Winship Cancer Institute, Emory University, Atlanta, GA, USA.
NIHR UCLH Clinical Research Facility, University College London Hospitals NHS Foundation Trust, London, UK.
Lancet Haematol. 2022 Nov;9(11):e822-e832. doi: 10.1016/S2352-3026(22)00290-3. Epub 2022 Oct 6.
Iberdomide is a novel cereblon E3 ligase modulator with enhanced tumouricidal and immune-stimulatory effects compared with immunomodulatory drugs. In preclinical myeloma models, iberdomide has shown synergy with dexamethasone, proteasome inhibitors, and CD38 monoclonal antibodies. We aimed to evaluate the safety and clinical activity of iberdomide plus dexamethasone in patients with heavily pretreated relapsed or refractory multiple myeloma.
We conducted a multicohort, open-label, phase 1/2 trial (CC-220-MM-001) at 42 treatment centres in Europe, Canada, and the USA. Patients aged 18 years or older with multiple myeloma who had received at least two previous lines of therapy, including lenalidomide or pomalidomide and a proteasome inhibitor, were enrolled into the dose-escalation cohort. Patients received escalating doses of oral iberdomide (0·3-1·6 mg on days 1-21 of each 28-day cycle) plus oral dexamethasone (40 mg [20 mg if age >75 years] once per week). A dose-expansion cohort at the recommended phase 2 dose was planned for patients who had received at least three previous lines of therapy and had triple-class refractory disease (refractory to immunomodulatory drugs, proteasome inhibitors, and CD38 antibodies). Treatment continued until progressive disease or unacceptable toxicity. The primary outcomes were the recommended phase 2 dose (in the dose-escalation cohort, phase 1) and overall response rate (defined as complete response or partial response; in the dose-expansion cohort, phase 2) in the full analysis set. This trial is ongoing and is registered with ClinicalTrials.gov, NCT02773030.
Between Dec 5, 2016, and Dec 16, 2020, 460 patients were assessed for eligibility across all cohorts and 197 were enrolled and treated with iberdomide plus dexamethasone (90 patients in the dose-escalation cohort and 107 in the dose-expansion cohort). In the dose-escalation cohort, 47 (52%) patients were female and 43 (48%) were male, 70 (78%) were White, and the median number of previous lines of therapy was 5 (IQR 4-8). In the dose-expansion cohort, 47 (44%) were female and 60 (56%) were male, 84 (79%) were White, and the median number of previous lines of therapy was 6 (IQR 5-8). At data cutoff (June 2, 2021), median follow-up was 5·8 months (IQR 3·0-13·7) in the dose-escalation cohort and 7·7 months (5·3-11·4) in the dose-expansion cohort. Two dose-limiting toxicities (both infections, at 1·2 mg and 1·3 mg) were observed in the dose-escalation cohort, and 1·6 mg was selected as the recommended phase 2 dose. In the dose-escalation cohort, the overall response rate was 32% (95% CI 23-43; 29 of 90 patients) across all doses, and the maximum tolerated dose was not reached. In the dose-expansion cohort, the overall response rate was 26% (95% CI 18-36; 28 of 107 patients). The most common grade 3 or worse adverse events were neutropenia (48 [45%] of 107 patients), anaemia (30 [28%]), infection (29 [27%]), and thrombocytopenia (23 [22%]). Serious adverse events occurred in 57 (53%) patients. There was one (1%) treatment-related death (sepsis) and five (5%) patients discontinued iberdomide due to adverse events.
Iberdomide plus dexamethasone was generally safe and showed meaningful clinical activity in heavily pretreated patients with multiple myeloma, including in disease that was refractory to immunomodulatory drugs. These data suggest that further evaluation of iberdomide plus dexamethasone or other standard antimyeloma therapies is warranted.
Bristol Myers Squibb.
Iberdomide 是一种新型的 cereblon E3 连接酶调节剂，与免疫调节药物相比，具有增强的肿瘤杀伤和免疫刺激作用。在多发性骨髓瘤的临床前模型中，iberdomide 与地塞米松、蛋白酶体抑制剂和 CD38 单克隆抗体联合具有协同作用。我们旨在评估 iberdomide 加地塞米松在经过大量预处理的复发性或难治性多发性骨髓瘤患者中的安全性和临床活性。
我们在欧洲、加拿大和美国的 42 个治疗中心进行了一项多队列、开放标签、1/2 期试验（CC-220-MM-001）。年龄在 18 岁及以上、接受过至少两种先前治疗的多发性骨髓瘤患者，包括 lenalidomide 或 pomalidomide 和蛋白酶体抑制剂，被纳入剂量递增队列。患者接受口服 iberdomide（每日 1-21 天，每个 28 天周期 0.3-1.6mg）加口服地塞米松（40mg[75 岁以上患者 20mg]每周一次）。在推荐的 2 期剂量下计划为接受至少三种先前治疗且具有三药难治性疾病（对免疫调节药物、蛋白酶体抑制剂和 CD38 抗体均耐药）的患者进行剂量扩展队列。治疗持续至疾病进展或不可接受的毒性。主要结局是推荐的 2 期剂量（在剂量递增队列中为 1 期）和总体缓解率（定义为完全缓解或部分缓解；在剂量扩展队列中为 2 期）在全分析集。该试验正在进行中，并在 ClinicalTrials.gov 上注册，NCT02773030。
2016 年 12 月 5 日至 2020 年 12 月 16 日，对所有队列进行了资格评估，共有 460 名患者符合条件，197 名患者接受了 iberdomide 加地塞米松治疗（剂量递增队列 90 名患者，剂量扩展队列 107 名患者）。在剂量递增队列中，47（52%）名患者为女性，43（48%）名患者为男性，70（78%）名患者为白人，先前治疗的中位数为 5（四分位距 4-8）。在剂量扩展队列中，47（44%）名患者为女性，60（56%）名患者为男性，84（79%）名患者为白人，先前治疗的中位数为 6（四分位距 5-8）。在数据截止日期（2021 年 6 月 2 日）时，剂量递增队列的中位随访时间为 5.8 个月（四分位距 3.0-13.7），剂量扩展队列为 7.7 个月（5.3-11.4）。在剂量递增队列中观察到 2 例剂量限制毒性（均为感染，分别为 1.2mg 和 1.3mg），选择 1.6mg 作为推荐的 2 期剂量。在剂量递增队列中，所有剂量的总体缓解率为 32%（95%CI 23-43；90 名患者中的 29 名），最大耐受剂量未达到。在剂量扩展队列中，总体缓解率为 26%（95%CI 18-36；107 名患者中的 28 名）。最常见的 3 级或更高级别的不良事件是中性粒细胞减少症（48[45%]例 107 名患者）、贫血（30[28%]例）、感染（29[27%]例）和血小板减少症（23[22%]例）。57（53%）名患者发生严重不良事件。有 1（1%）例治疗相关死亡（败血症）和 5（5%）例患者因不良事件停止 iberdomide 治疗。
Iberdomide 加地塞米松在经过大量预处理的多发性骨髓瘤患者中通常是安全的，并且具有有意义的临床活性，包括对免疫调节药物耐药的疾病。这些数据表明，需要进一步评估 iberdomide 加地塞米松或其他标准的抗骨髓瘤治疗。
百时美施贵宝。
