Felzartamab联合来那度胺-地塞米松对比来那度胺-地塞米松治疗复发或难治性多发性骨髓瘤：一项开放标签、平行对照、随机、3期试验。
完整摘要 · 中文译文
背景：CD38单克隆抗体的补体依赖性细胞毒性（CDC）与输注相关反应相关，并可能导致依赖CDC的CD38抗体临床疗效降低，尤其是在伴有1q21+的复发或难治性多发性骨髓瘤患者中。我们旨在评估菲泽妥单抗（felzartamab）——一种新型抗CD38单克隆抗体，在保留强效抗体依赖性细胞毒性（ADCC）和抗体依赖性细胞吞噬作用（ADCP）的同时，在中国复发或难治性多发性骨髓瘤患者中表现出显著减弱的CDC活性。 方法：这项开放标签、平行对照、随机、3期试验在中国41家医院进行，纳入年龄18岁及以上、患有复发或难治性多发性骨髓瘤、既往接受过至少一线全身治疗且对来那度胺非难治性的成人患者。患者通过中央交互式网络应答系统按2：1比例随机分组，分层因素包括国际分期系统分期、既往治疗线数和既往来那度胺暴露情况，接受静脉注射felzartamab（第1周第1天和第4天给予16 mg/kg，第2-12周每周一次，第13-24周每2周一次，此后每4周一次）联合每日一次来那度胺（每28天周期第1-21天口服25 mg）和每周一次口服地塞米松（年龄≤75岁患者40 mg，>75岁患者20 mg），或单独接受来那度胺和地塞米松。主要终点是无进展生存期，定义为从随机化至疾病进展或任何原因死亡的时间，以先发生者为准，由独立审查委员会在全分析集（所有接受至少一剂研究治疗的随机分配患者）中进行评估。安全性评估在所有接受至少一剂研究治疗的患者中进行。该试验在ClinicalTrials.gov注册（NCT03952091），现已停止入组。 结果：2019年3月27日至2021年10月20日期间，390例患者接受了资格评估，其中295例被入组并随机分配至felzartamab联合来那度胺-地塞米松组（n=195）或来那度胺-地塞米松组（n=100）。全分析集包括289例患者（felzartamab联合来那度胺-地塞米松组191例，来那度胺-地塞米松组98例）。289例患者中男性185例（64%），女性104例（36%），所有患者均为亚洲人。felzartamab联合来那度胺-地塞米松组的中位随访时间为34·5个月（IQR 16·8-40·2），来那度胺-地塞米松组为28·7个月（10·8-38·8）；中位无进展生存期在felzartamab联合来那度胺-地塞米松组为18·9个月（95% CI 13·6-24·0），在来那度胺-地塞米松组为10·4个月（5·8-13·9）（风险比0·62 [95% CI 0·45-0·86]；p=0·0035）。最常见的3-4级不良事件为中性粒细胞减少症（192例中105例[55%]对比97例中22例[23%]）、淋巴细胞减少症（79例[41%]对比15例[15%]）、白细胞减少症（74例[39%]对比11例[11%]）、血小板减少症（49例[26%]对比11例[11%]）、肺炎（44例[23%]对比13例[13%]）、贫血（33例[17%]对比19例[20%]）、低钾血症（30例[16%]对比10例[10%]）和上呼吸道感染（15例[8%]对比2例[2%]）。最常见的严重不良事件为肺炎（42例[22%]对比10例[10%]）。治疗相关死亡发生在felzartamab联合来那度胺-地塞米松组192例患者中的11例（6%）（5例死因不明[可能与治疗相关]，2例死于肺炎，1例死于发热性感染，1例死于心脏骤停，1例 其中一例死于脑梗死，一例死于肺炎；来那度胺-地塞米松组97例患者中有2例（2%）死亡（一例死于肺炎，一例死于跌倒）。 解读：与来那度胺-地塞米松单药相比，Felzartamab联合来那度胺-地塞米松显著延长了无进展生存期，支持Felzartamab联合来那度胺-地塞米松作为中国复发或难治性多发性骨髓瘤患者的潜在新治疗选择。 资助来源：天境生物。
完整摘要 · 英文原文
BACKGROUND: Complement-dependent cytotoxicity (CDC) of CD38 monoclonal antibodies has been associated with infusion-related reactions and might contribute to reduced clinical efficacy of CDC-reliant CD38 antibodies, particularly in patients with relapsed or refractory multiple myeloma with 1q21+. We aimed to evaluate felzartamab, a novel anti-CD38 monoclonal antibody that retains potent antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis while exhibiting markedly attenuated CDC activity in Chinese patients with relapsed or refractory multiple myeloma. METHODS: In this open-label, parallel-controlled, randomised, phase 3 trial conducted at 41 hospitals in China, adults aged 18 years or older with relapsed or refractory multiple myeloma who had received at least one previous line of systemic therapy, and were not refractory to lenalidomide were enrolled. Patients were randomly assigned (2:1) through a central interactive web response system, stratified by International Staging System stage, number of previous lines of therapy, and previous lenalidomide exposure, to receive intravenous felzartamab (16 mg/kg on days 1 and 4 during week 1, weekly week 2-12, every 2 weeks week 13-24, and every 4 weeks thereafter) plus once daily lenalidomide (25 mg orally on days 1-21 of each 28-day cycle) and once weekly oral dexamethasone (40 mg for patients aged ≤75 years and 20 mg for those >75 years) or lenalidomide and dexamethasone alone. The primary endpoint was progression-free survival, defined as the time from randomisation to disease progression or death from any cause, whichever occurred first, assessed by an independent review committee in the full analysis set (all randomly assigned patients who received at least one dose of study treatment). Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov (NCT03952091) and is closed to enrolment. FINDINGS: Between March 27, 2019, and Oct 20, 2021, 390 patients were assessed for eligibility, 295 of whom were enrolled and randomly assigned to felzartamab plus lenalidomide-dexamethasone (n=195) or lenalidomide-dexamethasone (n=100). The full analysis set included 289 patients (191 in the felzartamab plus lenalidomide-dexamethasone group and 98 in the lenalidomide-dexamethasone group). 185 (64%) of 289 patients were male, 104 (36%) were female, and all were of Asian ethnicity. At a median follow-up of 34·5 months (IQR 16·8-40·2) in the felzartamab plus lenalidomide-dexamethasone group and 28·7 months (10·8-38·8) in the lenalidomide-dexamethasone group, median progression-free survival was 18·9 months (95% CI 13·6-24·0) with felzartamab plus lenalidomide-dexamethasone versus 10·4 months (5·8-13·9) with lenalidomide-dexamethasone (hazard ratio 0·62 [95% CI 0·45-0·86]; p=0·0035). The most common grade 3-4 adverse events were neutropenia (105 [55%] of 192 vs 22 [23%] of 97), lymphopenia (79 [41%] vs 15 [15%]), leukopenia (74 [39%] vs 11 [11%]), thrombocytopenia (49 [26%] vs 11 [11%]), pneumonia (44 [23%] vs 13 [13%]), anaemia (33 [17%] vs 19 [20%]), hypokalaemia (30 [16%] vs ten [10%]), and upper respiratory tract infection (15 [8%] vs two [2%]). The most common serious adverse event was pneumonia (42 [22%] vs ten [10%]). Treatment-related deaths occurred in 11 (6%) of 192 patients in the felzartamab plus lenalidomide-dexamethasone group (five of unknown cause [possibly related to treatment], two due to pneumonia, one due to febrile infection, one due to cardiac arrest, one due to cerebral infarction, and one due to pneumonitis) and two (2%) of 97 patients in the lenalidomide-dexamethasone group (one due to pneumonia and one due to a fall]). INTERPRETATION: Felzartamab plus lenalidomide-dexamethasone significantly prolonged progression-free survival compared with lenalidomide-dexamethasone alone, supporting felzartamab plus lenalidomide-dexamethasone as a potential new treatment option for Chinese patients with relapsed or refractory multiple myeloma. FUNDING: TJ Biopharma.