达雷妥尤单抗、来那度胺和地塞米松治疗多发性骨髓瘤。

Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma.

机构信息

From the National and Kapodistrian University of Athens, Athens (M.A.D.); Institut Català d'Oncologia, Institut Josep Carreras, Hospital Germans Trias I Pujol, Barcelona (A.O.), and Clínica Universidad de Navarra-Centro de Investigación Médica Aplicada, Instituto de Investigación Sanitaria de Navarra, Pamplona (J.S.-M.) - both in Spain; Karolinska Institute and the Department of Medicine, Division of Hematology, Karolinska University Hospital at Huddinge, Stockholm (H.N.); Tom Baker Cancer Centre, University of Calgary, Calgary, AB (N.J.B.), and the Cancer Clinical Research Unit, Princess Margaret Cancer Centre, Toronto (D.R.) - both in Canada; Levine Cancer Institute-Carolinas HealthCare System, Charlotte, NC (S.Z.U.); the Department of Haematology, University College London Hospitals NHS Trust, London (N.R.); the Department of Lymphoma-Myeloma, University of Texas M.D. Anderson Cancer Center, Houston (R.Z.O.); the Department of Hematology and Stem Cell Transplantation, Poznan University of Medical Sciences, Poznan, Poland (M.K.); the Department of Hematology, Japanese Red Cross Medical Center, Tokyo (K.S.); Vejle Hospital and University of Southern Denmark, Vejle (T.P.), and Genmab, Copenhagen (S.L.) - both in Denmark; the Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea (S.-S.Y.); the Hematology Department, Hadassah-Hebrew University Medical Center, Jerusalem (D.B.Y.); Dana-Farber Cancer Institute, Harvard Medical School, Boston (P.G.R.); University Hospital Heidelberg and the German Cancer Research Center, Heidelberg, Germany (H.G.); Janssen Research and Development, Spring House, PA (N.Z.K., L.O., C.C., X.Q., M.G., T.A.); and the Department of Hematology, University Hospital Hôtel-Dieu, Nantes, France (P.M.).

出版信息

N Engl J Med. 2016 Oct 6;375(14):1319-1331. doi: 10.1056/NEJMoa1607751.

DOI:10.1056/NEJMoa1607751

PMID:27705267

Abstract

BACKGROUND

Daratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1-2 study involving patients with relapsed or refractory multiple myeloma.

METHODS

In this phase 3 trial, we randomly assigned 569 patients with multiple myeloma who had received one or more previous lines of therapy to receive lenalidomide and dexamethasone either alone (control group) or in combination with daratumumab (daratumumab group). The primary end point was progression-free survival.

RESULTS

At a median follow-up of 13.5 months in a protocol-specified interim analysis, 169 events of disease progression or death were observed (in 53 of 286 patients [18.5%] in the daratumumab group vs. 116 of 283 [41.0%] in the control group; hazard ratio, 0.37; 95% confidence interval [CI], 0.27 to 0.52; P<0.001 by stratified log-rank test). The Kaplan-Meier rate of progression-free survival at 12 months was 83.2% (95% CI, 78.3 to 87.2) in the daratumumab group, as compared with 60.1% (95% CI, 54.0 to 65.7) in the control group. A significantly higher rate of overall response was observed in the daratumumab group than in the control group (92.9% vs. 76.4%, P<0.001), as was a higher rate of complete response or better (43.1% vs. 19.2%, P<0.001). In the daratumumab group, 22.4% of the patients had results below the threshold for minimal residual disease (1 tumor cell per 10 white cells), as compared with 4.6% of those in the control group (P<0.001); results below the threshold for minimal residual disease were associated with improved outcomes. The most common adverse events of grade 3 or 4 during treatment were neutropenia (in 51.9% of the patients in the daratumumab group vs. 37.0% of those in the control group), thrombocytopenia (in 12.7% vs. 13.5%), and anemia (in 12.4% vs. 19.6%). Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients and were mostly of grade 1 or 2.

CONCLUSIONS

The addition of daratumumab to lenalidomide and dexamethasone significantly lengthened progression-free survival among patients with relapsed or refractory multiple myeloma. Daratumumab was associated with infusion-related reactions and a higher rate of neutropenia than the control therapy. (Funded by Janssen Research and Development; POLLUX ClinicalTrials.gov number, NCT02076009 .).

摘要

背景

在一项涉及复发或难治性多发性骨髓瘤患者的 1-2 期研究中，达雷妥尤单抗单独使用以及与来那度胺和地塞米松联合使用显示出了有前景的疗效。

方法

在这项 3 期试验中，我们将 569 名接受过一次或多次先前治疗的多发性骨髓瘤患者随机分配，分别接受来那度胺和地塞米松（对照组）或与达雷妥尤单抗联合治疗（达雷妥尤单抗组）。主要终点是无进展生存期。

结果

在一项按方案规定的中期分析中，中位随访 13.5 个月时，观察到 169 例疾病进展或死亡事件（达雷妥尤单抗组 53 例[18.5%]，对照组 116 例[41.0%]；风险比，0.37；95%置信区间[CI]，0.27 至 0.52；分层对数秩检验 P<0.001）。达雷妥尤单抗组 12 个月无进展生存率为 83.2%（95%CI，78.3 至 87.2），对照组为 60.1%（95%CI，54.0 至 65.7）。达雷妥尤单抗组的总缓解率明显高于对照组（92.9%比 76.4%，P<0.001），完全缓解或更好的缓解率也更高（43.1%比 19.2%，P<0.001）。达雷妥尤单抗组有 22.4%的患者的微小残留病灶结果低于检测阈值（每 10 个白细胞中有 1 个肿瘤细胞），而对照组为 4.6%（P<0.001）；微小残留病灶结果低于检测阈值与改善结局相关。治疗期间最常见的 3 级或 4 级不良事件是中性粒细胞减少症（达雷妥尤单抗组 51.9%，对照组 37.0%）、血小板减少症（12.7%比 13.5%）和贫血（12.4%比 19.6%）。达雷妥尤单抗相关的输注相关反应发生在 47.7%的患者中，大多为 1 级或 2 级。