University of Chicago Medical Center, Chicago, Illinois.
Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.
JAMA Oncol. 2022 Sep 1;8(9):1278-1286. doi: 10.1001/jamaoncol.2022.2424.
IMPORTANCE: Treatment of newly diagnosed multiple myeloma (NDMM) with a quadruplet regimen consisting of a monoclonal antibody, proteasome inhibitor, immunomodulatory imide, and corticosteroid has been associated with improved progression-free survival (PFS) compared with triplet regimens. The optimal quadruplet combination, and whether this obviates the need for frontline autologous stem cell transplant (ASCT), remains unknown. We evaluated elotuzumab and weekly carfilzomib, lenalidomide, and dexamethasone (Elo-KRd) without ASCT in NDMM. OBJECTIVE: To investigate the efficacy of Elo-KRd using a measurable residual disease (MRD)-adapted design in NDMM regardless of ASCT eligibility. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, single-arm, phase 2 study enrolled patients between July 2017 and February 2021. Median follow-up was 29 months. INTERVENTIONS: Twelve to 24 cycles of Elo-KRd; consecutive MRD-negative results at 10-6 by next-generation sequencing (NGS) after cycles 8 (C8) and 12 determined the duration of Elo-KRd. This was followed by Elo-Rd (no carfilzomib) maintenance therapy until disease progression. MAIN OUTCOMES AND MEASURES: The primary end point was the rate of stringent complete response (sCR) and/or MRD-negativity (10-5) after C8 Elo-KRd. Secondary end points included safety, rate of response, MRD status, PFS, and overall survival (OS). As an exploratory analysis, MRD was assessed using liquid chromatography mass spectrometry (MS) on peripheral blood samples. RESULTS: Forty-six patients were enrolled (median age 62 years, 11 [24%] aged >70 years). Overall, 32 (70%) were White, 6 (13%) were Black, 3 (6%) were more than 1 race, and 5 (11%) were of unknown race. Thirty-three (72%) were men and 13 (28%) were women. High-risk cytogenetic abnormalities were present in 22 (48%) patients. The rate of sCR and/or MRD-negativity after C8 was 26 of 45 (58%), meeting the predefined statistical threshold for efficacy. Responses deepened over time, with the MRD-negativity (10-5) rate increasing to 70% and MS-negativity rate increasing to 65%; concordance between MRD by NGS and MS increased over time. The most common (>10%) grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively). There was 1 grade 5 myocardial infarction. The estimated 3-year PFS was 72% overall and 92% for patients with MRD-negativity (10-5) at C8. CONCLUSIONS AND RELEVANCE: An MRD-adapted design using elotuzumab and weekly KRd without ASCT showed a high rate of sCR and/or MRD-negativity and durable responses. This approach provides support for further evaluation of MRD-guided deescalation of therapy to decrease treatment exposure while sustaining deep responses. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02969837.
重要性：与三联方案相比，新诊断多发性骨髓瘤（NDMM）中使用包含单克隆抗体、蛋白酶体抑制剂、免疫调节剂和皮质类固醇的四联方案治疗与无进展生存期（PFS）的改善相关。最佳四联方案，以及这是否需要一线自体干细胞移植（ASCT），仍然未知。我们评估了在 NDMM 中不进行 ASCT 的依洛尤单抗联合每周卡非佐米、来那度胺和地塞米松（Elo-KRd）。 目的：通过使用基于可测量残留疾病（MRD）的适应性设计，无论 ASCT 是否合格，在 NDMM 中调查 Elo-KRd 的疗效。 设计、地点和参与者：这项多中心、单臂、2 期研究于 2017 年 7 月至 2021 年 2 月间招募了患者。中位随访时间为 29 个月。 干预措施：12 至 24 个周期的 Elo-KRd；在第 8 周期（C8）和第 12 周期后，连续的 NGS 下 MRD-阴性结果为 10-6，确定 Elo-KRd 的持续时间。随后进行 Elo-Rd（无卡非佐米）维持治疗，直至疾病进展。 主要结果和测量：主要终点是 C8Elo-KRd 后严格完全缓解（sCR）和/或 MRD 阴性（10-5）的发生率。次要终点包括安全性、反应率、MRD 状态、PFS 和总生存（OS）。作为一项探索性分析，使用外周血样本的液相色谱-质谱法（MS）评估了 MRD。 结果：共纳入 46 例患者（中位年龄 62 岁，11 例[24%]年龄>70 岁）。总体而言，32 例（70%）为白人，6 例（13%）为黑人，3 例（6%）为多种族，5 例（11%）为未知种族。33 例（72%）为男性，13 例（28%）为女性。22 例（48%）患者存在高危细胞遗传学异常。C8 后 sCR 和/或 MRD 阴性率为 45 例中的 26 例（58%），达到了疗效的预设统计学阈值。反应随着时间的推移而加深，MRD 阴性（10-5）率增加到 70%，MS 阴性率增加到 65%；NGS 和 MS 之间的 MRD 一致性随着时间的推移而增加。>10%的最常见的 3 级或 4 级不良事件为肺部和非肺部感染（分别为 13%和 11%）。有 1 例 5 级心肌梗死。总的 3 年 PFS 为 72%，C8 时 MRD 阴性（10-5）的患者为 92%。 结论和相关性：使用依洛尤单抗和每周 KRd 且不进行 ASCT 的基于 MRD 的适应性设计显示出较高的 sCR 和/或 MRD 阴性率和持久的反应。这种方法为进一步评估 MRD 指导的治疗降级提供了支持，以减少治疗暴露，同时保持深度反应。 试验注册：ClinicalTrials.gov 标识符：NCT02969837。
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