Levine Cancer Institute, Atrium Health Wake Forest University School of Medicine, Charlotte, NC, USA.
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Lancet Haematol. 2023 Oct;10(10):e825-e837. doi: 10.1016/S2352-3026(23)00217-X. Epub 2023 Sep 11.
BACKGROUND: Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone (D-RVd) in the GRIFFIN study improved the stringent complete response rate by the end of consolidation in transplantation-eligible patients with newly diagnosed multiple myeloma. Here, we report the findings of the predefined final analysis. METHODS: GRIFFIN was an open-label, randomised, active-controlled, phase 2 trial done in 35 research centres in the USA. Patients had newly diagnosed multiple myeloma with measurable disease by M protein or free light chain, were aged 18-70 years, had an ECOG performance score of 0-2, and were eligible for autologous haematopoietic stem-cell transplantation (HSCT). Patients were randomly assigned (1:1) to four D-RVd or RVd induction cycles, autologous HSCT, two D-RVd or RVd consolidation cycles, and lenalidomide with or without daratumumab maintenance therapy for 2 years. Patients received 21-day cycles of oral lenalidomide (25 mg on days 1-14), subcutaneous bortezomib (1·3 mg/m on days 1, 4, 8, and 11), oral dexamethasone (40 mg weekly) with or without intravenous daratumumab (16 mg/kg weekly, cycles 1-4; day 1, cycles 5-6). Maintenance therapy (28-day cycles) was oral lenalidomide (10 mg on days 1-21) with or without daratumumab (16 mg/kg intravenously every 4 or 8 weeks, or 1800 mg subcutaneously monthly). Patients could continue lenalidomide maintenance after study treatment completion. The primary endpoint was stringent complete response rate by the end of consolidation in the response-evaluable population, and has already been reported. Here we report updated stringent complete response rates and secondary outcomes including progression-free survival and overall survival. The trial is registered with ClinicalTrials.gov (NCT02874742) and ended on April 8, 2022. FINDINGS: Between Dec 20, 2016, and April 10, 2018, 104 patients were randomly assigned to the D-RVd group and 103 were randomly assigned to the RVd group; most patients were White (85 [82%] in the D-RVd group and 76 [74%] in the RVd group) and male (58 [56%] in the D-RVd group and 60 [58%] in the RVd group). At a median follow-up of 49·6 months (IQR 47·4-52·1), D-RVd improved rates of stringent complete response (67 [67%] of 100] vs 47 [48%] of 98]; odds ratio 2·18 [95% CI 1·22-3·89], p=0·0079), and 4-year progression-free survival was 87·2% (95% CI 77·9-92·8) for D-RVd versus 70·0% (95% CI 55·9-80·3) for RVd, with a hazard ratio (HR) of 0·45 (95% CI 0·21-0·95, p=0·032) for risk of disease progression or death with D-RVd. Median overall survival was not reached for either group (HR 0·90 [95% CI 0·31-2·56], p=0·84). The most common grade 3-4 treatment-emergent adverse events in the D-RVd versus RVd groups were neutropenia (46 [46%] of 99 vs 23 [23%] of 102), lymphopenia (23 [23%] vs 23 [23%]), leukopenia (17 [17%] vs eight [8%]), thrombocytopenia (16 [16%] vs nine [9%]), pneumonia (12 [12%] vs 14 [14%]), and hypophosphataemia (ten [10%] vs 11 [11%]). Serious treatment-emergent adverse events occurred in 46 (46%) of 99 patients in the D-RVd group and in 53 (52%) of 102 patients in the RVd group. One patient in each treatment group reported a treatment-emergent adverse event that resulted in death (bronchopneumonia in the D-RVd group; cause unknown in the RVd group); neither was related to study treatment. No new safety concerns occurred with maintenance therapy. INTERPRETATION: Addition of daratumumab to RVd improved the depth of response and progression-free survival in transplantation-eligible patients with newly diagnosed multiple myeloma. These results justify further evaluation in phase 3 studies. FUNDING: Janssen Oncology.
背景：在适合移植的新诊断多发性骨髓瘤患者中，GRIFFIN 研究中将达雷妥尤单抗与来那度胺、硼替佐米和地塞米松（D-RVd）联合使用，在巩固治疗结束时可提高严格完全缓解率。在此，我们报告了预先设定的最终分析结果。
方法：GRIFFIN 是一项在美国 35 个研究中心进行的开放性、随机、主动对照、2 期临床试验。患者患有有可测量疾病的新诊断多发性骨髓瘤，通过 M 蛋白或游离轻链检测，年龄 18-70 岁，ECOG 表现评分为 0-2，适合自体造血干细胞移植（HSCT）。患者被随机分配（1:1）接受 4 个 D-RVd 或 RVd 诱导周期、自体 HSCT、2 个 D-RVd 或 RVd 巩固周期，以及来那度胺联合或不联合达雷妥尤单抗维持治疗 2 年。患者接受 21 天周期的口服来那度胺（第 1-14 天每天 25 mg）、皮下硼替佐米（第 1、4、8 和 11 天 1.3 mg/m）、每周口服地塞米松（40 mg），联合或不联合达雷妥尤单抗（第 1-4 周期 16 mg/kg 每周；第 5-6 周期每天 1 次）。维持治疗（28 天周期）为口服来那度胺（第 1-21 天每天 10 mg）联合或不联合达雷妥尤单抗（静脉内 16 mg/kg 每 4 或 8 周 1 次，或皮下每月 1800 mg）。患者可在研究治疗完成后继续来那度胺维持治疗。主要终点是在可评估反应人群中巩固治疗结束时的严格完全缓解率，该结果已报告。在此，我们报告更新的严格完全缓解率和次要结局，包括无进展生存期和总生存期。该试验在 ClinicalTrials.gov （NCT02874742）注册，于 2022 年 4 月 8 日结束。
结果：2016 年 12 月 20 日至 2018 年 4 月 10 日期间，104 名患者被随机分配到 D-RVd 组，103 名患者被随机分配到 RVd 组；大多数患者为白人（D-RVd 组 85 [82%]，RVd 组 76 [74%]）和男性（D-RVd 组 58 [56%]，RVd 组 60 [58%]）。中位随访 49.6 个月（IQR 47.4-52.1）时，D-RVd 提高了严格完全缓解率（67 [67%]例 100 例；57 [48%]例 98 例），优势比 2.18（95%CI 1.22-3.89），p=0.0079），D-RVd 组的 4 年无进展生存期为 87.2%（95%CI 77.9-92.8），而 RVd 组为 70.0%（95%CI 55.9-80.3），D-RVd 组的疾病进展或死亡风险比为 0.45（95%CI 0.21-0.95，p=0.032）。两组的中位总生存期均未达到（HR 0.90 [95%CI 0.31-2.56]，p=0.84）。D-RVd 组与 RVd 组最常见的 3-4 级治疗相关不良事件为中性粒细胞减少症（46 [46%]例 99 例；23 [23%]例 102 例）、淋巴细胞减少症（23 [23%]例 102 例；23 [23%]例 102 例）、白细胞减少症（17 [17%]例 99 例；8 [8%]例 102 例）、血小板减少症（16 [16%]例 99 例；9 [9%]例 102 例）、肺炎（12 [12%]例 99 例；14 [14%]例 102 例）和低磷血症（10 [10%]例 99 例；11 [11%]例 102 例）。D-RVd 组 99 例患者中有 46 例（46%）和 RVd 组 102 例患者中有 53 例（52%）发生严重治疗相关不良事件。两组各有 1 例患者发生治疗相关不良事件导致死亡（D-RVd 组为支气管肺炎；RVd 组病因不明）；均与研究治疗无关。维持治疗没有出现新的安全问题。
结论：在适合移植的新诊断多发性骨髓瘤患者中，RVd 联合达雷妥尤单抗可提高严格完全缓解率和无进展生存期。这些结果证明了在 3 期研究中进一步评估的合理性。
资助：杨森制药。
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