Background

Despite recent advances in therapeutic options, there remains an unmet need for treating patients with relapsed or refractory multiple myeloma, especially in those previously exposed or refractory to lenalidomide. This updated efficacy and safety analysis from the phase 3 CANDOR study compared carfilzomib, daratumumab, and dexamethasone (KdD) with carfilzomib and dexamethasone (Kd) in patients with relapsed or refractory multiple myeloma.

Methods

In this updated analysis of the randomised, multicentre, open-label, phase 3 CANDOR study, patients (aged ≥18 years) with relapsed or refractory multiple myeloma, at least a partial response to between one and three previous therapies, and Eastern Cooperative Oncology Group performance status of 0–2, were recruited from 102 medical centres globally and randomly assigned (2:1) by interactive voice or web response software to receive KdD or Kd. Participants were stratified by disease stage, previous proteasome inhibitor or anti-CD38 antibody exposure, and number of previous therapies. All patients received intravenous infusions of carfilzomib twice per week at 56 mg/m² (20 mg/m² on days 1 and 2 during cycle 1) on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Daratumumab (8 mg/kg) was administered intravenously on days 1 and 2 of cycle 1 and at 16 mg/kg weekly for the remaining doses of the first two cycles, then every 2 weeks for four cycles (cycles 3–6), and every 4 weeks thereafter. Patients received 40 mg dexamethasone weekly (20 mg for patients >75 years old). This analysis was a preplanned interim analysis for overall survival; however, at the time of data cutoff, overall survival data were not mature. The primary endpoint was progression-free survival. Here, we provide updated progression-free survival data, assessed centrally by Onyx Response Computer Algorithm in the intention-to-treat population, with 11 months additional follow-up. Adverse events were assessed in the safety population, which included all participants who received at least one dose of trial treatment. CANDOR is registered with ClinicalTrials.gov, NCT03158688, and is active but not recruiting.

Findings

Between June 13, 2017, and June 25, 2018, 466 patients were enrolled, of whom 312 received KdD and 154 received Kd. At data cutoff (June 15, 2020), median follow-up was 27·8 months (IQR 25·6–29·5) for KdD and 27·0 months (13·2–28·6) for Kd. Median progression-free survival was 28·6 months (95% CI 22·7–not estimable [NE]) in the KdD group and 15·2 months (11·1–19·9) in the Kd group (hazard ratio 0·59 [95% CI 0·45–0·78], log-rank p<0·0001). Treatment-emergent adverse events in the safety population were consistent with the primary analysis. Grade 3 or worse treatment-emergent adverse events occurred in 268 (87%) patients in the KdD group and 116 (76%) in the Kd group; most commonly thrombocytopenia (76 [25%] vs 25 [16%], respectively), hypertension (65 [21%] vs 23 [15%]), pneumonia (54 [18%] vs 14 [9%]), and anaemia (53 [17%] vs 23 [15%]). Serious adverse events occurred in 194 (63%) patients with KdD and 76 (50%) with Kd. Adverse events leading to death occurred in 27 (9%) patients in the KdD group and seven (5%) in the Kd group; most commonly septic shock (five [2%] vs one (1%]) and pneumonia (four [1%] vs none). No new treatment-related deaths have occurred since the primary analysis.

Interpretation

A clear, maintained progression-free survival benefit of KdD over Kd with longer follow-up was confirmed, making KdD an emerging standard-of-care for patients with relapsed or refractory multiple myeloma.

Funding

Amgen and Janssen.

中文翻译：

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卡非佐米、地塞米松和达雷妥尤单抗对比卡非佐米和地塞米松治疗复发或难治性多发性骨髓瘤 (CANDOR)：一项随机、多中心、开放标签、3 期研究的最新结果

背景

尽管最近在治疗选择方面取得了进展，但治疗复发性或难治性多发性骨髓瘤患者的需求仍未得到满足，特别是那些先前暴露于或难治性来那度胺的患者。这项来自 3 期 CANDOR 研究的最新疗效和安全性分析比较了卡非佐米、达雷妥尤单抗和地塞米松 (KdD) 与卡非佐米和地塞米松 (Kd) 在复发或难治性多发性骨髓瘤患者中的疗效。

方法

在这项对随机、多中心、开放标签、3 期 CANDOR 研究的更新分析中，患有复发性或难治性多发性骨髓瘤的患者（年龄≥18 岁）至少对一到三种先前的治疗有部分反应，以及东部合作肿瘤学从全球 102 个医疗中心招募 0-2 组绩效状态，并通过交互式语音或网络响应软件随机分配 (2:1) 接受 KdD 或 Kd。参与者按疾病阶段、先前的蛋白酶体抑制剂或抗 CD38 抗体暴露以及先前治疗的数量进行分层。所有患者每周两次以 56 mg/m ² (20 mg/m ²在周期 1 的第 1 天和第 2 天）在每个 28 天周期的第 1、2、8、9、15 和 16 天。达雷妥尤单抗 (8 mg/kg) 在第 1 周期的第 1 天和第 2 天静脉内给药，前两个周期的剩余剂量每周 16 mg/kg，然后每 2 周一次，共四个周期（周期 3-6），并且此后每 4 周。患者每周接受 40 mg 地塞米松（>75 岁的患者为 20 mg）。该分析是一项预先计划的总体生存期中期分析；然而，在数据截止时，总体生存数据还不成熟。主要终点是无进展生存期。在这里，我们提供更新的无进展生存数据，这些数据通过 Onyx 响应计算机算法在意向治疗人群中进行集中评估，并进行了 11 个月的额外随访。在安全人群中评估不良事件，其中包括接受至少一剂试验治疗的所有参与者。CANDOR 已在 ClinicalTrials.gov 注册，NCT03158688，处于活跃状态，但未招募。

发现

2017 年 6 月 13 日至 2018 年 6 月 25 日期间，466 名患者入组，其中 312 名接受 KdD，154 名接受 Kd。在数据截止时（2020 年 6 月 15 日），Kd 的中位随访时间为 27·8 个月（IQR 25·6-29·5），Kd 的中位随访时间为 27·0 个月（13·2-28·6）。KdD 组的中位无进展生存期为 28·6 个月（95% CI 22·7–不可估计 [NE]），Kd 组为 15·2 个月（11·1-19·9）（风险比 0 ·59 [95% CI 0·45–0·78]，对数秩 p<0·0001)。安全人群中出现的治疗不良事件与主要分析一致。KdD 组 268 例（87%）患者和 Kd 组 116 例（76%）患者发生 3 级或更严重的治疗中出现的不良事件；最常见的血小板减少症（分别为 76 [25%] vs 25 [16%]），高血压（65 [21%] vs23 [15%])、肺炎 (54 [18%] vs 14 [9%]) 和贫血 (53 [17%] vs 23 [15%])。194 名 (63%) 的 Kd 患者和 76 名 (50%) 的 Kd 患者发生了严重的不良事件。导致死亡的不良事件发生在 KdD 组 27 例 (9%) 患者和 Kd 组 7 例 (5%) 患者中；最常见的是感染性休克（5 [2%]对1 (1%]）和肺炎（4 [1%]对无）。自初步分析以来，未发生新的治疗相关死亡。

解释

证实了 KdD 与 Kd 相比具有明显、持续的无进展生存获益，且随访时间更长，这使得 KdD 成为复发或难治性多发性骨髓瘤患者的新兴护理标准。

资金

安进和詹森。