硼替佐米治疗新诊断多发性骨髓瘤期间心脏不良事件的影响因素及其对生存时间影响的真实世界研究

Associated Factors and Outcome of Cardiac Adverse Events in Newly Diagnosed Multiple Myeloma Patients with Bortezomib:a Real-world Study

背景多发性骨髓瘤(MM)是一种易发生于老年群体的血液系统肿瘤,随着人口老龄化其发病率逐渐升高。随着硼替佐米等新型靶向药物的广泛应用,MM患者的中位生存期已延长至5~7年。多项个案报道硼替佐米用药期间的心脏不良事件(CAEs)病死率高,鲜见真实世界的影响因素分析。目的分析新诊断多发性骨髓瘤(NDMM)患者在应用硼替佐米期间出现CAEs的影响因素及其对生存时间的影响。方法选取2009年1月-2019年1月北京朝阳医院西院血液与肿瘤科收治的NDMM患者164例作为研究对象,以硼替佐米为基础的化疗方案作为一线诱导化疗方案,仅在接受硼替佐米的治疗过程中评估CAEs并分为CAEs组26例,对照组138例。CAEs组中分为急性CAEs亚组(第1疗程过程中出现的CAEs)与非急性CAEs亚组(第2疗程及之后出现的CAEs)。收集比较CAEs组和对照组的临床资料;记录CAEs组患者发生CAEs时硼替佐米的累积剂量以及发生CAEs时的临床表现;分析NDMM患者在应用硼替佐米期间出现CAEs的影响因素及CAEs对生存时间的影响。结果CAEs组年龄﹥65岁、吸烟、心脏病史、高血压史、高危细胞遗传学比例及血清肌酐(Scr)、乳酸脱氢酶(LDH)水平高于对照组,血红蛋白(HGB)水平低于对照组(P<0.05)。26例CAEs患者中急性CAEs 14例,非急性CAEs 12例。急性CAEs中位累积剂量为2.7 mg/m^2;非急性CAEs中位累积剂量为20.8 mg/m^2。急性CAEs患者均发生心力衰竭(100.0%),非急性CAEs患者中心力衰竭4例(33.3%),心房颤动4例(33.3%),静脉血栓栓塞2例(16.6%),急性冠脉综合征2例(16.6%)。呼吸困难与心悸为最常见的CAEs症状,其次为水肿和体质量增加。多因素Logistic回归分析结果显示,年龄≥66岁、吸烟、HGB<76 g/L、Scr≥176μmol/L、LDH≥173 U/L是应用硼替佐米治疗期间发生CAEs的危险因素(P<0.05)。CAEs组与对照组的中位总体生存时间(OS)分别为28、77个月,两组比较差异有统计学意义(χ^2=66.563,P<0.01)。急性CAEs与非急性CAEs两亚组中位OS分别为9、36个月,两组比较差异有统计学意义(χ^2=7.229,P<0.01)。结论硼替佐米治疗期间出现CAEs的患者预后差,其危险因素为年龄≥66岁、吸烟、HGB<76 g/L、Scr≥176μmol/L、LDH≥173 U/L,急性CAEs生存时间较短。

Background Multiple myeloma(MM)is a hematological malignancy that easily occurs in older adults,whose morbidity increases with aging.The median overall survival of MM patients has been prolonged to 5-7 years largely owing to wide application of bortezomib and other novel targeted drugs.A number of cases have been reported to a high risk of mortality following cardiac adverse events(CAEs)during bortezomib treatment,but related real-world studies of the influencing factors are rare.Objective To explore the associated factors and outcome of CAEs in newly diagnosed MM patients with bortezomib.Methods In this retrospective study,164 newly diagnosed MM patients who were admitted to the Department of Hematology and Oncology,Beijing Chao-Yang Hospital(West),Capital Medical University from January 1,2009 to January 31,2019 were enrolled,and received bortezomib-based chemotherapy as the induction chemotherapy.During bortezomib treatment,26 with CAEs and 138 without were assigned to CAEs group〔including 14 had CAEs during the first treatment course(acute CAEs subgroup),and 12 had CAEs in the second or subsequent treatment course(non-acute CAEs subgroup)〕and control group,respectively.Clinical data of CAEs and control groups were collected and compared.The cumulative dose of bortezomib and clinical manifestations when CAEs occurred were recorded.Factors associated with CAEs were explored.The survival following CAEs was analyzed.Results Compared with control group,CAEs group had a higher proportion of patients aged over 65,or higher proportion of smokers,patients with a history of heart disease,hypertension,or high-risk cytogenetics(P<0.05).CAEs group also showed higher mean levels of Scr and LDH and lower mean HGB(P<0.05).The median cumulative dose of bortezomib for acute and non-acute CAEs patients was 2.69 mg/m^2,and 20.8 mg/m^2,respectively.Heart failure(100.0%)occurred in all patients with acute CAEs,while in non-acute CAEs subgroup there were 4 cases of heart failure(33.3%),4 cases of atrial fibrillation(33.3%),2 cases of venous thrombosis(16.6%),and 2 cases of coronary syndrome(16.6%).Dyspnea and palpitation were the most common symptoms of CAEs,followed by edema and increased body weight.Multivariate logistic regression analysis showed that age≥66,smoking,HGB<76 g/L,Scr≥176μmol/L and LDH≥173 U/L were independently associated with increased risk of CAEs during bortezomib treatment(P<0.05).The mean overall survival of the CAEs group and control group was 28 and 77 months,respectively,showing a significant difference(χ^2=66.563,P<0.01).The mean overall survival of acute CAEs and non-acute CAEs subgroups was 9 and 36 months,respectively,showing a notable difference as well(χ^2=7.229,P<0.01).Conclusion The risk factors for CAEs during bortezomib treatment were age≥66,smoking,HGB<76 g/L,Scr≥176μmol/L and LDH≥173 U/L.Those with CAEs had a poor outcome.In particular,those with acute CAEs had a shorter survival.