Background

In the primary analysis of the phase 3 MAIA trial (median follow-up 28·0 months), a significant improvement in progression-free survival was observed with daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in transplantation-ineligible patients with newly diagnosed multiple myeloma. Here, we report the updated efficacy and safety results from a prespecified interim analysis for overall survival.

Methods

MAIA is an ongoing, multicentre, randomised, open-label, phase 3 trial that enrolled patients at 176 hospitals in 14 countries across North America, Europe, the Middle East, and the Asia-Pacific region. Eligible patients were aged 18 years or older, had newly diagnosed multiple myeloma, had an Eastern Cooperative Oncology Group performance status score of 0–2, and were ineligible for high-dose chemotherapy with autologous stem-cell transplantation because of their age (≥65 years) or comorbidities. Patients were randomly assigned (1:1) using randomly permuted blocks (block size 4) by an interactive web response system to receive 28-day cycles of intravenous daratumumab (16 mg/kg, once per week during cycles 1–2, once every 2 weeks in cycles 3–6, and once every 4 weeks thereafter) plus oral lenalidomide (25 mg on days 1–21 of each cycle) and oral dexamethasone (40 mg on days 1, 8, 15, and 22 of each cycle; daratumumab group) or lenalidomide and dexamethasone alone (control group). Randomisation was stratified by International Staging System disease stage, geographical region, and age. Neither patients nor investigators were masked to treatment assignment. The primary endpoint was progression-free survival, which was centrally assessed, and a secondary endpoint was overall survival (both assessed in the intention-to-treat population). The safety population included patients who received at least one dose of the study treatment. The results presented here are from a prespecified interim analysis for overall survival, for which the prespecified stopping boundary was p=0·0414. This trial is registered with ClinicalTrials.gov, NCT02252172.

Findings

Between March 18, 2015, and Jan 15, 2017, 952 patients were assessed for eligibility, of whom 737 patients were enrolled and randomly assigned to the daratumumab group (n=368) or the control group (n=369). At a median follow-up of 56·2 months (IQR 52·7–59·9), median progression-free survival was not reached (95% CI 54·8–not reached) in the daratumumab group versus 34·4 months (29·6–39·2) in the control group (hazard ratio [HR] 0·53 [95% CI 0·43–0·66]; p<0·0001). Median overall survival was not reached in either group (daratumumab group, 95% CI not reached–not reached; control group, 95% CI 55·7–not reached; HR 0·68 [95% CI 0·53–0·86]; p=0·0013). The most common (>15%) grade 3 or higher treatment-emergent adverse events were neutropenia (197 [54%] patients in the daratumumab group vs 135 [37%] patients in the control group), pneumonia (70 [19%] vs 39 [11%]), anaemia (61 [17%] vs 79 [22%]), and lymphopenia (60 [16%] vs 41 [11%]). Serious adverse events occurred in 281 (77%) patients in the daratumumab group and 257 (70%) patients in the control group. Treatment-related deaths occurred in 13 (4%) patients in the daratumumab group and ten (3%) patients in the control group.

Interpretation

Daratumumab plus lenalidomide and dexamethasone increased overall survival and progression-free survival in patients ineligible for stem-cell transplantation with newly diagnosed multiple myeloma. There were no new safety concerns. Our results support the frontline use of daratumumab plus lenalidomide and dexamethasone for patients with multiple myeloma who are ineligible for transplantation.

Funding

Janssen Research & Development.

中文翻译：

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在新诊断的多发性骨髓瘤 (MAIA) 中，达雷妥尤单抗、来那度胺和地塞米松对比来那度胺和地塞米松单药：一项随机、开放标签、3 期试验的总生存期结果

背景

在 3 期 MAIA 试验（中位随访 28·0 个月）的主要分析中，在不适合移植的新诊断患者中观察到达雷妥尤单抗联合来那度胺和地塞米松与单独来那度胺和地塞米松相比，无进展生存期显着改善多发性骨髓瘤。在这里，我们报告了预先指定的总生存期中期分析的最新疗效和安全性结果。

方法

MAIA 是一项正在进行的、多中心、随机、开放标签的 3 期试验，在北美、欧洲、中东和亚太地区的 14 个国家的 176 家医院招募了患者。符合条件的患者年龄在 18 岁或以上，新诊断出多发性骨髓瘤，东部肿瘤协作组体能状态评分为 0-2，由于年龄（≥65年）或合并症。通过交互式网络响应系统使用随机排列的块（块大小 4）随机分配（1:1）患者接受 28 天周期的静脉注射达雷妥尤单抗（16 mg/kg，在周期 1-2 期间每周一次，每个周期一次）第 3-6 周期中的 2 周，此后每 4 周一次）加口服来那度胺（每个周期的第 1-21 天 25 毫克）和口服地塞米松（每个周期的第 1、8、15 和 22 天，40 毫克；达雷妥尤单抗组）或来那度胺和地塞米松单药（控制组）。随机化按国际分期系统疾病分期、地理区域和年龄进行分层。患者和研究人员都不知道治疗分配。主要终点是集中评估的无进展生存期，次要终点是总生存期（均在意向治疗人群中评估）。安全人群包括接受至少一剂研究治疗的患者。此处显示的结果来自预先指定的总生存期中期分析，其中预先指定的停止边界为 p=0·0414。

发现

2015 年 3 月 18 日至 2017 年 1 月 15 日期间，对 952 名患者进行了资格评估，其中 737 名患者被纳入并随机分配到达雷妥尤单抗组（n=368）或对照组（n=369）。在中位随访 56·2 个月（IQR 52·7–59·9）时，达雷妥尤单抗组与 34·4 个月相比，未达到中位无进展生存期（95% CI 54·8-未达到） (29·6–39·2) 在对照组中（风险比 [HR] 0·53 [95% CI 0·43-0·66]；p<0·0001）。两组均未达到中位总生存期（达雷妥尤单抗组，95% CI 未达到-未达到；对照组，95% CI 55·7-未达到；HR 0·68 [95% CI 0·53-0·86 ]；p=0·0013)。最常见 (>15%) 3 级或更高级别的治疗出现的不良事件是中性粒细胞减少症（达雷妥尤单抗组与对照组 135 [37%] 名患者）、肺炎（70 [19%]对39 [11%]）、贫血（61 [17%]对79 [22%]）和淋巴细胞减少（60 [16%]）对比41 [11%]）。达雷妥尤单抗组 281 名 (77%) 患者和对照组 257 名 (70%) 患者发生严重不良事件。达雷妥尤单抗组 13 名 (4%) 患者和对照组 10 名 (3%) 患者发生治疗相关死亡。

解释

达雷妥尤单抗联合来那度胺和地塞米松可提高不适合干细胞移植的新诊断多发性骨髓瘤患者的总生存期和无进展生存期。没有新的安全问题。我们的结果支持在一线使用达雷妥尤单抗加来那度胺和地塞米松治疗不适合移植的多发性骨髓瘤患者。

资金

杨森研发。