Preclinical studies have demonstrated activity of the oral proteasome inhibitor (PI) ixazomib (IXA) in bortezomib-resistant multiple myeloma (MM) and synergy with immunomodulatory drugs. We therefore conducted a phase I/II study to establish the safety and preliminary efficacy of IXA with pomalidomide (POM) and dexamethasone (DEX) in lenalidomide (LEN)/PI-refractory MM. Dose escalation established a 4 mg dose of POM and IXA and 20/40 mg dose of DEX as the maximum tolerated dose. The phase II portion of the trial was redesigned and started anew after six patients had been randomized to IXA-POM-DEX due to a rapidly changing treatment landscape. Among the 29 evaluable LEN/PI-refractory patients treated with IXA-POM-DEX in phase I/II, the overall response rate (partial response or better) was 51.7% with a median duration of response of 16.8 months (range 56 days to 4.1 years), median progression-free survival of 4.4 months (95% confidence interval [CI]: 3.0–18.4), and median overall survival of 34.3 months (95% CI: 19.2 to not reached). Hematologic, gastrointestinal, and constitutional adverse events were common and consistent with the side-effect profiles of the individual agents. Our results support further evaluation of this all-oral regimen in relapsed/refractory MM.

中文翻译：

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伊沙佐米、泊马度胺和地塞米松治疗来那度胺和蛋白酶体抑制剂难治性多发性骨髓瘤的 I/II 期研究（联盟 A061202）

临床前研究表明口服蛋白酶体抑制剂 (PI) ixazomib (IXA) 在硼替佐米耐药多发性骨髓瘤 (MM) 中的活性以及与免疫调节药物的协同作用。因此，我们进行了 I/II 期研究，以确定 IXA 联合泊马度胺 (POM) 和地塞米松 (DEX) 治疗来那度胺 (LEN)/PI 难治性 MM 的安全性和初步疗效。剂量递增确定了 4 mg 剂量的 POM 和 IXA 以及 20/40 mg 剂量的 DEX 作为最大耐受剂量。由于治疗环境的快速变化，在六名患者被随机分配到 IXA-POM-DEX 后，该试验的 II 期部分被重新设计并重新开始。在 I/II 期接受 IXA-POM-DEX 治疗的 29 名可评估 LEN/PI 难治性患者中，总反应率（部分反应或更好）为 51.7%，中位反应持续时间为 16。8 个月（范围从 56 天到 4.1 年），中位无进展生存期为 4.4 个月（95% 置信区间 [CI]：3.0–18.4），中位总生存期为 34.3 个月（95% CI：19.2 至未达到） . 血液学、胃肠道和体质不良事件很常见，并且与各个药物的副作用特征一致。我们的结果支持在复发/难治性 MM 中进一步评估这种全口服方案。