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Deep MRD profiling defines outcome and unveils different modes of treatment resistance in standard- and high-risk myeloma.

深度MRD分析定义了结果,并揭示了标准和高风险骨髓瘤的不同治疗耐药模式。

  • 影响因子:7.27
  • DOI:10.1182/blood.2020006731
  • 作者列表:"Goicoechea I","Puig N","Cedena MT","Burgos L","Cordón L","Vidriales MB","Flores-Montero J","Gutierrez NC","Calasanz MJ","Ramos MM","Lara-Astiaso D","Vilas-Zornoza A","Alignani D","Rodriguez I","Sarvide S","Alameda D","Garcés JJ","Rodriguez S","Fresquet V","Celay J","Garcia-Sanz R","Martinez-Lopez J","Oriol A","Rios R","Martin-Sanchez J","Martinez-Martinez R","Sarra J","Hernandez MT","de la Rubia J","Krsnik I","Moraleda JM","Palomera L","Bargay J","Martinez-Climent JA","Orfao A","Rosiñol L","Mateos MV","Lahuerta JJ","Blade J","San Miguel J","Paiva B
  • 发表时间:2021-01-07
Abstract

:Patients with multiple myeloma (MM) carrying standard- or high-risk cytogenetic abnormalities (CAs) achieve similar complete response (CR) rates, but the later have inferior progression-free survival (PFS). This questions the legitimacy of CR as a treatment endpoint and represents a biological conundrum regarding the nature of tumor reservoirs that persist after therapy in high-risk MM. We used next-generation flow (NGF) cytometry to evaluate measurable residual disease (MRD) in MM patients with standard- vs high-risk CAs (n = 300 and 90, respectively) enrolled in the PETHEMA/GEM2012MENOS65 trial, and to identify mechanisms that determine MRD resistance in both patient subgroups (n = 40). The 36-month PFS rates were higher than 90% in patients with standard- or high-risk CAs achieving undetectable MRD. Persistent MRD resulted in a median PFS of ∼3 and 2 years in patients with standard- and high-risk CAs, respectively. Further use of NGF to isolate MRD, followed by whole-exome sequencing of paired diagnostic and MRD tumor cells, revealed greater clonal selection in patients with standard-risk CAs, higher genomic instability with acquisition of new mutations in high-risk MM, and no unifying genetic event driving MRD resistance. Conversely, RNA sequencing of diagnostic and MRD tumor cells uncovered the selection of MRD clones with singular transcriptional programs and reactive oxygen species-mediated MRD resistance in high-risk MM. Our study supports undetectable MRD as a treatment endpoint for patients with MM who have high-risk CAs and proposes characterizing MRD clones to understand and overcome MRD resistance. This trial is registered at www.clinicaltrials.gov as #NCT01916252.

摘要

: 携带标准或高风险细胞遗传学异常 (CAs) 的多发性骨髓瘤 (MM) 患者获得相似的完全缓解率 (CR),但后者的无进展生存期 (PFS) 较差。这对CR作为治疗终点的合法性提出了质疑,并代表了一个关于高风险MM治疗后持续存在的肿瘤储库性质的生物学难题。我们使用新一代流式 (NGF) 细胞术评估了参加PETHEMA/GEM2012MENOS65试验的MM患者中标准与高危CAs (分别为n = 300和90) 可测量的残留病 (MRD),并确定在两个患者亚组 (n = 40) 中确定MRD抗性的机制。在标准或高风险CAs患者中,36个月的PFS率高于90%,达到不可检测的MRD。在标准和高危CAs患者中,持续MRD导致的中位PFS分别为 ∼ 3年和2年.进一步使用NGF分离MRD,然后对配对诊断和MRD肿瘤细胞进行全外显子组测序,发现标准风险CAs患者的克隆选择更大,高风险MM获得新突变的基因组不稳定性更高,并且没有驱动MRD耐药的统一遗传事件.相反,诊断和MRD肿瘤细胞的RNA测序揭示了高风险MM中具有单一转录程序和活性氧介导的MRD抗性的MRD克隆的选择。我们的研究支持不可检测的MRD作为具有高风险CAs的MM患者的治疗终点,并提出表征MRD克隆以理解和克服MRD抗性。该试验在www.clinicaltrials.gov注册为 # nct01916252。

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