Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial,The Lancet

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Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial
The Lancet ( IF 168.9 ) Pub Date : 2021-06-04 , DOI: 10.1016/s0140-6736(21)00592-4
Philippe Moreau ₁ , Meletios-Athanasios Dimopoulos ₂ , Joseph Mikhael ₃ , Kwee Yong ₄ , Marcelo Capra ₅ , Thierry Facon ₆ , Roman Hajek ₇ , Ivan Špička ₈ , Ross Baker ₉ , Kihyun Kim ₁₀ , Gracia Martinez ₁₁ , Chang-Ki Min ₁₂ , Ludek Pour ₁₃ , Xavier Leleu ₁₄ , Albert Oriol ₁₅ , Youngil Koh ₁₆ , Kenshi Suzuki ₁₇ , Marie-Laure Risse ₁₈ , Gaelle Asset ₁₉ , Sandrine Macé ₁₈ , Thomas Martin ₂₀ ,

Affiliation

Department of Hematology, University Hospital Hôtel-Dieu, Nantes, France.
The National and Kapodistrian University of Athens, Athens, Greece.
Translational Genomics Research Institute, City of Hope Cancer Center, Phoenix, AZ, USA.
Department of Haematology, University College Hospital, London, UK.
Centro Integrado de Hematologia e Oncologia, Hospital Mãe de Deus, Porto Alegre, Brazil.
Lille University Hospital, Lille, France.
Department of Hemato-Oncology, University Hospital Ostrava and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.
1st Department of Medicine-Department of Hematology, 1st Faculty of Medicine, Charles University and General Hospital in Prague, Prague, Czech Republic.
Perth Blood Institute, Murdoch University, Perth, WA, Australia.
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Sao Paolo, Brazil.
Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul, South Korea.
Department of Internal Medicine, Hematology and Oncology, University Hospital Brno, Brno, Czech Republic.
Service d'Hématologie et Thérapie Cellulaire, CHU and CIC Inserm 1402, Poitiers, France.
Institut Josep Carreras and Institut Catala d'Oncologia, Hospital Germans Trias I Pujol, Badalona, Spain.
Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.
Myeloma/Amyloidosis Center, Japanese Red Cross Medical Center, Tokyo, Japan.
Sanofi R&D, Vitry-sur-Seine, France.
Sanofi R&D, Chilly-Mazarin, France.
Department of Hematology, University of California San Francisco, San Francisco, CA, USA.

Background

Isatuximab is an anti-CD38 monoclonal antibody approved in combination with pomalidomide–dexamethasone and carfilzomib–dexamethasone for relapsed or refractory multiple myeloma. This phase 3, open-label study compared the efficacy of isatuximab plus carfilzomib–dexamethasone versus carfilzomib–dexamethasone in patients with relapsed multiple myeloma.

Methods

This was a prospective, randomised, open-label, parallel-group, phase 3 study done at 69 study centres in 16 countries across North America, South America, Europe, and the Asia-Pacific region. Patients with relapsed or refractory multiple myeloma aged at least 18 years who had received one to three previous lines of therapy and had measurable serum or urine M-protein were eligible. Patients were randomly assigned (3:2) to isatuximab plus carfilzomib–dexamethasone (isatuximab group) or carfilzomib–dexamethasone (control group). Patients in the isatuximab group received isatuximab 10 mg/kg intravenously weekly for the first 4 weeks, then every 2 weeks. Both groups received the approved schedule of intravenous carfilzomib and oral or intravenous dexamethasone. Treatment continued until progression or unacceptable toxicity. The primary endpoint was progression-free survival and was assessed in the intention-to-treat population according to assigned treatment. Safety was assessed in all patients who received at least one dose according to treatment received. The study is registered at ClinicalTrials.gov, NCT03275285.

Findings

Between Nov 15, 2017, and March 21, 2019, 302 patients with a median of two previous lines of therapy were enrolled. 179 were randomly assigned to the isatuximab group and 123 to the control group. Median progression-free survival was not reached in the isatuximab group compared with 19·15 months (95% CI 15·77–not reached) in the control group, with a hazard ratio of 0·53 (99% CI 0·32–0·89; one-sided p=0·0007). Treatment-emergent adverse events (TEAEs) of grade 3 or worse occurred in 136 (77%) of 177 patients in the isatuximab group versus 82 (67%) of 122 in the control group, serious TEAEs occurred in 105 (59%) versus 70 (57%) patients, and TEAEs led to discontinuation in 15 (8%) versus 17 (14%) patients. Fatal TEAEs during study treatment occurred in six (3%) versus four (3%) patients.

Interpretation

The addition of isatuximab to carfilzomib–dexamethasone significantly improves progression-free survival and depth of response in patients with relapsed multiple myeloma, representing a new standard of care for this patient population.

Funding

Sanofi.

Video Abstract

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Video abstract

YouTube link: https://youtu.be/5kXtQQlzRh4

中文翻译：

Isatuximab、carfilzomib 和 dexamethasone 治疗复发性多发性骨髓瘤 (IKEMA)：一项多中心、开放标签、随机 3 期试验

背景

Isatuximab 是一种抗 CD38 单克隆抗体，被批准与 pomalidomide-dexamethasone 和 carfilzomib-dexamethasone 联合用于复发或难治性多发性骨髓瘤。这项 3 期开放标签研究比较了艾妥昔单抗联合卡非佐米-地塞米松与卡非佐米-地塞米松在复发性多发性骨髓瘤患者中的疗效。

方法

这是一项前瞻性、随机、开放标签、平行组、3 期研究，在北美、南美、欧洲和亚太地区 16 个国家的 69 个研究中心进行。年龄至少 18 岁的复发性或难治性多发性骨髓瘤患者接受过 1 至 3 线治疗并具有可测量的血清或尿液 M 蛋白是合格的。患者被随机分配 (3:2) 至 isatuximab + carfilzomib-dexamethasone（isatuximab 组）或 carfilzomib-dexamethasone（对照组）。isatuximab 组患者在前 4 周每周静脉内接受 10 mg/kg 的 isatuximab，然后每 2 周一次。两组都接受了批准的静脉卡非佐米和口服或静脉地塞米松的时间表。治疗持续到进展或出现不可接受的毒性。主要终点是无进展生存期，并根据分配的治疗在意向治疗人群中进行评估。根据所接受的治疗，在接受至少一剂的所有患者中评估安全性。该研究在 ClinicalTrials.gov 注册，NCT03275285。

发现

在 2017 年 11 月 15 日至 2019 年 3 月 21 日期间，共有 302 名中位数为之前两条治疗线的患者入组。179 人被随机分配到 isatuximab 组，123 人被随机分配到对照组。与对照组的 19·15 个月（95% CI 15·77–未达到）相比，isatuximab 组未达到中位无进展生存期，风险比为 0·53（99% CI 0·32– 0·89；单侧 p=0·0007)。isatuximab 组 177 名患者中有 136 名（77%）发生了 3 级或更严重的治疗中出现的不良事件（TEAE），而对照组 122 名患者中有 82 名（67%）发生了严重的 TEAE，105 名（59%）发生了严重的 TEAE 70 名 (57%) 患者，TEAE 导致 15 名 (8%) 和 17 名 (14%) 患者停药。研究治疗期间的致命 TEAE 发生在 6 名 (3%) 和 4 名 (3%) 患者中。