多参数流式细胞术检测多发性骨髓瘤患者微小残留病106例临床观察

Role of minimal residual disease detection by multiparameter flow cytometry in newly diagnosed multiple myeloma： an analysis of 106 patients

目的探讨多参数流式细胞术（MFC）检测微小残留病（MRD）在我国初诊多发性骨髓瘤（MM）患者中的可行性及其预后意义。方法回顾性分析2013年6月至2015年6月106例采用MFC进行MRD检测连续收治的初诊MM患者的临床资料。结果①106例患者中48例（45.3%）MRD转为阴性，中位达MRD阴性时间为3个月。接受自体造血干细胞移植（ASCT）患者MRD转阴率显著高于未接受ASCT患者（62.2%对36.2%，χ^2=6.536，P=0.011）。②48例完全缓解（CR）患者中7例（14.6%）MRD持续阳性，这7例患者中5例已疾病进展，中位无进展生存（PFS）时间为19个月，3例死亡，中位总生存（OS）时间为28个月，MRD持续阳性CR患者的PFS及OS时间均明显短于MRD转阴CR患者（P值均〈0.05）。③中位随访38个月，MRD转阴患者的预后显著优于阳性患者，二者中位PFS时间分别为未达到和17个月（P〈0.001），中位OS均未达到（P〈0.001）。根据MRD水平将患者分为四组：≥1%、0.1%-〈1%、0.01%-〈0.1%和阴性，结果显示随着MRD水平的降低，患者PFS及OS时间有逐渐延长趋势。④多因素分析显示，MRD是影响MM患者PFS[HR=0.133（95% CI 0.062-0.288），P〈0.001]和OS[HR=0.156（95% CI 0.050-0.484），P=0.001]的独立预后因素。根据MRD、细胞遗传学情况将患者分为4组，结果显示MRD转阴的高危患者预后（PFS及OS）明显好于MRD阳性的高危患者（P〈0.05），而与MRD转阴的标危患者预后相近（P〉0.05）。结论ASCT患者中MFC检测的MRD转阴率更高。MRD是MM患者的独立预后因素，根据MRD水平可以对患者预后进行分层。MRD转阴的细胞遗传学高危患者的预后与标危患者相近。MFC检测MRD值得在临床推广应用。

ObjectiveTo assess the feasibility and prognostic value of the minimal residual disease （MRD） evaluated by multiparameter flow cytometry （MFC） in the newly diagnosed multiple myeloma （MM） patients of China.MethodsClinical data of 106 consecutively newly diagnosed MM patients with MRD data were retrospectively analyzed in a single center in China from June 2013 to June 2015.Results① Of 106 patients, 48 （45.3%） achieved MRD negativity. The median time to MRD-negative was 3 months. More patients undergoing autologous stem cell transplantation （ASCT） achieved MRD negativity compared with non-ASCT patients （62.2% vs 36.2%, χ^2=6.536, P=0.011）. ② Of 48 patients in complete remission （CR）, 7 （14.6%） was MRD positive, 5 of them showed disease progression （PD） during the follow-up, and 3 died. The median progression free survival （PFS） was 19 months, and the median overall survival （OS） was 28 months, both were significantly shorter than the CR patients with MRD-negative （P〈0.05）. ③At a median follow-up of 38 months, MRD-negative patients showed significantly superior outcomes compared with MRD positive ones, the PFS was not reach versus 17 months and the OS was not reach for both （P〈0.001）. Patients were grouped into 4 categories according to their MRD levels： 1% or higher, 0.1% to less than 1%, 0.01% to less than 0.1%, or negative. It showed that the outcomes （PFS and OS） tended to be improved along with the tumor depletion. ④ Multivariate prognostic analysis showed that MRD was a powerful independent prognostic factor for PFS[HR=0.133 （95% CI 0.062-0.288） , P〈0.001] and OS[HR=0.156 （95% CI 0.050-0.484） , P=0.001]. According to MRD and cytogenetics, the patients were classified into 4 groups. High risk patients with MRD negative presented a significantly better outcome than high risk patients with MRD-positive, and a similar one to the standard risk patients with MRD-negative.ConclusionsMRD negativity by MFC was more popular in MM patients undergoing ASCT. MRD was an independent prognostic factor in MM. And the prognosis of MM patients can be stratified according to the level of MRD. MRD-negative patients with high risk cytogenetics presented a similar outcome to the standard risk ones. MRD by MFC should therefore be considered more widely applied in the clinic.