Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma
Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma
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DOI：
10.1056/nejmoa1606038
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发表时间：
2016-08-25
影响因子：
158.5
通讯作者：
Sonneveld, Pieter
中科院分区：
文献类型：
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作者：
Palumbo, Antonio;Chanan-Khan, Asher;Sonneveld, Pieter
研究背景达雷妥尤单抗是一种靶向CD 38的人IgG κ单克隆抗体，可诱导直接和间接的抗骨髓瘤活性，并且在重度预治疗的多发性骨髓瘤患者中作为单药治疗以及与硼替佐米联合治疗新诊断的多发性骨髓瘤患者中显示出显著的疗效。我们将498例复发或复发难治性多发性骨髓瘤患者随机分配接受硼替佐米治疗，（1.3 mg/m2体表面积）和地塞米松（20 mg）单独给药（对照组）或与达雷妥尤单抗（16 mg/kg体重）联合给药（达雷妥尤单抗组）。主要终点为无进展生存期，CITTSA预先规定的中期分析显示，达雷妥尤单抗组的无进展生存率显著高于对照组;达雷妥尤单抗组的12个月无进展生存率为60.7%，对照组为26.9%。中位随访期为7.4个月后，达雷妥尤单抗组未达到中位无进展生存期，对照组为7.2个月（达雷妥尤单抗组与对照组相比，进展或死亡的风险比为0.39; 95%置信区间为0.28 - 0.53; P < 0.001）。达雷妥尤单抗组的总体缓解率高于对照组（82.9% vs. 63.2%，P < 0.001），非常好的部分缓解或更好（59.2% vs. 29.1%，P < 0.001）和完全缓解或更好（19.2% vs. 9.0%，P = 0.001）的比率也是如此。达雷妥尤单抗组和对照组报告的3起最常见的3级或4级不良事件为血小板减少（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（分别为12.8%和4.2%）。达雷妥尤单抗组45.3%的患者报告了与达雷妥尤单抗治疗相关的输注相关反应;这些反应大多为1级或2级（8.6%的患者中为3级），并且在这些患者中的98.2%中，它们发生在第一次输注期间。达雷妥尤单抗联合硼替佐米和地塞米松导致的无进展生存期显著长于硼替佐米和地塞米松单药治疗，与输注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高于硼替佐米和地塞米松单药治疗。（由Janssen Research and Development资助; ClinicalTrials.gov编号，NCT 02136134。
BACKGROUNDDaratumumab, a human IgG kappa 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.METHODSIn 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.RESULTSA 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.CONCLUSIONSAmong 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.)