Background: Studies have suggested a synergism between lenalidomide (LEN) and ibrutinib (IBR) in multiple myeloma (MM). Both downregulate IRF4, a key target and master transcriptional factor regulating myeloma cell survival. Method: A 3 + 3 phase I trial was conducted to determine the maximum tolerated dose (MTD) of IBR in combination with LEN + dexamethasone (DEX) in patients with relapsed/refractory (RR) MM who had at least one prior line of therapy. Three dose levels (DLs) were planned. The cycle length was 28 days. IBR was administered orally daily in doses of 560 mg on DL1-2 and 840 mg on DL3, LEN was administered orally on days 1–21 in doses of 15 mg on DL1 and 25 mg on DL2-3, and DEX was administered orally on days 1, 8, 15, and 22 in a dose of 40 mg if age < 75 years or in a dose of 20 mg if it was ≥75 years for DL1-3. Patients with a glomerular filtration rate (GFR) <60 but ≥30 mL/min were treated in accordance with the manufacturer’s instructions with LEN 10 mg. Dose-limiting toxicities (DLTs) included the following: grade 4 neutropenia lasting more than 5 days, thrombocytopenia, febrile neutropenia, nausea, vomiting or diarrhea; grade 3 thrombocytopenia with bleeding or platelet transfusion; and grade 3–4 hyperglycemia or a thrombotic/embolic event, and other nonhematologic toxicities. The overall response rate (ORR) was defined as the percentage of patients with a partial response (PR), very good partial response (VGPR), or complete response (CR) according to IMWG criteria on two consecutive evaluations at least 4 weeks apart. The clinical benefit rate (CBR) was defined as the percentage of patients with stable disease (SD) or a better outcome on two consecutive evaluations at weeks apart. Results: Fourteen patients (DL1: six patients; DL2: three patients; DL3: five patients) were registered for the study from March 2019 to May 2023, prior to its closure due to limited accrual. Thirteen patients are included in the summary of toxicities and response as one patient on DL3 halted participation prior to the start of the treatment. Two patients on DL3 were excluded from the determination of MTD: one having discontinued cycle 1 treatment due to COVID-19 infection and the another having mistakenly taken 280 mg/day of IBR instead of the assigned 840 mg/day dose during cycle 1. Only one patient developed a DLT, on DL1 with grade 3 non-viral hepatitis. The median number of cycles administered was 4 (range: 1–56). Severe toxicities reported included grade 4 lymphocytopenia (1), grade 4 thrombocytopenia (1), and grade 5 sepsis in the setting of PD (1). Disease responses included a VGPR on DL1 and CR on DL3. Thus, the ORR was 15.4% (90% CI: 2.8–41.0%). One patient on DL1 maintained SD for 4.6 years before discontinuing the treatment to undergo an alternative therapy. Another five patients maintained SD for ≥ 2 consecutive cycles. Thus, the CBR was 61.5% (90% CI: 35.5–83.4%). Conclusions: The combination of LEN with IBR in RR MM proved feasible, with manageable toxicities and the majority of discontinuations being due to disease progression.
背景：研究表明，来那度胺（LEN）与伊布替尼（IBR）在多发性骨髓瘤（MM）治疗中存在协同作用。两者均可下调IRF4，这是调控骨髓瘤细胞存活的关键靶点和主要转录因子。方法：本研究采用3+3设计的I期临床试验，旨在确定IBR联合LEN及地塞米松（DEX）在至少接受过一线治疗的复发/难治性（RR）MM患者中的最大耐受剂量（MTD）。共设计三个剂量水平（DLs），治疗周期为28天。IBR每日口服给药，DL1-2剂量为560 mg，DL3为840 mg；LEN于第1-21天口服给药，DL1剂量为15 mg，DL2-3为25 mg；DEX于第1、8、15、22天口服给药，DL1-3中年龄<75岁者剂量为40 mg，≥75岁者为20 mg。肾小球滤过率（GFR）<60但≥30 mL/min的患者根据生产商说明书使用LEN 10 mg治疗。剂量限制性毒性（DLTs）包括：持续超过5天的4级中性粒细胞减少、血小板减少、发热性中性粒细胞减少、恶心、呕吐或腹泻；伴有出血或需输注血小板的3级血小板减少；3-4级高血糖或血栓/栓塞事件，以及其他非血液学毒性。总缓解率（ORR）定义为根据IMWG标准，在至少间隔4周的两次连续评估中达到部分缓解（PR）、非常好的部分缓解（VGPR）或完全缓解（CR）的患者百分比。临床获益率（CBR）定义为在间隔数周的两次连续评估中达到疾病稳定（SD）或更好疗效的患者百分比。结果：自2019年3月至2023年5月研究因入组有限而终止前，共登记14例患者（DL1：6例；DL2：3例；DL3：5例）。其中13例患者纳入毒性和缓解总结，因DL3组1例患者在治疗开始前退出。DL3组另有2例患者被排除在MTD确定之外：1例因感染COVID-19中断第1周期治疗，另1例在第1周期误服IBR 280 mg/日（而非规定的840 mg/日）。仅1例患者出现DLT（DL1组发生3级非病毒性肝炎）。中位治疗周期数为4（范围：1-56）。报告的严重毒性包括4级淋巴细胞减少（1例）、4级血小板减少（1例）以及疾病进展（PD）背景下发生的5级败血症（1例）。疾病缓解包括DL1组1例VGPR和DL3组1例CR。因此，ORR为15.4%（90% CI：2.8–41.0%）。DL1组1例患者维持SD达4.6年，后因接受替代治疗而停药。另有5例患者维持SD≥2个连续周期。因此，CBR为61.5%（90% CI：35.5–83.4%）。结论：LEN联合IBR治疗RR MM的方案被证明可行，毒性可控，且多数停药原因为疾病进展。
肿瘤(癌症)患者之家