Background Lenalidomide maintenance improves progression-free survival for patients with multiple myeloma, although its optimal duration is unknown. Clearance of minimal residual disease (MRD) in the bone marrow results in superior outcomes, although its attainment or sustainment does not alter clinical decision-making. Studies that have evaluated MRD serially are limited in length. We therefore aimed to evaluate longitudinal changes in MRD-status (dynamics) and their association with progression-free survival in patients with multiple myeloma. METHODS In this single-centre, single-arm, phase 2 study, we enrolled patients aged 18 years and older from the Memorial Sloan Kettering Cancer Center (New York, NY, USA) who had newly diagnosed multiple myeloma following unrestricted frontline therapy and an Eastern Cooperative Oncology Group Performance Status of 2 or lower, including patients who started maintenance before study enrolment. All participants received lenalidomide maintenance at 10 mg for 21 days of 28-day cycles until progression or unacceptable toxic effects for up to 5 years on protocol. The primary endpoint was progression-free survival at 60 months per protocol and key secondary endpoints were MRD rates after completion of the 12th, 24th, and 36th cycle of maintenance and the association between progression-free survival and annual measurement of MRD status. MRD was assessed from first-pull bone marrow aspirates at baseline and annually by flow cytometry per International Myeloma Working Group criteria, (limit of detection of at least 1 × 10-5) up to a maximum of 5 years. Patients who completed at least four cycles of treatment were included in the analysis of the primary endpoint, and patients who had completed at least one dose of treatment on protocol were assessable for secondary endpoints. The study was registered at ClinicalTrials.gov, NCT02538198, and is now closed to accrual. FINDINGS Between Sept 8, 2015, and Jan 25, 2019, 108 patients (100 evaluable for the primary endpoint) were enrolled. Median follow-up was 40·7 months (95% CI 38·7-45·0). At 60 months, progression-free survival was 64% (95% CI 52-79). Median progression-free survival was unreached (95% CI unreached-unreached). MRD dynamics were assessed using 340 MRD assessments done over 5 years for 103 evaluable patients. Patients who sustained MRD negativity for 2 years (n=34) had no recorded disease progression at median 19·8 months (95% CI 15·8-22·3) past the 2-year maintenance landmark. By contrast, patients who lost their MRD-negative responses (n=10) were more likely to progress than those with sustained MRD negativity (HR infinite; p<0·0001) and those with persistent MRD positivity (HR 5·88, 95% CI 1·18-33·33; p=0·015) at the 2-year landmark. Haematological and non-haematological serious adverse events occurred in 19 patients (18%). The most common adverse events of grade 3 or worse were decreased lymphocyte count in 48 (44%) patients and decreased neutrophil count in 47 (44%) patients. One death occurred on study due to sepsis and heart failure and was considered unrelated to the study drug. INTERPRETATION Serial measurements of MRD allow for dynamic assessment of risk for disease progression. Early intervention should be investigated for patients with loss of MRD negativity. Sustained MRD positivity is not categorically an unfavourable outcome and might portend prolonged stability of low-level disease. FUNDING Memorial Sloan Kettering and Celgene.

中文翻译：

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多发性骨髓瘤患者连续来那度胺维持治疗的微小残留病动态：单臂、单中心、2 期试验。

背景 来那度胺维持治疗可改善多发性骨髓瘤患者的无进展生存期，尽管其最佳持续时间尚不清楚。骨髓中微小残留病（MRD）的清除可带来优异的结果，尽管其实现或维持不会改变临床决策。连续评估 MRD 的研究长度有限。因此，我们的目的是评估 MRD 状态（动态）的纵向变化及其与多发性骨髓瘤患者无进展生存期的关系。方法 在这项单中心、单臂、2 期研究中，我们招募了来自纪念斯隆凯特琳癌症中心（纽约州纽约市）的 18 岁及以上患者。美国）在不受限制的一线治疗后新诊断出多发性骨髓瘤且东部肿瘤合作组表现状态为 2 或更低的患者，包括在研究入组之前开始维持治疗的患者。所有参与者均接受 10 mg 来那度胺维持治疗，为期 21 天（每 28 天为一个周期），直至按照方案进行长达 5 年的进展或不可接受的毒性作用。主要终点是每个方案 60 个月的无进展生存期，关键次要终点是完成第 12、24 和 36 个维持周期后的 MRD 率，以及无进展生存期和每年 MRD 状态测量之间的关联。根据国际骨髓瘤工作组标准，每年通过流式细胞术对基线时首次抽取的骨髓抽吸物进行 MRD 评估，（检测限至少为 1 × 10-5）最长 5 年。完成至少四个治疗周期的患者被纳入主要终点的分析，而按照方案完成至少一剂治疗的患者可评估次要终点。该研究已在 ClinicalTrials.gov 上注册，NCT02538198，现已停止计提。结果 2015 年 9 月 8 日至 2019 年 1 月 25 日期间，共有 108 名患者（100 名可评估主要终点）入组。中位随访时间为 40·7 个月 (95% CI 38·7-45·0)。60 个月时，无进展生存率为 64% (95% CI 52-79)。中位无进展生存期未达到（95% CI 未达到-未达到）。MRD 动态评估采用 5 年来对 103 名可评估患者进行的 340 次 MRD 评估。持续 MRD 阴性 2 年的患者 (n=34) 在 2 年维持里程碑后的中位 19·8 个月 (95% CI 15·8-22·3) 没有记录到疾病进展。相比之下，失去 MRD 阴性反应的患者 (n=10) 比持续 MRD 阴性的患者 (HR 无穷大；p<0·0001) 和持续 MRD 阳性的患者 (HR 5·88, 95) 更有可能进展。 % CI 1·18-33·33；p=0·015）在 2 年里程碑处。19 名患者（18%）发生血液学和非血液学严重不良事件。最常见的 3 级或更严重不良事件是 48 名患者 (44%) 中淋巴细胞计数减少，以及 47 名患者 (44%) 中性粒细胞计数减少。研究中发生了 1 例死亡，原因是脓毒症和心力衰竭，被认为与研究药物无关。解释 MRD 的连续测量可以动态评估疾病进展的风险。对于 MRD 阴性消失的患者应进行早期干预。持续的 MRD 阳性并不是绝对的不利结果，并且可能预示着低水平疾病的长期稳定。资助纪念斯隆·凯特琳和新基公司。