Elotuzumab, lenalidomide, bortezomib, dexamethasone, and autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GMMG-HD6): results from a randomised, phase 3 trial

Elias K Mai, Hartmut Goldschmid, Kaya Miah, Uta Bertsch, Britta Besemer, Mathias Hänel, Julia Krzykalla, Roland Fenk, Jana Schlenzka, Markus Munder, Jan Dürig, Igor W Blau, Stefanie Huhn, Dirk Hose, Anna Jauch, Christina Kunz, Christoph Mann, Niels Weinhold, Christof Scheid, Roland Schroers, Iris Zirpel
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Adult patients (aged 18–70 years) with previously untreated, symptomatic multiple myeloma, and a WHO performance status of 0–3, with 3 being allowed only if caused by myeloma disease and not by comorbid conditions, were randomly assigned 1:1:1:1 to four treatment groups. Induction therapy consisted of four 21-day cycles of RVd (lenalidomide 25 mg orally on days 1–14; bortezomib 1·3 mg/m<sup>2</sup> subcutaneously on days 1, 4, 8, and 11]; and dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11, 12, and 15 for cycles 1–2) or, RVd induction plus elotuzumab (10 mg/kg intravenously on days 1, 8, and 15 for cycles 1–2, and on days 1 and 11 for cycles 3–4; E-RVd). Autologous haematopoietic stem-cell transplantation was followed by two 21-day cycles of either RVd consolidation (lenalidomide 25 mg orally on days 1–14; bortezomib 1·3 mg/m<sup>2</sup> subcutaneously on days 1, 8, and 15; and dexamethasone 20 mg orally on days 1, 2, 8, 9, 15, and 16) or elotuzumab plus RVd consolidation (with elotuzumab 10 mg/kg intravenously on days 1, 8, and 15) followed by maintenance with either lenalidomide (10 mg orally on days 1–28 for cycles 1–3; thereafter, up to 15 mg orally on days 1–28; RVd/R or E-RVd/R group) or lenalidomide plus elotuzumab (10 mg/kg intravenously on days 1 and 15 for cycles 1–6, and on day 1 for cycles 7–26; RVd/E-R or E-RVd/E-R group) for 2 years. The primary endpoint was progression-free survival analysed in a modified intention-to-treat (ITT) population. Safety was analysed in all patients who received at least one dose of trial medication. 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引用次数: 0

Abstract

Background

The aim of this trial was to investigate the addition of the anti-SLAMF7 monoclonal antibody elotuzumab to lenalidomide, bortezomib, and dexamethasone (RVd) in induction and consolidation therapy as well as to lenalidomide maintenance treatment in transplant-eligible patients with newly diagnosed multiple myeloma.

Methods

GMMG-HD6 was a phase 3, randomised trial conducted at 43 main trial sites and 26 associated trial sites throughout Germany. Adult patients (aged 18–70 years) with previously untreated, symptomatic multiple myeloma, and a WHO performance status of 0–3, with 3 being allowed only if caused by myeloma disease and not by comorbid conditions, were randomly assigned 1:1:1:1 to four treatment groups. Induction therapy consisted of four 21-day cycles of RVd (lenalidomide 25 mg orally on days 1–14; bortezomib 1·3 mg/m2 subcutaneously on days 1, 4, 8, and 11]; and dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11, 12, and 15 for cycles 1–2) or, RVd induction plus elotuzumab (10 mg/kg intravenously on days 1, 8, and 15 for cycles 1–2, and on days 1 and 11 for cycles 3–4; E-RVd). Autologous haematopoietic stem-cell transplantation was followed by two 21-day cycles of either RVd consolidation (lenalidomide 25 mg orally on days 1–14; bortezomib 1·3 mg/m2 subcutaneously on days 1, 8, and 15; and dexamethasone 20 mg orally on days 1, 2, 8, 9, 15, and 16) or elotuzumab plus RVd consolidation (with elotuzumab 10 mg/kg intravenously on days 1, 8, and 15) followed by maintenance with either lenalidomide (10 mg orally on days 1–28 for cycles 1–3; thereafter, up to 15 mg orally on days 1–28; RVd/R or E-RVd/R group) or lenalidomide plus elotuzumab (10 mg/kg intravenously on days 1 and 15 for cycles 1–6, and on day 1 for cycles 7–26; RVd/E-R or E-RVd/E-R group) for 2 years. The primary endpoint was progression-free survival analysed in a modified intention-to-treat (ITT) population. Safety was analysed in all patients who received at least one dose of trial medication. This trial is registered with ClinicalTrials.gov, NCT02495922, and is completed.

Findings

Between June 29, 2015, and on Sept 11, 2017, 564 patients were included in the trial. The modified ITT population comprised 559 (243 [43%] females and 316 [57%] males) patients and the safety population 555 patients. After a median follow-up of 49·8 months (IQR 43·7–55·5), there was no difference in progression-free survival between the four treatment groups (adjusted log-rank p value, p=0·86), and 3-year progression-free survival rates were 69% (95% CI 61–77), 69% (61–76), 66% (58–74), and 67% (59–75) for patients treated with RVd/R, RVd/E-R, E-RVd/R, and E-RVd/E-R, respectively. Infections (grade 3 or worse) were the most frequently observed adverse event in all treatment groups (28 [20%] of 137 for RVd/R; 32 [23%] of 138 for RVd/E-R; 35 [25%] of 138 for E-RVd/R; and 48 [34%] of 142 for E-RVd/E-R). Serious adverse events (grade 3 or worse) were observed in 68 (48%) of 142 participants in the E-RVd/E-R group, 53 (39%) of 137 in the RVd/R, 53 (38%) of 138 in the RVd/E-R, and 50 (36%) of 138 in the E-RVd/R (36%) group. There were nine treatment-related deaths during the study. Two deaths (one sepsis and one toxic colitis) in the RVd/R group were considered lenalidomide-related. One death in the RVd/E-R group due to meningoencephalitis was considered lenalidomide and elotuzumab-related. Four deaths (one pulmonary embolism, one septic shock, one atypical pneumonia, and one cardiovascular failure) in the E-RVd/R group and two deaths (one sepsis and one pneumonia and pulmonary fibrosis) in the E-RVd/E-R group were considered related to lenalidomide or elotuzumab, or both.

Interpretation

Addition of elotuzumab to RVd induction or consolidation and lenalidomide maintenance in patients with transplant-eligible newly diagnosed multiple myeloma did not provide clinical benefit. Elotuzumab-containing therapies might be reserved for patients with relapsed or refractory multiple myeloma.

Funding

Bristol Myers Squibb/Celgene and Chugai.

埃洛珠单抗、来那度胺、硼替佐米、地塞米松和自体造血干细胞移植治疗新诊断多发性骨髓瘤(GMMG-HD6):一项随机三期试验的结果
背景本试验旨在研究在来那度胺、硼替佐米和地塞米松(RVd)的诱导和巩固治疗中,以及在来那度胺的维持治疗中,对符合移植条件的新诊断多发性骨髓瘤患者加用抗SLAMF7单克隆抗体艾洛妥珠单抗。既往未接受过治疗、无症状的多发性骨髓瘤成人患者(18-70 岁),WHO 表观状态为 0-3(3 为骨髓瘤疾病所致,而非合并症),按 1:1:1:1 的比例随机分配到四个治疗组。诱导治疗包括四个 21 天周期的 RVd(第 1-14 天口服来那度胺 25 毫克;第 1、4、8 和 11 天皮下注射硼替佐米 1-3 毫克/平方米];1-2周期第1、2、4、5、8、9、11、12和15天口服地塞米松20毫克)或RVd诱导加艾洛妥珠单抗(1-2周期第1、8和15天静脉注射10毫克/千克,3-4周期第1和11天静脉注射;E-RVd)。自体造血干细胞移植后进行两个 21 天周期的 RVd 巩固治疗(来那度胺 25 毫克,口服,第 1-14 天;硼替佐米 1-3 毫克/平方米,皮下注射,第 1、8 和 15 天;地塞米松 20 毫克,口服,第 1、2、8、9、15 和 16 天)或艾洛妥珠单抗加 RVd 巩固疗法(艾洛妥珠单抗 10 毫克/公斤,静脉注射,第 1、8 和 15 天),然后使用来那度胺(10 毫克,口服,第 1-28 天,第 1-3 周期;RVd/R组或E-RVd/R组)或来那度胺加依洛珠单抗(第1-6周期第1天和第15天静脉注射10毫克/千克,第7-26周期第1天静脉注射10毫克/千克;RVd/E-R组或E-RVd/E-R组)维持治疗2年。主要终点是无进展生存期,在改良的意向治疗(ITT)人群中进行分析。对所有至少接受过一次试验药物治疗的患者进行了安全性分析。该试验已在ClinicalTrials.gov上注册,编号为NCT02495922,并已完成。研究结果从2015年6月29日至2017年9月11日,共有564名患者参与了试验。修改后的ITT人群包括559名患者(女性243名[43%],男性316名[57%]),安全人群包括555名患者。中位随访49-8个月(IQR 43-7-55-5)后,四个治疗组的无进展生存期无差异(调整后的对数秩P值,P=0-86),接受RVd/R、RVd/E-R、E-RVd/R和E-RVd/E-R治疗的患者的3年无进展生存率分别为69%(95% CI 61-77)、69%(61-76)、66%(58-74)和67%(59-75)。感染(3级或更严重)是所有治疗组中最常见的不良事件(RVd/R治疗组137例中有28例[20%];RVd/E-R治疗组138例中有32例[23%];E-RVd/R治疗组138例中有35例[25%];E-RVd/E-R治疗组142例中有48例[34%])。E-RVd/E-R组142名参与者中有68人(48%)、RVd/R组137人中有53人(39%)、RVd/E-R组138人中有53人(38%)、E-RVd/R组138人中有50人(36%)出现严重不良事件(3级或更严重)。研究期间共有九例与治疗相关的死亡病例。RVd/R组的两例死亡(一例败血症,一例中毒性结肠炎)被认为与来那度胺有关。RVd/E-R组的1例脑膜脑炎死亡被认为与来那度胺和埃洛珠单抗有关。E-RVd/R组的4例死亡(1例肺栓塞、1例脓毒性休克、1例非典型肺炎和1例心血管衰竭)和E-RVd/E-R组的2例死亡(1例败血症、1例肺炎和肺纤维化)被认为与来那度胺或埃洛珠单抗或两者相关。解读在RVd诱导或巩固治疗和来那度胺维持治疗的基础上,对符合移植条件的新诊断多发性骨髓瘤患者加用伊洛珠单抗并不能带来临床获益。复发或难治性多发性骨髓瘤患者可保留含伊洛珠单抗的疗法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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