Risk Factors And Prognosis Of Cardiovascular Adverse Events In Patients With Multiple Myeloma Receiving Chemotherapy

BackgroundMultiple myeloma?MM?is a malignant disease with abnormal proliferation of clonal plasma cells.Abnormal plasma cells and their products lead to a series of target organ dysfunction and clinical manifestations in MM patients.The clinical manifestations include bone destruction?bone pain and fractures?,kidney damage,hypercalcemia,anemia,and an increased risk of infection.MM accounted for 1%of all malignant tumors.And it is the second most common malignancy of the blood system,accounting for about 13%^[1].Multiple myeloma is more common among old people.The median age of diagnosis is 70years old^[4].In recent years,the maturity of autologous stem cell transplantation technology and the application of new drugs such as proteasome inhibitors and immune modulators have significantly prolonged the progression-free survival?PFS?and overall survival?OS?of such patients.It has been reported that the 10-year survival rate for patients under 60 is about 30%^[5].Altough the development and application of chemotherapy drugs had greatly improved the survival rate of tumor patients and prolonged the survival period of tumor patients,the chemotherapy-related side effects,especially cardiac side effects,have greatly affected the quality of life and survival rate of tumor patients^[7].Studies show that patients who have received chemotherapy have a higher risk of cardiovascular death compared with tumor recurrence.With the prolongation of PFS and OS in MM patients,how to reduce treatment-related side effects,especially cardiac toxicity,and the incidence of adverse cardiovascular events is a key but unsolved clinical issue in the current treatment of multiple myeloma.Data from plenty of studies showed that the proportion of MM patients with cardiovascular diseases and the proportion of MM patients with cardiovascular adverse events?CVAEs?were large.The occurrence of cardiovascular adverse events has a great impact on the survival rate of MM patients.However,there are no clear guidelines and consensus on the early identification and monitoring indicators of cardiovascular adverse events in MM patients,and further clinical studies are needed.Objectives1.To determine the incidence of cardiovascular adverse events?CVAEs?after chemotherapy for multiple myeloma,to explore the potential risk factors associated with CVAEs after chemotherapy for multiple myeloma,and the potential risk factors of CVAEs among different grades of patients.2.To explore the correlation between CVAEs and disease recurrence and the effect of CVAEs on progression-free Survival?PFS?in patients with multiple myeloma.MethodA retrospective case-control study was conducted in the second affiliated hospital of naval medical university enrolling patients who underwent more than 4 cycles of standardized chemotherapy during the period of June 30,2018 to December 31,2019.We established the inclusion and exclusion criteria,collected the patients'name,gender,age,height,weight,BMI,body surface area,phone number,home address and other personal information.And also collected the diagnostic information of patients,Durie-Salmon staget,ISS stage,m SMART risk stratification,history of smoking,drinking,hypertension,coronary heart disease,diabetes,dyslipidemia,stroke,the history of usage of drugs?antiplatelet agents,ACEI/ARB drugs,beta blockers,calcium channel blockers,diuretics,lipid-lowering drugs,etc.?,for the first time to the hospital at the beginning of measuring blood pressure,heart rate,Electrocardiogram?ECG?before treatment?including PR interval,QRS duration,and QT interphase?and echocardiography?including valve,structure,LVEF,left atrial diameter,interventricular septum thickness,left ventricular end systolic diameter,left ventricular end-diastolic diameter,left ventricular posterior wall thickness,left ventricular weight?and some laboratory indexes?C-reactive protein,hemoglobin,troponin,BNP,alanine amino transferase,straw glycine transferase,albumin,uric acid,creatinine and GFR,electrolyte,beta 2 microglobulin level?,We have followed up chemotherapy regimen,cycle number and application time of chemotherapy,occurrence time and grade of first cardiovascular adverse events?CVAEs?,and efficacy evaluation of4 cycles.The internationally common durie-salmon?DS?staging system and the international staging system?ISS?staging system were adopted to help with the MM diagnostic staging.The risk stratification of cytogenetics is only conducted by m SMART,and the Mayo version is updated by m SMART3.0.Curative effect evaluation standard adopts the 2017revision of the guidelines of curative effect evaluation standard of diagnosis and treatment of multiple myeloma in China,after chemotherapy in patients with curative effect evaluation standard mainly includes nine levels::strictly the complete response?s CR?,complete response?CR?,very good partial response?VGPR?,partial response?PR?,tiny response?MR?,stable disease?SD?,progression disease?PD?,clinical relapse and recurrence after CR.The common adverse events evaluation standard 5.0 was used to determine the occurrence and classification of cardiovascular adverse events.The cardiovascular adverse events include sick sinus syndrome,sinus bradycardia,sinus tachycardia,atrial fibrillation,atrial flutter,paroxysmal on the room tachycardia and ventricular tachycardia and ventricular arrhythmia?ventricular fibrillation,ventricular tachycardia?,cardiac arrest and complete atrioventricular block,I degree atrioventricular block,Morse type I/Morse II atrioventricular block,cardiac arrest,cardiac chest pain,cyanosis,heart failure,left ventricular systolic dysfunction,right ventricular dysfunction,myocardial infarction and myocarditis,pericardial effusion and pericardial tamponade,pericarditis,restrictive cardiomyopathy,tricuspid valve disease,aortic valvular disease,pulmonary valve disease,mitral valve disease.The study was divided into grades 1-2 and 3-5.Grades 1-2 indicated the presence of imaging evidence but no symptoms,and no treatment or intervention was required;grades 3-5 indicated the need for treatment and intervention or death.All data were analyzed with SPSS 19.0 software and differences were considered significant when P<0.05.Results1.Analysis of indicators related to occurrence of CVAEsThe included MM patients were divided into CVAEs group and non-CVAEs group according to whether CVAEs occurred during the follow-up period.Univariate and multivariate Cox regression analysis was performed on the clinical data of the two groups,and the results showed that age,smoking history,elevated baseline blood pressure and elevated left ventricular mass index?LVMI?were independent risk factors for CVAEs?P<0.05?.The ROC curve of LVMI indicated that the cutoff value of age was 56.5 years?sensitivity 86.00%,specificity 57.20%?and the cutoff value of LVMI was 111.77g/m2?sensitivity 31.60%,specificity 82.80%?.2.Prognostic analysis of patients with CVAEsThe difference of progression-free survival time?PFS?between the CVAEs group and the non-CVAEs group was compared.The results of Kaplan-Meier survival analysis and log-rank test showed that PFS in the CVAEs group significantly decreased compared with the non-CVAEs group.3.Subgroup analysis of CVAEs at different levelsPatients with CVAEs of different grades were divided into grade 1-2 CVAEs group and grade 3-5 CVAEs group.Univariate and multivariate Cox regression analysis showed that LVMI before treatment was an independent risk factor for high grade?grade 3 or above?CVAEs.Patients with grade 3-5 CVAEs had higher LVMI before treatment than those with grade 1-2 CVAEs.The ROC curve of LVMI indicated that the cutoff value of LVMI was 93.45g/m2?sensitivity 78.10%,specificity 56.00%?.Conclusion1.In this study,patients with multiple myeloma were followed up for 13.07±9.72months,with a median follow-up time of 13 months.The results showed that the incidence of cardiovascular adverse events was 28.22%.The most common type of adverse cardiovascular events was heart failure?45.61%?.Grade 5 cardiovascular adverse events?death?accounted for 7.02%of the total number of cardiovascular adverse events,and the main cause was heart failure.The proportion of newly occurring cardiovascular events in patients with CVAEs was the largest?71.93%?,and the newly occurring heart failure accounts for the largest proportion?48.78%?.2.Age,smoking history,elevated baseline blood pressure,and baseline left ventricular mass index were independent risk factors for cardiovascular adverse events in patients with multiple myeloma.Elevated left ventricular mass index at baseline was also associated with more severe cardiovascular adverse events;3.Patients with multiple myeloma who have had cardiovascular adverse events also have a shorter progression-free survival,which may indicate a higher recurrence rate.