From the Department of Hematology, University Medical Center Utrecht, Utrecht (H.M.L., M.C.M., N.W.C.J.D.), and the Department of Hematology, VU University Medical Center, Amsterdam (H.M.L., N.W.C.J.D.) - both in the Netherlands; Vejle Hospital and University of Southern Denmark, Vejle (T.P., J.K.), and Rigshospitalet and University of Copenhagen (P.G., U.L.) and Genmab (N.L., S.L., L.B., N.B.), Copenhagen - all in Denmark; Dana-Farber Cancer Institute, Harvard Medical School, Boston (J.P.L., P.G.R.); Karolinska Institute and the Department of Medicine, Division of Hematology, Karolinska University Hospital at Huddinge, Stockholm (H.N.), and Skåne University Hospital and Lund University, Lund (M.H.) - all in Sweden; Myeloma Unit, Division of Hematology, University of Turin, Turin, Italy (A.P.); Janssen Research and Development, Spring House, PA (T.A., C.M.U., A.K.S.); and Janssen Research and Development, Raritan, NJ (I.K., J.W.).
N Engl J Med. 2015 Sep 24;373(13):1207-19. doi: 10.1056/NEJMoa1506348. Epub 2015 Aug 26.
Multiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1κ monoclonal antibody, in a phase 1-2 trial involving patients with relapsed myeloma or relapsed myeloma that was refractory to two or more prior lines of therapy.
In part 1, the dose-escalation phase, we administered daratumumab at doses of 0.005 to 24 mg per kilogram of body weight. In part 2, the dose-expansion phase, 30 patients received 8 mg per kilogram of daratumumab and 42 received 16 mg per kilogram, administered once weekly (8 doses), twice monthly (8 doses), and monthly for up to 24 months. End points included safety, efficacy, and pharmacokinetics.
No maximum tolerated dose was identified in part 1. In part 2, the median time since diagnosis was 5.7 years. Patients had received a median of four prior treatments; 79% of the patients had disease that was refractory to the last therapy received (64% had disease refractory to proteasome inhibitors and immunomodulatory drugs and 64% had disease refractory to bortezomib and lenalidomide), and 76% had received autologous stem-cell transplants. Infusion-related reactions in part 2 were mild (71% of patients had an event of any grade, and 1% had an event of grade 3), with no dose-dependent adverse events. The most common adverse events of grade 3 or 4 (in ≥ 5% of patients) were pneumonia and thrombocytopenia. The overall response rate was 36% in the cohort that received 16 mg per kilogram (15 patients had a partial response or better, including 2 with a complete response and 2 with a very good partial response) and 10% in the cohort that received 8 mg per kilogram (3 had a partial response). In the cohort that received 16 mg per kilogram, the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 8.1), and 65% (95% CI, 28 to 86) of the patients who had a response did not have progression at 12 months.
Daratumumab monotherapy had a favorable safety profile and encouraging efficacy in patients with heavily pretreated and refractory myeloma. (Funded by Janssen Research and Development and Genmab; ClinicalTrials.gov number, NCT00574288.).
多发性骨髓瘤细胞普遍过表达 CD38。我们研究了靶向 CD38 的人源 IgG1κ 单克隆抗体达雷妥尤单抗，该药物在一项复发或经两种以上前期治疗方案难治的多发性骨髓瘤患者参与的 1 期和 2 期试验中进行了评估。
在剂量递增部分 1 中，我们给予患者 0.005 至 24mg/kg 的达雷妥尤单抗剂量。在剂量扩展部分 2 中，30 名患者接受 8mg/kg 的达雷妥尤单抗，42 名患者接受 16mg/kg 的达雷妥尤单抗，每周一次（8 个剂量）、每两周一次（8 个剂量）和每月一次（最多 24 个月）。主要终点包括安全性、疗效和药代动力学。
在部分 1 中，未确定最大耐受剂量。在部分 2 中，中位诊断后时间为 5.7 年。患者中位接受过 4 次前期治疗；79%的患者对最后一次治疗方案难治（64%的患者对蛋白酶体抑制剂和免疫调节剂难治，64%的患者对硼替佐米和来那度胺难治），76%的患者接受过自体干细胞移植。部分 2 中的输注相关反应为轻度（71%的患者发生任何级别事件，1%发生 3 级事件），无剂量相关性不良事件。≥5%的患者发生的最常见 3 级或 4 级不良事件为肺炎和血小板减少症。接受 16mg/kg 剂量的患者中，总体缓解率为 36%（15 名患者有部分缓解或更好反应，包括 2 名完全缓解和 2 名非常好的部分缓解），接受 8mg/kg 剂量的患者中，缓解率为 10%（3 名患者有部分缓解）。接受 16mg/kg 剂量的患者中，中位无进展生存期为 5.6 个月（95%置信区间[CI]：4.2 至 8.1），有缓解的患者中，65%（95%CI：28 至 86）在 12 个月时未进展。
达雷妥尤单抗单药治疗在既往大量治疗和难治性多发性骨髓瘤患者中具有良好的安全性和疗效。（由 Janssen Research and Development 和 Genmab 资助；ClinicalTrials.gov 编号，NCT00574288。）
