Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Myeloma Program, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida.
JAMA Oncol. 2021 Jun 1;7(6):862-868. doi: 10.1001/jamaoncol.2021.0611.
Recently, the benefit of adding daratumumab to the proteasome inhibitor-based, 3-drug combination of bortezomib, lenalidomide, and dexamethasone for patients with newly diagnosed multiple myeloma who underwent high-dose melphalan chemotherapy and autologous hemopoietic cell transplant was assessed. Here, we examine the addition of daratumumab to the second-generation proteasome inhibitor-based, 3-drug combination of carfilzomib, lenalidomide, and dexamethasone.
To assess the safety and effectiveness of carfilzomib-lenalidomide-dexamethasone-daratumumab combination therapy for patients with newly diagnosed multiple myeloma, in the absence of high-dose melphalan chemotherapy and autologous hemopoietic cell transplant.
DESIGN, SETTING, AND PARTICIPANTS: Clinical and correlative pilot study at the Memorial Sloan Kettering Cancer Center in New York, New York. Patients with newly diagnosed multiple myeloma were enrolled between October 1, 2018, and November 15, 2019. The median follow-up from start of treatment was 20.3 months (95% CI, 19.2-21.9 months).
Eight 28-day cycles with intravenous carfilzomib, 20/56 mg/m2 (days 1, 8, and 15); oral lenalidomide, 25 mg, (days 1-21); dexamethasone, 40 mg weekly, orally or intravenously (cycles 1-4), and 20 mg after cycle 4; and intravenous daratumumab, 16 mg/kg (days 1, 8, 15, and 22 [cycles 1-2]; days 1 and 15 [cycles 3-6]; and day 1 [cycles 7 and 8]).
The primary end point was the minimal residual disease (MRD) rate, in the absence of high-dose melphalan chemotherapy and autologous hemopoietic cell transplant. Secondary end points included determining safety and tolerability, evaluating rates of clinical response per the International Myeloma Working Group, and estimating progression-free survival (PFS) and overall survival (OS) rates.
Forty-one evaluable patients were enrolled (median age, 59 years; range, 30-70 years); 25 (61%) were female, and 20 (49%) had high-risk multiple myeloma. The primary end point (MRD negativity in the bone marrow; 10-5 sensitivity) was achieved in 29 of 41 patients (71%; 95% CI, 54%-83%), and therefore the trial was deemed successful. Median time to MRD negativity was 6 cycles (range, 1-8 cycles). Secondary end points of the overall response rate and the very good partial response or complete response rate were 100% (41 of 41 patients) and 95% (39 of 41 patients), respectively. At 11 months of the median follow-up, the 1-year PFS rate and the OS rate were 98% (95% CI, 93%-100%) and 100%, respectively. Most common (≥2 patients) grade 3 or 4 adverse events were neutropenia (12 patients [27%]), rash (4 patients [9%]), lung infection (3 patients [7%]), and increased alanine aminotransferase level (2 patients [4%]). There were no deaths.
In this nonrandomized clinical trial, carfilzomib-lenalidomide-dexamethasone-daratumumab combination therapy was associated with high rates of MRD negativity in patients with newly diagnosed multiple myeloma and high rates of PFS.
重要性：最近，评估了在接受高剂量美法仑化疗和自体造血细胞移植的新诊断多发性骨髓瘤患者中，在蛋白酶体抑制剂基础上的 3 药联合硼替佐米、来那度胺和地塞米松的基础上添加达雷妥尤单抗的获益。在此，我们检查了在第二代蛋白酶体抑制剂卡非佐米、来那度胺和地塞米松的基础上添加达雷妥尤单抗的 3 药联合。
目的：评估卡非佐米-来那度胺-地塞米松-达雷妥尤单抗联合治疗新诊断多发性骨髓瘤患者的安全性和有效性，不进行高剂量美法仑化疗和自体造血细胞移植。
设计、地点和参与者：在纽约州纽约市纪念斯隆凯特琳癌症中心进行的临床和相关试点研究。2018 年 10 月 1 日至 2019 年 11 月 15 日期间招募了新诊断为多发性骨髓瘤的患者。从开始治疗到中位随访 20.3 个月（95%CI，19.2-21.9 个月）。
干预措施：8 个 28 天周期的静脉注射卡非佐米，20/56mg/m2（第 1、8 和 15 天）；口服来那度胺，25mg（第 1-21 天）；地塞米松，40mg 每周，口服或静脉内（第 1-4 周期），第 4 周期后 20mg；静脉注射达雷妥尤单抗，16mg/kg（第 1、8、15 和 22 天[第 1-2 周期]；第 3-6 周期第 1 和 15 天；第 7 和 8 周期第 1 天）。
主要终点和措施：主要终点是在不进行高剂量美法仑化疗和自体造血细胞移植的情况下，微小残留疾病（MRD）率。次要终点包括确定安全性和耐受性，评估国际骨髓瘤工作组的临床反应率，并估计无进展生存期（PFS）和总生存期（OS）率。
结果：41 名可评估患者入组（中位年龄 59 岁；范围，30-70 岁）；25 名（61%）为女性，20 名（49%）为多发性骨髓瘤高危患者。主要终点（骨髓中 MRD 阴性；10-5 敏感性）在 41 名患者中的 29 名（71%；95%CI，54%-83%）中达到，因此试验被认为是成功的。达到 MRD 阴性的中位时间为 6 个周期（范围，1-8 个周期）。总体反应率和非常好的部分缓解或完全缓解率的次要终点分别为 100%（41 名患者中的 41 名）和 95%（41 名患者中的 39 名）。在中位随访 11 个月时，1 年 PFS 率和 OS 率分别为 98%（95%CI，93%-100%）和 100%。最常见（≥2 名患者）的 3 级或 4 级不良事件是中性粒细胞减少症（12 名患者[27%]）、皮疹（4 名患者[9%]）、肺部感染（3 名患者[7%]）和丙氨酸氨基转移酶水平升高（2 名患者[4%]）。没有死亡。
结论和相关性：在这项非随机临床试验中，新诊断多发性骨髓瘤患者接受卡非佐米-来那度胺-地塞米松-达雷妥尤单抗联合治疗与高 MRD 阴性率和高 PFS 率相关。
