【作者】 徐杰；

【导师】 房佰俊；

【作者基本信息】 郑州大学 ， 内科学（专业学位）， 2020， 硕士

【摘要】 研究背景多发性骨髓瘤(Multiple Myeloma,MM)是一种恶性浆细胞异常增殖性疾病,异常增殖的浆细胞可分泌单克隆免疫球蛋白或其片段,进而导致相关器官或组织损伤。相关研究表明,蛋白酶体抑制剂(Proteasome Inhibitors,PIs)和免疫调节药物(Immunomodulatory Drugs,IMi Ds)以及自体干细胞移植(Autologous Stem Cell Transplantation,ASCT)明显改善了MM患者的预后,但是由于疾病本身高度的细胞遗传学异质性,使其容易复发,并且难以治愈。来那度胺是第二代免疫调节剂,通过抑制肿瘤细胞增殖、诱导肿瘤细胞凋亡以及激活免疫效应细胞进而发挥抗MM肿瘤细胞作用。该药与地塞米松联用在关键性III期临床试验(MM-009、MM-010、MM-021)中均显示出良好的临床益处。但是在该治疗方案中,各中心对影响复发难治性多发性骨髓瘤(Relapsed or Refractory Multiple Myeloma,RRMM)患者预后因素报道并不一致。目的评估来那度胺联合低剂量地塞米松在RRMM患者中的临床疗效、安全性及药物动力学特征,并分析影响其预后因素。方法本研究收集了2016年10月至2019年12月在河南省肿瘤医院血液科就诊的42例RRMM患者,随访日期截止到2019年12月31日。该研究获首都医科大学附属北京朝阳医院伦理委员会批准实施(伦理号:LNDA201605)。患者口服来那度胺25mg/d,共21天,停药7天,28天为一个周期,剂量依据肾功能情况进行调整。每个用药周期的第1、8、15和22天口服地塞米松40mg。计算患者总缓解率(Overall Response Rate,ORR)、无进展生存期(Progress Free Survival,PFS)、总生存期(Overall survival,OS)、总缓解持续时间(Duration of Remission,DOR)、疾病控制率(Disease Control Rate,DCR)以评估疗效。统计患者年龄、肾功能情况、R-ISS分期、乳酸脱氢酶(LDH)、骨髓浆细胞比例(Bone Marrow Plasma Cell ratio,BMPC)、既往硼替佐米或沙利度胺应用情况、先前自体干细胞移植史、既往复发次数、既往化疗次数、是否合并髓外侵犯等指标以探讨影响RRMM患者预后因素。分析患者血液系统及非血液系统不良事件以评估其安全性。检测用药第一天来那度胺血药浓度变化以观察其药代动力学特征。结果本研究共纳入了42例RRMM患者,其中4例患者用药1疗程后失访,38例患者接受疗效评价,在可评价人群中,ORR为60.5%(23/38),其中47.4%(18/38)的患者达到PR及其以上,DCR高达92.1%(35/38),中位DOR为6个月(0.6-24.0),中位PFS为5.5个月(1.1-24.0),中位OS为23.8个月(3.5-35.4)。单因素Cox分析显示:影响PFS的因素有髓外病变、多次复发、R-ISS分期、LDH升高。影响OS的因素有髓外病变、多次复发、R-ISS分期、LDH升高。Cox多因素分析显示合并髓外侵犯、R-ISS分期、LDH升高、多次复发是影响PFS的独立预后不良因素(P<0.05)。LDH升高是影响OS的独立预后不良因素。最常见的不良事件为贫血(52.6%)、中性粒细胞减少(50.0%)、白细胞较少(39.5%)),其中最常见的3/4级不良事件为贫血(29.0%)和中性粒细胞减少(21.0%),其次为血小板减少(15.8%)。肾功能正常患者中,来那度胺血药浓度监测显示Tmax中位数为1.00小时,t1/2介于2.15-8.97小时,Cmax介于352-1110ng/m L;AUC0-t介于1378-10136 h*ng/m L;AUC0-∞介于1405-12064h*ng/m L,与白种人和亚洲患者报道的结果相似。结论1.来那度胺联合低剂量地塞米松对于RRMM患者具有较好的疗效和安全性。2.合并LDH升高、髓外侵犯、R-ISS分期(Ⅲ期)的RRMM患者应用来那度胺联合低剂量地塞米松疗效不佳。3.对于首次复发,接受过多次治疗(既往未使用过来那度胺),年龄≥65岁、合并肾功能不全、既往使用过硼替佐米或者沙利度胺、先前接受过自体干细胞移植、BMPC较高的RRMM患者,来那度胺联合低剂量地塞米松仍具有较好的疗效。4.肾功能正常的RRMM患者体内来那度胺的药代动力学特征与所报道的白种人和亚洲患者一致。更多还原

【Abstract】 Background Multiple myeloma(MM)is a hematologic disorder characterized by abnormal proliferation of plasmacytes.Those plasmacytes secret monoclonal immunoglobulin or the fragments,leading to relative organ or tissue injure.Although enormous advances with the appearance of Proteasome inhibitors(PIs),immunomodulatory drugs(IMi Ds)and autologous stem cell transplantation(ASCT),MM remains incurable due to cytogenetic heterogeneity.Lenalidomide is a second-generation immunomodulatory.It works on MM by reducing proliferation and inducing apoptosis of tumor cells,and activating immunologic effector cells.Several critical phase III clinical trials(MM-009,MM-010,MM-021)have shown the significant clinical benefits by using lenalidomide combining with low-dose dexamethasone.However,those factors,which may affect prognosis of relapsed or refractory multiple myeloma(RRMM)patients treated with lenalidomide combining with low-dose dexamethasone,are not consistent in these studies.Objective To evaluate the efficiency,safety and pharmacokinetics of lenalidomide combining with low dose dexamethasone in RRMM patients,and analyze the factors that may affect prognosis of RRMM patients.Methods In this study,42 patients with RRMM in Henan Cancer Hospital from October2016 to December,2019 were collected and the follow-up date was up to Dec 31,2019.The study was approved by Beijing Chao-yang Hospital Affiliated to Capital Medical University Ethics Committee(Ethics No.:LNDA201605).These patients took lenalidomide orally 25mg/d,which was adjusted based on renal function,for 21 days with a break for 7 days.Dexamethasone(40mg)was taken orally on day 1,8,15 and 22 on each cycle.Overall response rate(ORR),progess free survival(PFS),overall surval(OS),duration of remission(DOR)and disease control rate(DCR)were calculated for efficacy analysis.Correlation of prognosis and age,renal function,revised International Staging System(R-ISS),serum lactate dehydrogenase(LDH),bone marow plasma cell ration(BMPC),bortezomide/thalidomide used or not,history of autologous stem cell transplantation,times of relapse,times of chemotherapies used before,extamedually lesions was stastistically analyzed,respectively.Safety was evaluated based on the adverse events on hematology and non-hematology.The concentration of lenalidomide in blood was measured on the 1st day of the 1st cycle to observe pharmacokinetics.Results Among 42 RRMM patients collected,38 patients could be analyzed while 4 out of them inconnected after the 1st cycle treatment.ORR was 60.5%(23/38),and47.4%(18/38)could reach PR and even above.DCR was 92.1%(35/38),median DOR was 6 months(0.6-24.0),and median PFS was 5.5 months(1.1-24.0),median PFS was 5.5 months(1.1-35.4).Univariate cox analusis was performed that the PFS was affected by extramedullary lesions,multi-times of recurrence,R-ISS,high LDH;OS was affected by extramedullary lesions,multi-times of recurrence,R-ISS stage,high LDH.Cox multivariate analysis was showed that extrameduallary invasion,R-ISS stage,high LDH,and multi-times of recurrence were independent factors of PFS for RRMM patients(P<0.05).High LDH were independent factor of OS of RRMM patients(P<0.05).The most common adverse events were anemia(52.6%),neutropenia(50.0%),and leukopenia(39.5%).The most common 3/4 level adverse events were anemia(29.0%)and neutropenia(21.0%),followed by thrombocytopenia(15.8%).For RRMM patients with normal renal function,median Tmax of lenalidomide blood concentration was 1hr,t1/2 was between 2.15-8.97 hrs,Cmax between 352-1110ng/m L,AUC0-t between 1378-10136h*ng/m L and AUC0-∞between 1405-12064h*ng/m L,which were similar in Caucasian and Asian patients reported by relative studies.Conclusions1.Lenalidomide combined with low-dose dexamethasone is a highly effectively therapy with an acceptable adverse event profile for RRMM patients.2.High serum lactate dehydrogenase,R-ISS stage(III stage),extramedullary invasion are factors of poor prognostic for RRMM patients.3.For RRMM patients with first recurrence,multi-times of therapy,≥ 65 years,renal insufficiency,or history of bortezomib or thalidomide application,history of bortezomib or thalidomide application history of autologous stem cell transplantation,high bone marrow plasma cell ration(BMPC),lenalidomide combined with low-dose dexamethasone also shows highly efficacy.4.Pharmacokinetic characteristics of leinalidomide in this study is similar to that in previous studies on Caucasian and other Asian.更多还原