Combining carfilzomib and panobinostat to treat relapsed/refractory multiple myeloma: results of a Multiple Myeloma Research Consortium Phase I Study
Combining carfilzomib and panobinostat to treat relapsed/refractory multiple myeloma: results of a Multiple Myeloma Research Consortium Phase I Study
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DOI：
10.1038/s41408-018-0154-8
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发表时间：
2019-01-04
影响因子：
12.8
通讯作者：
Lonial, Sagar
中科院分区：
文献类型：
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作者：
Kaufman, Jonathan L.;Mina, Roberto;Lonial, Sagar
蛋白酶体 (PI) 和海蛋白脱乙酰酶抑制剂 (HDACis) 此前已在治疗复发/难治性多发性骨髓瘤 (RRMM) 患者中表现出协同活性。在这项 1 期研究中，我们将第二代 PI 卡非佐米与 HDACi 帕比司他联合使用，以确定联合用药 (CarPan) 的最大耐受剂量 (MTD)，并评估 RRMM 患者的安全性和有效性。共有 32 名患者（之前接受过 4 种治疗的中位数）入组。 MTD 为卡非佐米 36 mg/m(2)（第 1、2、8、9、15 和 16 天）和帕比司他 20 mg（TIW，用药 3 周/停药 1 周，每 28 天），给药直至疾病进展。在 MTD 中，最常见的 3/4 级治疗相关不良事件是血小板减少症 (41%)、疲劳 (17%) 和恶心/呕吐 (12%)。客观缓解率（ORR）和临床受益率分别为63%和68%。整个人群的中位无进展生存期 (PFS) 和总生存期 (OS) 分别为 8 个月和 23 个月。硼替佐米敏感和难治性患者之间在 ORR（55% 与 57%）、中位 PFS（8 个月与 7 个月）和 OS（24 与 22 个月）方面没有观察到差异。 CarPan 被证明是一种安全有效的类固醇节约方案，适用于经过大量预先治疗的 MM 患者群体。
Proteasome (PIs) and hystone deacetylase inhibitors (HDACis) have previously shown synergistic activity in the treatment of relapesed/ refractory multiple myeloma (RRMM) patients. In this phase 1 study, we combined carfilzomib, a second generation PI, with panobinostat, a HDACi, to determine the maximum tolerated dose (MTD) of the combination (CarPan) and assess safety and efficacy among RRMM patients. Thirty-two patients (median of 4 prior lines of therapy) were enrolled. The MTD was carfilzomib 36 mg/m(2) (on days 1, 2, 8, 9, 15, and 16) and panobinostat 20 mg (TIW, 3 weeks on/1 week off, every 28 days), administered until progression. At the MTD, the most common grade 3/4, treatment-related adverse events were thrombocytopenia (41%), fatigue (17%), and nausea/vomiting (12%). The objective response rate (ORR) and clinical benefit rate were 63% and 68%, respectively. Median progression-free survival (PFS) and overall survival (OS) for the entire population were 8 and 23 months, respectively. No differences in terms of ORR (55% vs. 57%), median PFS (months 8 vs. 7 months) and OS (24 vs. 22 months) were observed between bortezomib-sensitive and -refractory patients. CarPan proved to be a safe and effective steroid-sparing regimen in a heavily pre-treated population of MM patients.