newly diagnosed multiple myeloma. Here we report updated efficacy and safety results from a prespecified, interim, overall survival analysis of ALCYONE with more than 36 months of follow-up.
 
Methods
 
ALCYONE was a multicentre, randomised, open-label, active-controlled, phase 3 trial that enrolled patients between Feb 9, 2015, and July 14, 2016, at 162 sites in 25 countries across North America, South America, Europe, and the Asia-Pacific region. Patients were eligible for inclusion if they had newly diagnosed multiple myeloma and were ineligible for high-dose chemotherapy with autologous stem-cell transplantation, because of their age (≥65 years) or because of substantial comorbidities. Patients were randomly assigned in a 1:1 ratio and by permuted block randomisation to receive D-VMP or VMP. An interactive web-based randomisation system was used. Randomisation was stratified by International Staging System disease stage, geographical region, and age. There was no masking to treatment assignments. All patients received up to nine 6-week cycles of subcutaneous bortezomib (1·3 mg/m 2 of body surface area on days 1, 4, 8, 11, 22, 25, 29, and 32 of cycle one and on days 1, 8, 22, and 29 of cycles two through nine), oral melphalan (9 mg/m 2 once daily on days 1 through 4 of each cycle), and oral prednisone (60 mg/m 2 once daily on days 1 through 4 of each cycle). Patients in the D-VMP group also received intravenous daratumumab (16 mg/kg of bodyweight, once weekly during cycle one, once every 3 weeks in cycles two through nine, and once every 4 weeks thereafter as maintenance therapy until disease progression or unacceptable toxicity). The primary endpoint was progression-free survival, which has been reported previously. Results presented are from a prespecified interim analysis for overall survival. The primary analysis population (including for overall survival) was the intention-to-treat population of all patients who were randomly assigned to treatment. The safety population included patients who received any dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02195479.
 
Findings
 
706 patients were randomly assigned to treatment groups (350 to the D-VMP group, 356 to the VMP group). At a median follow-up of 40·1 months (IQR 37·4–43·1), a significant benefit in overall survival was observed for the D-VMP group. The hazard ratio (HR) for death in the D-VMP group compared with the VMP group was 0·60 (95% CI 0·46–0·80; p=0·0003). The Kaplan-Meier estimate of the 36-month rate of overall survival was 78·0% (95% CI 73·2–82·0) in the D-VMP group and 67·9% (62·6–72·6) in the VMP group. Progression-free survival, the primary endpoint, remained significantly improved for the D-VMP group (HR 0·42 [0·34–0·51]; p<0·0001). The most frequent adverse events during maintenance daratumumab monotherapy in patients in the D-VMP group were respiratory infections (54 [19%] of 278 patients had upper respiratory tract infections; 42 [15%] had bronchitis, 34 [12%] had viral upper respiratory tract infections), cough (34 [12%]), and diarrhoea (28 [10%]).
 
Interpretation
 
D-VMP prolonged overall survival in patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. With more than 3 years of follow-up, the D-VMP group continued to show significant improvement in progression-free survival, with no new safety concerns. 

DOI: 10.1016/S0140-6736(19)32956-3

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)32956-3/fulltext

期刊信息

LANCET:《柳叶刀》,创刊于1823年。隶属于爱思唯尔出版社,最新IF:59.102
官方网址:http://www.thelancet.com/
投稿链接:http://ees.elsevier.com/thelancet