Chari Ajai, Cho Hearn J, Dhadwal Amishi, Morgan Gillian, La Lisa, Zarychta Katarzyna, Catamero Donna, Florendo Erika, Stevens Nadege, Verina Daniel, Chan Elaine, Leshchenko Violetta, Laganà Alessandro, Perumal Deepak, Mei Anna Huo-Chang, Tung Kaity, Fukui Jami, Jagannath Sundar, Parekh Samir
Division of Hematology and Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
Blood Adv. 2017 Aug 21;1(19):1575-1583. doi: 10.1182/bloodadvances.2017007427. eCollection 2017 Aug 22.
Phase 3 studies combining histone deacetylase inhibitors with bortezomib were hampered by gastrointestinal (GI) intolerance, which was not observed when combined with immunomodulatory drugs. This study is a single-center phase 2 study of panobinostat with lenalidomide and dexamethasone (FRD). Twenty-seven relapsed multiple myeloma patients were enrolled. Twenty-two patients (81%) were lenalidomide refractory and 9 (33%), 14 (52%), and 7 (26%) were refractory to pomalidomide, bortezomib, and carfilzomib, respectively. High-risk molecular findings were present in 17 (63%) patients. Responses included 2 complete responses (CRs), 4 very good partial responses (VGPRs), 5 partial responses (PRs), and 9 minimal responses (MRs) for an overall response rate of 41%, clinical benefit rate of 74%, and a disease control rate of 96%. The median progression-free survival (PFS) was 7.1 months. In the 22 lenalidomide-refractory patients, there were 1 CR, 4 VGPRs, 3 PRs, and 7 MRs, with a median PFS of 6.5 months. Median overall survival was not reached. Grade 3/4 toxicities were primarily hematologic. Gene expression profiling of enrollment tumor samples revealed a set of 1989 genes associated with short (<90 days) PFS to therapy. MAGEA1 RNA and protein expression were correlated with short PFS, and laboratory studies demonstrated a role for MAGE-A in resistance to panobinostat-induced cell death. FRD demonstrates durable responses, even in high-risk, lenalidomide-refractory patients, indicating the essential role of panobinostat in attaining responses. MAGEA1 expression may represent a functional biomarker for resistance to panobinostat. In contrast to PANORAMA 1, there were no significant GI toxicities and primarily expected hematologic toxicities. This trial was registered at www.clinicaltrials.gov as #NCT00742027.
将组蛋白去乙酰化酶抑制剂与硼替佐米联合使用的3期研究因胃肠道不耐受而受阻，但与免疫调节药物联合使用时未观察到这种情况。本研究是一项关于帕比司他联合来那度胺和地塞米松（FRD）的单中心2期研究。招募了27例复发的多发性骨髓瘤患者。22例患者（81%）对来那度胺耐药，9例（33%）、14例（52%）和7例（26%）分别对泊马度胺、硼替佐米和卡非佐米耐药。17例（63%）患者存在高危分子特征。缓解包括2例完全缓解（CR）、4例非常好的部分缓解（VGPR）、5例部分缓解（PR）和9例最小缓解（MR），总缓解率为41%，临床获益率为74%，疾病控制率为96%。无进展生存期（PFS）的中位数为7.1个月。在22例对来那度胺耐药的患者中，有1例CR、4例VGPR、3例PR和7例MR，PFS的中位数为6.5个月。总生存期的中位数未达到。3/4级毒性主要是血液学毒性。入组肿瘤样本的基因表达谱分析揭示了一组1989个与治疗后短（<90天）PFS相关的基因。MAGEA1 RNA和蛋白质表达与短PFS相关，实验室研究表明MAGE-A在对帕比司他诱导的细胞死亡的抗性中起作用。FRD显示出持久的缓解，即使在高危、对来那度胺耐药的患者中也是如此，表明帕比司他在获得缓解中起着重要作用。MAGEA1表达可能代表对帕比司他耐药的功能性生物标志物。与PANORAMA 1不同，没有明显的胃肠道毒性，主要是预期的血液学毒性。本试验在www.clinicaltrials.gov上注册为#NCT00742027。
