基于新一代流式细胞术的多发性骨髓瘤微小残留病灶检测。

Measurable Residual Disease by Next-Generation Flow Cytometry in Multiple Myeloma.

机构信息

Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada Instituto de Investigacion Sanitaria de Navarra, Pamplona, Spain.

Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca, Salamanca, Spain.

出版信息

J Clin Oncol. 2020 Mar 10;38(8):784-792. doi: 10.1200/JCO.19.01231. Epub 2019 Nov 26.

DOI:10.1200/JCO.19.01231

PMID:31770060

Abstract

PURPOSE

Assessing measurable residual disease (MRD) has become standard with many tumors, but the clinical meaning of MRD in multiple myeloma (MM) remains uncertain, particularly when assessed by next-generation flow (NGF) cytometry. Thus, we aimed to determine the applicability and sensitivity of the flow MRD-negative criterion defined by the International Myeloma Working Group (IMWG).

PATIENTS AND METHODS

In the PETHEMA/GEM2012MENOS65 trial, 458 patients with newly diagnosed MM had longitudinal assessment of MRD after six induction cycles with bortezomib, lenalidomide, and dexamethasone (VRD), autologous transplantation, and two consolidation courses with VRD. MRD was assessed in 1,100 bone marrow samples from 397 patients; the 61 patients without MRD data discontinued treatment during induction and were considered MRD positive for intent-to-treat analysis. The median limit of detection achieved by NGF was 2.9 × 10. Patients received maintenance (lenalidomide ± ixazomib) according to the companion PETHEMA/GEM2014MAIN trial.

RESULTS

Overall, 205 (45%) of 458 patients had undetectable MRD after consolidation, and only 14 of them (7%) have experienced progression thus far; seven of these 14 displayed extraosseous plasmacytomas at diagnosis and/or relapse. Using time-dependent analysis, patients with undetectable MRD had an 82% reduction in the risk of progression or death (hazard ratio, 0.18; 95% CI, 0.11 to 0.30; < .001) and an 88% reduction in the risk of death (hazard ratio, 0.12; 95% CI, 0.05 to 0.29; < .001). Timing of undetectable MRD (after induction intensification) had no impact on patient survival. Attaining undetectable MRD overcame poor prognostic features at diagnosis, including high-risk cytogenetics. By contrast, patients with Revised International Staging System III status and positive MRD had dismal progression-free and overall survivals (median, 14 and 17 months, respectively). Maintenance increased the rate of undetectable MRD by 17%.

CONCLUSION

The IMWG flow MRD-negative response criterion is highly applicable and sensitive to evaluate treatment efficacy in MM.

摘要

目的

评估可测量的残留疾病（MRD）已经成为许多肿瘤的标准，但在多发性骨髓瘤（MM）中，MRD 的临床意义仍不确定，尤其是通过下一代流式细胞术（NGF）评估时。因此，我们旨在确定国际骨髓瘤工作组（IMWG）定义的流式细胞术 MRD 阴性标准的适用性和敏感性。

方法

在 PETHEMA/GEM2012MENOS65 试验中，458 例新诊断的 MM 患者在接受硼替佐米、来那度胺和地塞米松（VRD）、自体移植和两个 VRD 巩固疗程的 6 个诱导周期后进行纵向 MRD 评估。397 例患者的 1100 个骨髓样本进行了 MRD 评估；61 例无 MRD 数据的患者在诱导期间停止治疗，意向治疗分析中被认为是 MRD 阳性。NGF 检测到的最低检测限中位数为 2.9×10-5。根据 PETHEMA/GEM2014MAIN 试验，患者接受维持治疗（来那度胺±伊沙佐米）。

结果

总体而言，458 例患者中有 205 例（45%）在巩固治疗后 MRD 不可检测，其中只有 14 例（7%）迄今为止出现进展；这 14 例中有 7 例在诊断和/或复发时出现骨外浆细胞瘤。使用时间依赖性分析，MRD 不可检测的患者进展或死亡的风险降低了 82%（风险比，0.18；95%CI，0.11 至 0.30；<0.001），死亡风险降低了 88%（风险比，0.12；95%CI，0.05 至 0.29；<0.001）。不可检测 MRD 的时间（诱导强化后）对患者生存没有影响。在诊断时达到不可检测的 MRD 可克服预后不良的特征，包括高危细胞遗传学。相比之下，具有修订后的国际分期系统 III 状态和阳性 MRD 的患者的无进展生存期和总生存期均较差（中位数分别为 14 个月和 17 个月）。维持治疗使不可检测 MRD 的比例增加了 17%。