Moreau Philippe, Dimopoulos Meletios-Athanasios, Mikhael Joseph, Yong Kwee, Capra Marcelo, Facon Thierry, Hajek Roman, Špička Ivan, Baker Ross, Kim Kihyun, Martinez Gracia, Min Chang-Ki, Pour Ludek, Leleu Xavier, Oriol Albert, Koh Youngil, Suzuki Kenshi, Risse Marie-Laure, Asset Gaelle, Macé Sandrine, Martin Thomas
Department of Hematology, University Hospital Hôtel-Dieu, Nantes, France.
The National and Kapodistrian University of Athens, Athens, Greece.
Lancet. 2021 Jun 19;397(10292):2361-2371. doi: 10.1016/S0140-6736(21)00592-4. Epub 2021 Jun 4.
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.
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.
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.
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.
Sanofi. VIDEO ABSTRACT.
isatuximab是一种抗CD38单克隆抗体，已被批准与泊马度胺-地塞米松以及卡非佐米-地塞米松联合用于复发或难治性多发性骨髓瘤的治疗。这项3期开放标签研究比较了isatuximab联合卡非佐米-地塞米松与卡非佐米-地塞米松在复发多发性骨髓瘤患者中的疗效。
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、既往接受过1至3线治疗且血清或尿M蛋白可测量的复发或难治性多发性骨髓瘤患者符合条件。患者被随机分配（3:2）至isatuximab联合卡非佐米-地塞米松组（isatuximab组）或卡非佐米-地塞米松组（对照组）。isatuximab组患者在最初4周每周静脉注射isatuximab 10 mg/kg，之后每2周一次。两组均接受批准的静脉注射卡非佐米和口服或静脉注射地塞米松方案。治疗持续至疾病进展或出现不可接受的毒性。主要终点为无进展生存期，根据分配的治疗方案在意向性治疗人群中进行评估。根据接受的治疗对所有接受至少一剂治疗的患者进行安全性评估。该研究已在ClinicalTrials.gov注册，编号为NCT03275285。
在2017年11月15日至2019年3月21日期间，纳入了302例既往中位数为2线治疗的患者。179例被随机分配至isatuximab组，123例被分配至对照组。isatuximab组未达到中位无进展生存期，而对照组为19.15个月（95%CI 15.77 - 未达到），风险比为0.53（99%CI 0.32 - 0.89；单侧p = 0.0007）。isatuximab组中177例患者中有136例（77%）发生3级或更严重的治疗中出现的不良事件（TEAE），而对照组122例患者中有82例（67%）发生；严重TEAE分别发生在105例（59%）和70例（57%）患者中；TEAE导致停药的分别为15例（8%）和17例（14%）患者。研究治疗期间致命TEAE分别发生在6例（3%）和4例（3%）患者中。
在卡非佐米-地塞米松基础上加用isatuximab可显著改善复发多发性骨髓瘤患者的无进展生存期和缓解深度，代表了该患者群体的一种新的治疗标准。
赛诺菲。视频摘要。
