达雷妥尤单抗、硼替佐米和地塞米松治疗多发性骨髓瘤。
Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma.
机构信息
From the Department of Hematology, University of Turin, Turin, Italy (A.P.); the Division of Hematology and Medical Oncology, Mayo Clinic Florida, Jacksonville (A.C.-K.); Universitaetsklinikum Tuebingen der Eberhard-Karls-Universitaet, Abteilung fuer Innere Medizin II, Tuebingen (K.W.), and University Medical Center of the Johannes Gutenberg-University, Third Department of Medicine, Mainz (M.M.) - both in Germany; Winship Cancer Institute, Emory University, Atlanta (A.K.N.); the Department of Hematology and Stem Cell Transplantation, St. László Hospital, Semmelweis University, Budapest, Hungary (T.M.); Ankara University, Department of Hematology, Ankara, Turkey (M.B.); Clinical Department of Hematology, 1st Medical Department, Charles University in Prague, Prague, Czech Republic (I.S.); Irmandade Da Santa Casa De Misericordia De São Paulo, São Paulo (V.H.); University Hospital of Salamanca-Instituto de Investigación Biomédica de Salamanca, Salamanca, Spain (M.V.M.); Weill Cornell Medical College, New York (T.M.M.); Janssen Research and Development, Spring House, PA (M.Q., X.Q., T.A.); Janssen Research and Development, Raritan, NJ (J.S., H.A.); Janssen Research and Development, Beerse, Belgium (W.D.); Malignant Haematology and Stem Cell Transplantation Service, Alfred Health-Monash University, Melbourne, VIC, Australia (A.S.); and the Department of Hematology, Erasmus MC, Rotterdam, the Netherlands (P.S.).
出版信息
N Engl J Med. 2016 Aug 25;375(8):754-66. doi: 10.1056/NEJMoa1606038.
BACKGROUND
Daratumumab, a human IgGκ monoclonal antibody that targets CD38, induces direct and indirect antimyeloma activity and has shown substantial efficacy as monotherapy in heavily pretreated patients with multiple myeloma, as well as in combination with bortezomib in patients with newly diagnosed multiple myeloma.
METHODS
In this phase 3 trial, we randomly assigned 498 patients with relapsed or relapsed and refractory multiple myeloma to receive bortezomib (1.3 mg per square meter of body-surface area) and dexamethasone (20 mg) alone (control group) or in combination with daratumumab (16 mg per kilogram of body weight) (daratumumab group). The primary end point was progression-free survival.
RESULTS
A prespecified interim analysis showed that the rate of progression-free survival was significantly higher in the daratumumab group than in the control group; the 12-month rate of progression-free survival was 60.7% in the daratumumab group versus 26.9% in the control group. After a median follow-up period of 7.4 months, the median progression-free survival was not reached in the daratumumab group and was 7.2 months in the control group (hazard ratio for progression or death with daratumumab vs. control, 0.39; 95% confidence interval, 0.28 to 0.53; P<0.001). The rate of overall response was higher in the daratumumab group than in the control group (82.9% vs. 63.2%, P<0.001), as were the rates of very good partial response or better (59.2% vs. 29.1%, P<0.001) and complete response or better (19.2% vs. 9.0%, P=0.001). Three of the most common grade 3 or 4 adverse events reported in the daratumumab group and the control group were thrombocytopenia (45.3% and 32.9%, respectively), anemia (14.4% and 16.0%, respectively), and neutropenia (12.8% and 4.2%, respectively). Infusion-related reactions that were associated with daratumumab treatment were reported in 45.3% of the patients in the daratumumab group; these reactions were mostly grade 1 or 2 (grade 3 in 8.6% of the patients), and in 98.2% of these patients, they occurred during the first infusion.
CONCLUSIONS
Among patients with relapsed or relapsed and refractory multiple myeloma, daratumumab in combination with bortezomib and dexamethasone resulted in significantly longer progression-free survival than bortezomib and dexamethasone alone and was associated with infusion-related reactions and higher rates of thrombocytopenia and neutropenia than bortezomib and dexamethasone alone. (Funded by Janssen Research and Development; ClinicalTrials.gov number, NCT02136134.).
背景
达雷妥尤单抗是一种靶向 CD38 的人源 IgGκ 单克隆抗体，可直接和间接发挥抗骨髓瘤作用，在既往接受过多线治疗的多发性骨髓瘤患者中作为单药治疗具有显著疗效，在新诊断的多发性骨髓瘤患者中与硼替佐米联合应用也具有显著疗效。
方法
在这项 3 期临床试验中，我们将 498 例复发或复发且难治的多发性骨髓瘤患者随机分组，分别接受硼替佐米（1.3mg/ 平方米体表面积）联合地塞米松（20mg）（对照组）或联合达雷妥尤单抗（16mg/ 千克体重）（达雷妥尤单抗组）治疗。主要终点是无进展生存期。
结果
预先设定的中期分析结果显示，达雷妥尤单抗组的无进展生存期率显著高于对照组；达雷妥尤单抗组 12 个月的无进展生存率为 60.7%，对照组为 26.9%。在中位随访 7.4 个月后，达雷妥尤单抗组未达到中位无进展生存期，而对照组为 7.2 个月（达雷妥尤单抗组与对照组相比，进展或死亡风险比为 0.39；95%置信区间为 0.28 至 0.53；P<0.001）。达雷妥尤单抗组的总缓解率高于对照组（82.9% vs. 63.2%，P<0.001），非常好的部分缓解或更好的缓解率（59.2% vs. 29.1%，P<0.001）和完全缓解或更好的缓解率（19.2% vs. 9.0%，P=0.001）也更高。达雷妥尤单抗组和对照组报告的最常见的 3 级或 4 级不良事件包括血小板减少症（分别为 45.3%和 32.9%）、贫血（分别为 14.4%和 16.0%）和中性粒细胞减少症（分别为 12.8%和 4.2%）。达雷妥尤单抗组中有 45.3%的患者报告了与达雷妥尤单抗治疗相关的输液相关反应；这些反应主要为 1 级或 2 级（8.6%的患者为 3 级），在这些患者中，98.2%的反应发生在第一次输液期间。
结论
在复发或复发且难治的多发性骨髓瘤患者中，与硼替佐米和地塞米松联合应用达雷妥尤单抗可显著延长无进展生存期，且与硼替佐米和地塞米松单药治疗相比，与输液相关反应以及血小板减少症和中性粒细胞减少症的发生率更高相关。（由 Janssen Research and Development 资助；ClinicalTrials.gov 编号，NCT02136134）。
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