Induction therapy with bortezomib, melphalan, and prednisone followed by lenalidomide and dexamethasone versus carfilzomib, lenalidomide, and dexamethasone with or without daratumumab in older, fit patients with newly diagnosed multiple myeloma (GEM-2017FIT): a phase 3, open-label, multicentre, randomised clinical trial.

However, the high risk of toxic effects in this population requires frailty-based therapy adaptation.

然而，这一人群高风险的毒性效应需要基于脆弱性的治疗适应。

We aimed to compare the response of carfilzomib-based triplet and quadruplet regimens with a VMP-Rd regimen in newly diagnosed transplant-ineligible patients with multiple myeloma, considering patient frailty.

我们旨在比较卡非佐米为基础的三药和四药方案与VMP-Rd方案在新诊断的不适合移植的多发性骨髓瘤患者中的疗效，同时考虑患者的脆弱性。

Methods

GEM-2017FIT was an open-label, randomised, phase 3 trial at 57 hospitals in Spain.

GEM-2017FIT是一项在西班牙57家医院进行的开放标签、随机、III期临床试验。

Patients aged 65-80 years were enrolled and assessed for frailty using the Geriatric Assessment in Hematology (GAH) scale.

招募了年龄在65至80岁之间的患者，并使用血液学老年评估（GAH）量表评估其虚弱状况。

Patients were randomly assigned (1:1:1) to receive 18-cycle induction therapy of VMP 9-Rd 9 (one six-week cycle of melphalan 9 mg/m2 and prednisone 60 mg/m2 on days 1-4; bortezomib 1·3 mg/m2 subcutaneous twice weekly, followed by eight four-week cycles of weekly VMP and nine four-week cycles of lenalidomide 25 mg on days 1-21 and dexamethasone 40 mg weekly), carfilzomib-based triplet (KRd; carfilzomib intravenously 20 mg/m2 [only in the infusion on day 1 in first cycle] or 36 mg/m2 on days 1, 2, 8, 9, 15, and 16 in cycles 1-2, 56 mg/m2 in cycles 3-18, plus Rd) or daratumumab-KRd (D-KRd; daratumumab 16 mg/kg intravenous weekly [cycles 1-2], biweekly [cycles 3-6], and every 4 weeks [cycles 7-18]).

患者被随机分配（1:1:1）接受18个周期的诱导治疗，包括VMP 9-Rd 9方案（一个六周周期，其中美法兰9 mg/m²和泼尼松60 mg/m²在第1-4天使用；硼替佐米1·3 mg/m²皮下注射，每周两次，随后是八个四周周期的每周VMP和九个四周周期的来那度胺25 mg在第1-21天使用以及地塞米松每周一次），卡非佐米布三联疗法（KRd；卡非佐米布静脉注射，在第一周期的第1天为20 mg/m²，或在第1-2周期的第1、2、8、9、15和16天为36 mg/m²，在第3-18周期为56 mg/m²，加上Rd）或达雷妥尤单抗-KRd（D-KRd；达雷妥尤单抗16 mg/kg静脉注射，第1-2周期每周一次，第3-6周期每两周一次，第7-18周期每四周一次）。

All patients who completed induction therapy and consolidation were stratified by measurable residual disease status and both those with undetectable measurable residual disease and detectable measurable residual disease were subsequently randomly assigned (1:1) to maintenance therapy with daratumumab and lenalidomide or no maintenance therapy.

所有完成诱导治疗和巩固治疗的患者根据可测量的残余疾病状态进行分层，随后将那些可测量的残余疾病无法检测到和可检测到的患者随机分配（1:1）接受达雷妥尤单抗和雷莫芦单抗的维持治疗或不接受维持治疗。

The primary endpoint was measurable residual disease negativity after induction, which was assessed in the intention-to-treatpopulation.

主要终点是诱导治疗后可测量残余疾病的阴性状态，该状态在意向治疗人群中进行了评估。

The trial is registered with ClinicalTrials.gov, NCT03742297.

该试验已在ClinicalTrials.gov注册，注册号为NCT03742297。

Results

Between October 15, 2018 and December 15, 2021, 540 patients were enrolled and assessed for eligibility. 462 were eligible for the study and randomly assigned to VMP 9-Rd 9 (n=154), KRd (n=154) or D-KRd (n=154, with one patient subsequently found to be ineligible). 230 (50%) of 461 patients were male and 231 (50%) were female.

在2018年10月15日至2021年12月15日期间，共有540名患者被纳入并评估其资格。其中462名患者符合研究条件，并被随机分配到VMP 9-Rd 9组（n=154），KRd组（n=154）或D-KRd组（n=154，其中一名患者后来被发现不符合条件）。在461名患者中，有230名（50%）为男性，231名（50%）为女性。

Patients were followed up for a median of 33·15 months (IQR 25·82-43·08).

患者的中位随访时间为33.15个月（四分位数间距25.82-43.08）。

The 18-cycle undetectable measurable residual disease rate with a sensitivity level of 10-5 in the intention-to-treatpopulation was higher in the KRd group (83 [54%] of 154 patients; odds ratio [OR] 1·73, 95% CI 1·39-2·16; p<0·0001) and D-KRd group (94 [61%] of 153 patients; 2·03, 1·61-2·57; p<0·0001) than in the VMP 9-Rd 9 group (41 [27%] of 154 patients).

在意向治疗人群中，18个周期内可检测到的最小残留病灶率为10^-5的患者中，KRd组（154名患者中有83名，即54%；比值比[OR]为1.73，95%置信区间为1.39-2.16；p<0.0001）和D-KRd组（153名患者中有94名，即61%；OR为2.03，95%置信区间为1.61-2.57；p<0.0001）的无病生存率均高于VMP 9-Rd 9组（154名患者中有41名，即27%）。

The incidenceof grade 3-4 neutropenia was lower in the KRd group (37 [24%] of 154 patients) compared with the VMP 9-Rd 9 group (62 [40%] of 154 patients) and D-KRd group (63 [41%] of 153 patients).

KRd组中3-4级中性粒细胞减少症的发生率为24%（154名患者中有37名），而VMP 9-Rd 9组为40%（154名患者中有62名），D-KRd组为41%（153名患者中有63名）。

Grade 3-4 infections occurred in 19 (12%) patients in the VMP 9-Rd 9 group, 23 (15%) patients in the KRd group, and 25 (16%) patients in the D-KRd group.

VMP 9-Rd 9组中3-4级感染的发生率为12%（19名患者），KRd组为15%（23名患者），D-KRd组为16%（25名患者）。

Toxicity-related death occurred in a similar frequency in the VMP 9-Rd 9 (seven [5%] patients) and KRd (five [3%] patients) groups, but was significantly higher in the D-KRd group (13 [8%] patients; OR 0·53, 95% CI 0·22-1·30; p=0·16).

毒性相关死亡在VMP 9-Rd 9组（七名[5%]患者）和KRd组（五名[3%]患者）中发生频率相似，但在D-KRd组中显著更高（13名[8%]患者；OR 0·53，95% 置信区间 0·22-1·30；p=0·16）。

interpretation

KRd and D-KRd were superior to VMP 9-Rd 9 in achieving measurable residual disease negativity after 18 cycles.

KRd和D-KRd在18个周期后实现可测量的残余疾病阴性方面优于VMP 9-Rd 9。

This study could contribute to incorporation of quadruplet therapy into clinical practice and supports the need for frailty-based assessment in therapy selection.

本研究可能有助于将四联疗法纳入临床实践，并支持在选择治疗时需要基于虚弱状况的评估。

funding

PETHEMA.

PETHEMA.