2017-06-09 00:00:00来源：医脉通阅读：16次
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2017年6月2-6日，一年一度的美国临床肿瘤学会（ASCO）年会已在芝加哥举办。当地时间6月3日下午的非霍奇金淋巴瘤专场上，研究人员报道了一项摘要号为8000的1b期试验结果。该研究中，daratumumab联合卡非佐米、来那度胺和地塞米松（KRd）可作为初治多发性骨髓瘤患者自体干细胞移植（ASCT）联合KRd一种合理的替代方案，也可用于诱导方案中，并且未对干细胞采集产生不利影响。
来自芝加哥大学医学中心的Andrzej J. Jakubowiak教授表示，Daratumumab+ KRd耐受性很好，安全事件与之前报道一致。首次剂量分开给药有利于降低输液反应发生率。
Daratumumab+ KRd在该研究中表现出的总反应率（ORR）为100%。
目前，多发性骨髓瘤的标准治疗方案为蛋白酶体抑制剂和/或免疫调节制剂联合或不联合干细胞移植。
Jakubowiak教授指出。该三联方案在初治MM患者中表现出极高的疗效，并且干细胞移植的加入看似改善了KRd治疗后的结局。
Daratumumab是一种人免疫球蛋白G1κCD38单克隆抗体，可通过免疫调节作用直接和间接地靶向CD38，与硼替佐米或来那度胺联合应用时，可产生“快速、深入且持久的反应”。目前，该联合方案已被批准成为既往至少经一种方案治疗后的复发/难治性MM患者的标注治疗方案。
不考虑是否具有移植资格，该开放性、多中心1b研究共纳入22例患者，有心血管疾病的患者不符合纳入标准。
在为期28天的治疗周期内，受试者接受了分剂量的daratumumab（第1个周期，第1、2天，8 mg/kg；第1、2个周期，16 mg/kg ，每周一次；第3~6个周期，每2周一次；之后每4周一次）， 20-mg/m2卡非佐米， 25-mg来那度胺（每个周期的第1~21天）以及40mg地塞米松，每周一次。第1、8和15天，卡非佐米剂量从20 mg/m2增加至70 mg/m2。患者治疗至选择是否进一步进行ASCT。所有患者均接受阿司匹林预防治疗。
大多数患者为男性（68%），ECOG评分为0（55%）或1（41%），白种人居多（86%）。主要研究终点为安全性和耐受性，次要终点为ORR。
中位随访期为10.8个月。8（36%）例患者停止治疗：1例疾病进展，1例不良事件，6例进行ASCT。
最常见的血液学不良反应为淋巴细胞减少（所有级别68%；3 / 4级64%）、血小板减少（55%；9%）、贫血（46%；9%）、白细胞减少症（41%；9%）和中性粒细胞减少（32%；14%）。另外常见的不良反应还有腹泻（73%；14%）、上呼吸道感染（59%；0%）、咳嗽（55%；5%）、便秘（50%；0%）、疲劳（50%；0%）、呼吸困难（46%，；0%）和失眠（46%；5%）。
10/22例（46%）患者发生了严重的治疗相关不良事件，包括肺栓塞（3例）、发热（2例）、病毒性流感（2例）和心脏毒性（心动过速、充血性心力衰竭和高血压各1例）。1例患者因daratumumab或卡非佐米无关性肺栓塞中止治疗。
27%的患者发生了与输液相关反应，包括咳嗽、咽喉炎、恶心和头痛。无3或4级不良反应发生。随访12个月，中位无进展生存率为94%，总生存率为100%。
摘要原文
Daratumumab (DARA) in combination with carfilzomib, lenalidomide, and dexamethasone (KRd) in patients (pts) with newly diagnosed multiple myeloma (MMY1001): An open-label, phase 1b study.
Background: DARA in combination with established standard of care regimens prolongs PFS, deepens responses, and demonstrates a favorable safety profile in relapsed or refractory multiple myeloma (MM). The tolerability and efficacy of DARA-KRd in newly diagnosed MM pts was examined.
Methods: Newly diagnosed pts regardless of transplantation eligibility were enrolled. Pts received DARA 16 mg/kg QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W thereafter. All pts received the 1st dose of DARA split over 2 days. Carfilzomib (K) was administered on Days 1, 8 and 15 of each 28-day cycle (20 mg/m2 on C1D1, 36 or 70 mg/m2 subsequently based on tolerability of first dose) for ≤13 cycles or elective discontinuation for ASCT. Lenalidomide 25 mg was given on Days 1-21 and dexamethasone 20-40 mg per week. The primary endpoint was tolerability.
Results: Twenty-two pts (median [range] age, 60 [34-74] y) were enrolled and received a median of 8 (1-10) treatment cycles. Nineteen pts escalated K dose to 70 mg/m2 by C1D15. Median (range) duration of follow-up was 7.4 (4.0-9.3) months. Six (27%) pts discontinued treatment (1 AE [pulmonary embolism]; 1 PD; 4 other [ASCT]). Serious AEs occurred in 46% of pts, and 14% were possibly related to DARA; 18 (82%) experienced a grade 3/4 TEAE. The most common grade 3/4 TEAEs (>10%) were lymphopenia (50%) and neutropenia (23%); 1 (5%) cardiac grade 3 TEAE was observed (congestive heart failure) which resolved; pt quickly resumed study treatment with reduced K dose. No grade 5 TEAE was reported. All DARA-associated infusion reactions (27% of pts) were grade ≤2. Treatment with DARA-KRd yielded an ORR (≥partial response) of 100% (5% complete response, 86% ≥very good partial response) in 21 response-evaluable pts. The 6-month PFS rate was 100%.
Conclusions: The addition of DARA to KRd was well tolerated; the overall safety profile was consistent with that previously reported for KRd, with no additional toxicity observed with the addition of DARA. Deep and durable responses were observed. These data support further investigation of DARA-KRd as a frontline treatment regimen. Updated data will be presented based on longer follow up. Clinical trial information: NCT01998971
医脉通编译自：Daratumumab Plus Standard of Care Well Tolerated in Multiple Myeloma.CancerNetwork.2017