Carfilzomib-lenalidomide-dexamethasone versus lenalidomide-dexamethasone in patients with newly diagnosed myeloma ineligible for autologous stem-cell transplantation (EMN20): a randomised, open-label, multicentre, phase 3 trial.

We aimed to explore whether addition of the second-generation proteasome inhibitor carfilzomib to lenalidomide-dexamethasone improved the rates of measurable residual disease (MRD) negativity and progression-free survival.

我们旨在探讨将第二代蛋白酶体抑制剂卡非佐米加入雷尼替丁-地塞米松是否提高了可测量的残留疾病（MRD）阴性率和无进展生存率。

Methods

EMN20 is a randomised, open-label, multicentre, phase 3 trial comparing weekly carfilzomib-lenalidomide-dexamethasone versus lenalidomide-dexamethasone in patients with newly diagnosed transplant-ineligible multiple myeloma, conducted in 27 centres in Italy.

EMN20 是一项随机、开放标签、多中心、III 期试验，比较了每周卡非佐米-雷尼替丁-地塞米松与雷尼替丁-地塞米松在新诊断的、不适合移植的多发性骨髓瘤患者中的效果，该试验在意大利的 27 个中心进行。

Key inclusion criteria included fit or intermediate-fit status according to the International Myeloma Working Group (IMWG) frailty score, measurable disease according to IMWG criteria, and Eastern Cooperative Oncology Group performance status lower than 3.

主要纳入标准包括根据国际骨髓瘤工作组（IMWG）脆弱性评分的健康或中等健康状态，根据 IMWG 标准可测量的疾病，以及东部肿瘤协作组（ECOG）表现状态低于 3。

Patients randomly assigned to the carfilzomib-lenalidomide-dexamethasone group received 28-day carfilzomib-lenalidomide-dexamethasone cycles (carfilzomib 20 mg/m2 intravenously on day 1 for cycle 1, followed by 56 mg/m2 intravenously on days 8 and 15 for cycle 1, then 56 mg/m2 intravenously on days 1, 8, and 15 for cycles 2-12, and 56 mg/m2 intravenously on days 1 and 15 from cycle 13 until 5 years after randomisation; lenalidomide 25 mg orally on days 1-21 until disease progression or intolerance; dexamethasone 40 mg orally on days 1, 8, 15, and 22 until disease progression or intolerance).

被随机分配到卡非佐米-雷尼替丁-地塞米松组的患者接受了28天的卡非佐米-雷尼替丁-地塞米松周期治疗（第1个周期的第1天静脉注射20 mg/m2的卡非佐米，随后第1个周期的第8天和第15天静脉注射56 mg/m2的卡非佐米，然后从第2个周期到第12个周期的第1天、第8天和第15天静脉注射56 mg/m2的卡非佐米，从第13个周期开始直到随机分配后5年，第1天和第15天静脉注射56 mg/m2的卡非佐米；雷尼替丁25 mg口服，第1天至第21天，直到疾病进展或无法耐受；地塞米松40 mg口服，第1天、第8天、第15天和第22天，直到疾病进展或无法耐受）。

Patients assigned to the lenalidomide-dexamethasone group received 28-day cycles with lenalidomide-dexamethasone (same dosing and schedule used in the carfilzomib-lenalidomide-dexamethasone group).

被分配到雷尼替丁-地塞米松组的患者接受了28天的雷尼替丁-地塞米松周期治疗（使用与卡非佐米-雷尼替丁-地塞米松组相同的剂量和方案）。

Primary endpoints were MRD negativity by next-generation sequencing (sensitivity 10-5) after 2 years of treatment and progression-free survival; and were assessed in the intention-to-treat(ITT) population (all patients who were eligible to receive treatment and who were randomly assigned to one of the treatment groups).

主要终点是在治疗2年后通过下一代测序（灵敏度为10^-5）实现的微小残留病灶（MRD）阴性以及无进展生存期；这些终点在意向治疗（ITT）人群中进行了评估（所有有资格接受治疗并被随机分配到任一治疗组的患者）。

On Nov 23, 2021, after enrolling 30% of planned patients (101/340), the trial was prematurely stopped due to the introduction of daratumumab-lenalidomide-dexamethasone as a first-line treatment in Italy, which caused the lenalidomide-dexamethasone control group to no longer be considered a standard treatment.

2021年11月23日，在计划招募的患者中完成了30%（101/340）后，由于意大利将达雷妥尤单抗-雷莫芦单抗-地塞米松作为一线治疗引入，导致雷莫芦单抗-地塞米松对照组不再被认为是标准治疗，因此该试验被提前终止。

This trial is registered with ClinicalTrials.gov, NCT04096066, and study recruitment is complete.

该试验已在ClinicalTrials.gov注册，编号为NCT04096066，研究招募已经完成。

Results

Between Nov 14, 2019, and Nov 23, 2021, 82 of 101 enrolled patients were assessed for eligibility and were randomised to receive carfilzomib-lenalidomide-dexamethasone (n=42) or lenalidomide-dexamethasone (n=40).

在2019年11月14日至2021年11月23日期间，共有101名入组患者中有82名被评估为符合资格并被随机分配接受卡非佐米-雷那度胺-地塞米松(n=42)或雷那度胺-地塞米松(n=40)治疗。

In the ITT population, 35 (43%) of 82 patients were female and 47 (57%) were male.

在意向性治疗人群中，82名患者中有35名（43%）为女性，47名（57%）为男性。

At data cutoff (March 29, 2024), the median follow-up was 35·2 months (IQR 30·3-38·7).

在数据截止日期（2024年3月29日），中位随访时间为35.2个月（四分位数间距30.3-38.7）。

The 2-year MRD negativity rates were 25 (60% 95% CI 43-74) of 42 patients with carfilzomib-lenalidomide-dexamethasone versus 0 (0%; 0-9) of 40 patients with lenalidomide-dexamethasone (p<0·0001).

两年微小残留病灶阴性率在使用卡非佐米-雷尼替丁-地塞米松的42名患者中为25例（60%，95%置信区间43-74），而在使用雷尼替丁-地塞米松的40名患者中为0例（0%；0-9）（p<0.0001）。

Median progression-free survivalwas not reached (not reached-not reached) with carfilzomib-lenalidomide-dexamethasone versus 20·9 months (15·7-not reached) with lenalidomide-dexamethasone (hazard ratio0·24 [95% CI 0·11-0·56], p=0·00084).

使用卡非佐米-雷尼替丁-地塞米松的中位无进展生存期未达到（未达到-未达到），而使用雷尼替丁-地塞米松的中位无进展生存期为20.9个月（15.7-未达到）（风险比0.24 [95%置信区间0.11-0.56]，p=0.00084）。

One patient was excluded from the safety analysis because they died before starting treatment.

一名患者因在开始治疗前死亡而被排除在安全性分析之外。

The most frequent grade 3 or worse adverse events were neutropenia (nine [22%] of 41 patients), thrombocytopenia (four [10%]), diarrhoea (four [10%]), cardiac events (three [7%]), infections (three [7%]), and arterial hypertension (two [5%]) with carfilzomib-lenalidomide-dexamethasone, and neutropenia (six [15%] of 40) and skin rash (four [10%]) with lenalidomide-dexamethasone.

最常见的3级或更严重的不良事件是中性粒细胞减少症（41名患者中有9名[22%]），血小板减少症（4名[10%]），腹泻（4名[10%]），心脏事件（3名[7%]），感染（3名[7%]）和动脉高血压（2名[5%]），这些都发生在使用卡非佐米-雷尼替丁-地塞米松的患者中，以及中性粒细胞减少症（40名患者中有6名[15%]）和皮疹（4名[10%]），这些都发生在使用雷尼替丁-地塞米松的患者中。

The most common serious adverse eventwas SARS-CoV-2-related pneumonia in both the carfilzomib-lenalidomide-dexamethasone group (two [5%] of 41 patients) and lenalidomide-dexamethasone group (three [7%] of 40 patients).

最常见的严重不良事件是卡非佐米-雷尼替丁-地塞米松组中的SARS-CoV-2相关性肺炎（41名患者中有2名[5%]）和雷尼替丁-地塞米松组中的SARS-CoV-2相关性肺炎（40名患者中有3名[7%]）。

Treatment-emergent adverse events leading to death were observed in two patients in the carfilzomib-lenalidomide-dexamethasone (two SARS-CoV-2 infections) and four patients in the lenalidomide-dexamethasone group (one acute myocardial infraction, one heart failure, one septic shock, and one SARS-CoV-2 infection).

在卡非佐米-雷尼替丁-地塞米松组中，有2名患者因治疗相关的不良事件死亡（2例SARS-CoV-2感染），而在雷尼替丁-地塞米松组中，有4名患者死亡（1例急性心肌梗死，1例心力衰竭，1例脓毒性休克，和1例SARS-CoV-2感染）。

interpretation

With the limitation of a smaller sample size than planned due to the trial's early interruption, these results, to our knowledge, showed for the first-time high rates of MRD negativity with weekly carfilzomib added to lenalidomide-dexamethasone in patients with transplantation-ineligible newly diagnosed multiple myeloma.

由于试验提前中断，样本量小于计划，据我们所知，这些结果首次显示，在不适合移植的新诊断多发性骨髓瘤患者中，每周加入卡非佐米到来那度胺-地塞米松治疗，可获得高比例的微小残留病灶（MRD）阴性。

In the carfilzomib-lenalidomide-dexamethasone group, higher MRD negativity rates were associated with a progression-free survivaladvantage over lenalidomide-dexamethasone.

在卡非佐米-来那度胺-地塞米松组中，更高的MRD阴性率与来那度胺-地塞米松组相比，具有无进展生存优势。

Toxicities were predictable and generally manageable.

毒性是可预测的，通常是可以管理的。

funding

Amgen, Bristol Myers Squibb.

安进公司，百时美施贵宝公司。