Voorhees Peter M, Gasparetto Cristina, Moore Dominic T, Winans Diane, Orlowski Robert Z, Hurd David D
Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC.
Division of Hematological Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC.
Clin Lymphoma Myeloma Leuk. 2017 Jul;17(7):424-432. doi: 10.1016/j.clml.2017.05.007. Epub 2017 May 10.
INTRODUCTION/BACKGROUND: Deacetylase inhibitors have synergistic activity in combination with proteasome inhibitors and anthracyclines in preclinical models of multiple myeloma (MM). We therefore evaluated the safety and efficacy of the deacetylase inhibitor vorinostat in combination with pegylated liposomal doxorubicin (PLD) and bortezomib in relapsed/refractory MM.
Thirty-two patients were treated with PLD and bortezomib in combination with escalating doses of vorinostat on days 4 to 11 or 1 to 14.
The maximum tolerated dose of vorinostat was 400 mg on days 4 to 11. Neutropenia and thrombocytopenia attributable to protocol therapy were seen in 59% and 94% of patients, of which 37% and 47% were of grade 3 or higher severity, respectively. Constitutional and gastrointestinal adverse events of all grades were common, the majority of which were less than grade 3 in severity. The overall response rate (partial response rate or better) was 65% and the clinical benefit rate (minimal response rate or better) 74%. The overall response rate was 83%, 71%, and 45% for patients with bortezomib-naive, -sensitive, and -refractory MM, respectively. The median progression-free survival was 13.9 months and the 3-year overall survival 77%. Whole blood proteasome activity assays demonstrated a potential impact of vorinostat on the chymotryptic-like activity of the proteasome.
Further evaluation of PLD, bortezomib, and deacetylase inhibitor combinations is warranted, with special attention directed toward strategies to improve tolerability.
引言/背景：在多发性骨髓瘤（MM）的临床前模型中，去乙酰化酶抑制剂与蛋白酶体抑制剂及蒽环类药物联合使用具有协同活性。因此，我们评估了去乙酰化酶抑制剂伏立诺他联合聚乙二醇化脂质体阿霉素（PLD）和硼替佐米用于复发/难治性MM的安全性和疗效。
32例患者在第4至11天或第1至14天接受PLD、硼替佐米联合递增剂量伏立诺他治疗。
伏立诺他在第4至11天的最大耐受剂量为400mg。59%的患者出现了与方案治疗相关的中性粒细胞减少，94%的患者出现了血小板减少，其中分别有37%和47%为3级或更严重程度。所有级别的全身性和胃肠道不良事件很常见，其中大多数严重程度低于3级。总缓解率（部分缓解率或更高）为65%，临床获益率（最小缓解率或更高）为74%。对于既往未使用过硼替佐米、对硼替佐米敏感和对硼替佐米耐药的MM患者，总缓解率分别为83%、71%和45%。中位无进展生存期为13.9个月，3年总生存率为77%。全血蛋白酶体活性检测表明伏立诺他对蛋白酶体的类胰凝乳蛋白酶活性有潜在影响。
有必要进一步评估PLD、硼替佐米和去乙酰化酶抑制剂的联合使用，尤其要关注提高耐受性的策略。
