Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Institut Català d'Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Barcelona, Spain.
Lancet Oncol. 2019 Jun;20(6):781-794. doi: 10.1016/S1470-2045(19)30152-4. Epub 2019 May 13.
As lenalidomide becomes increasingly established for upfront treatment of multiple myeloma, patients refractory to this drug represent a population with an unmet need. The combination of pomalidomide, bortezomib, and dexamethasone has shown promising results in phase 1/2 trials of patients with relapsed or refractory multiple myeloma. We aimed to assess the efficacy and safety of this triplet regimen in patients with relapsed or refractory multiple myeloma who previously received lenalidomide.
We did a randomised, open-label, phase 3 trial at 133 hospitals and research centres in 21 countries. We enrolled patients (aged ≥18 years) with a diagnosis of multiple myeloma and measurable disease, an Eastern Cooperative Oncology Group performance status of 0-2, who received one to three previous regimens, including a lenalidomide-containing regimen for at least two consecutive cycles. We randomly assigned patients (1:1) to bortezomib and dexamethasone with or without pomalidomide using a permutated blocked design in blocks of four, stratified according to age, number of previous regimens, and concentration of β microglobulin at screening. Bortezomib (1·3 mg/m) was administered intravenously until protocol amendment 1 then either intravenously or subcutaneously on days 1, 4, 8, and 11 for the first eight cycles and subsequently on days 1 and 8. Dexamethasone (20 mg [10 mg if age >75 years]) was administered orally on the same days as bortezomib and the day after. Patients allocated pomalidomide received 4 mg orally on days 1-14. Treatment cycles were every 21 days. The primary endpoint was progression-free survival in the intention-to-treat population, as assessed by an independent review committee. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered at ClinicalTrials.gov, number NCT01734928; patients are no longer being enrolled.
Between Jan 7, 2013, and May 15, 2017, 559 patients were enrolled. 281 patients were assigned pomalidomide, bortezomib, and dexamethasone and 278 were allocated bortezomib and dexamethasone. Median follow-up was 15·9 months (IQR 9·9-21·7). Pomalidomide, bortezomib, and dexamethasone significantly improved progression-free survival compared with bortezomib and dexamethasone (median 11·20 months [95% CI 9·66-13·73] vs 7·10 months [5·88-8·48]; hazard ratio 0·61, 95% CI 0·49-0·77; p<0·0001). 278 patients received at least one dose of pomalidomide, bortezomib, and dexamethasone and 270 patients received at least one dose of bortezomib and dexamethasone, and these patients were included in safety assessments. The most common grade 3 or 4 treatment-emergent adverse events were neutropenia (116 [42%] of 278 patients vs 23 [9%] of 270 patients; nine [3%] vs no patients had febrile neutropenia), infections (86 [31%] vs 48 [18%]), and thrombocytopenia (76 [27%] vs 79 [29%]). Serious adverse events were reported in 159 (57%) of 278 patients versus 114 (42%) of 270 patients. Eight deaths were related to treatment; six (2%) were recorded in patients who received pomalidomide, bortezomib, and dexamethasone (pneumonia [n=2], unknown cause [n=2], cardiac arrest [n=1], cardiorespiratory arrest [n=1]) and two (1%) were reported in patients who received bortezomib and dexamethasone (pneumonia [n=1], hepatic encephalopathy [n=1]).
Patients with relapsed or refractory multiple myeloma who previously received lenalidomide had significantly improved progression-free survival when treated with pomalidomide, bortezomib, and dexamethasone compared with bortezomib and dexamethasone. Adverse events accorded with the individual profiles of pomalidomide, bortezomib, and dexamethasone. This study supports use of pomalidomide, bortezomib, and dexamethasone as a treatment option in patients with relapsed or refractory multiple myeloma who previously received lenalidomide.
Celgene.
来那度胺在多发性骨髓瘤的一线治疗中应用日益广泛，对于该药物耐药的患者仍存在未满足的治疗需求。硼替佐米、来那度胺和地塞米松联合方案在复发/难治性多发性骨髓瘤的 1/2 期临床试验中显示出良好的疗效。本研究旨在评估该三联方案在既往接受来那度胺治疗的复发/难治性多发性骨髓瘤患者中的疗效和安全性。
在 21 个国家的 133 家医院和研究中心进行了一项随机、开放标签、3 期临床试验。我们招募了诊断为多发性骨髓瘤且可测量疾病、东部肿瘤协作组体力状态为 0-2 级、接受过至少 1 种含来那度胺方案（连续 2 个周期以上）的患者。采用 4 个区组的随机区组设计，按照年龄、之前方案的数量和筛选时β微球蛋白的浓度，以 1:1 的比例随机分配患者接受硼替佐米和地塞米松加或不加泊马度胺治疗。硼替佐米（1.3 mg/m2）静脉给药，直到方案修订 1 后，在前 8 个周期中，每周 1、4、8 和 11 天以及随后的第 1 和 8 天，皮下或静脉给药。地塞米松（20 mg[年龄>75 岁时为 10 mg]）与硼替佐米同日口服，在硼替佐米给药后一天口服。给予泊马度胺的患者口服 4 mg，每日 1-14 天。治疗周期为每 21 天一次。主要终点是意向治疗人群的无进展生存期，由独立审查委员会评估。所有接受至少一剂研究药物的患者均进行安全性评估。本试验在 ClinicalTrials.gov 登记，编号为 NCT01734928；患者不再入组。
2013 年 1 月 7 日至 2017 年 5 月 15 日期间，共纳入 559 例患者。281 例患者接受泊马度胺、硼替佐米和地塞米松治疗，278 例患者接受硼替佐米和地塞米松治疗。中位随访时间为 15.9 个月（IQR 9.9-21.7）。与硼替佐米和地塞米松组相比，泊马度胺、硼替佐米和地塞米松组显著改善了无进展生存期（中位无进展生存期 11.20 个月[95%CI 9.66-13.73] vs 7.10 个月[5.88-8.48]；风险比 0.61，95%CI 0.49-0.77；p<0.0001）。278 例患者至少接受了一剂泊马度胺、硼替佐米和地塞米松，270 例患者至少接受了一剂硼替佐米和地塞米松，这些患者被纳入安全性评估。最常见的 3 级或 4 级治疗相关不良事件为中性粒细胞减少症（278 例患者中有 116 例[42%]，270 例患者中有 23 例[9%]；9 例[3%]患者发生发热性中性粒细胞减少症，无患者发生中性粒细胞减少症）、感染（278 例患者中有 86 例[31%]，270 例患者中有 48 例[18%]）和血小板减少症（278 例患者中有 76 例[27%]，270 例患者中有 79 例[29%]）。278 例患者中有 159 例（57%）报告了严重不良事件，270 例患者中有 114 例（42%）报告了严重不良事件。8 例死亡与治疗相关；6 例（2%）发生在接受泊马度胺、硼替佐米和地塞米松治疗的患者（肺炎[n=2]，原因不明[n=2]，心脏骤停[n=1]，心肺骤停[n=1]），2 例（1%）发生在接受硼替佐米和地塞米松治疗的患者（肺炎[n=1]，肝性脑病[n=1]）。
与接受硼替佐米和地塞米松治疗相比，既往接受来那度胺治疗的复发/难治性多发性骨髓瘤患者接受泊马度胺、硼替佐米和地塞米松治疗后，无进展生存期显著延长。不良事件与泊马度胺、硼替佐米和地塞米松的个体特征一致。本研究支持在既往接受来那度胺治疗的复发/难治性多发性骨髓瘤患者中使用泊马度胺、硼替佐米和地塞米松作为一种治疗选择。
Celgene。
