Meta Analysis Of The Efficacy And Safety Of Monoclonal Antibody-based Three-drug Regimens For Relapsed And Refractory Multiple Myeloma

Objective:A comprehensive search of randomized controlled clinical trials of three-drug regimens containing monoclonal antibody for patients with relapsed and refractory multiple myeloma was conducted.The efficacy and safety of triplet combinations were analyzed by the meta-analysis as the Cochrane administrated to provide scientific guidance for the application of monoclonal antibodies for patients with relapsed and refractory multiple myeloma in China.Methods:Firstly,the inclusion criteria was developed: the type of study must be a randomized controlled clinical trial;the patients were diagnosed with relapsed and refractory multiple myeloma by clinicians;the intervention of the test group was a monoclonal antibody-based three-drug regimen and the counterpart of the control group is a corresponding two-drug combination;the main outcomes were progression-free survival and overall survival,and the secondary outcomes were overall response rate and incidence of adverse effects;only Chinese and English literatures were included.Literatures that didn't meet any of the inclusion criteria were excluded.Secondly,Chinese databases such as China Knowledge Internet,Wanfang Data,VIP Chinese Periodical Service System,SinoMed and English databases such as PubMed,ClinicalTrials.gov,Web of science,Wiley online library,Springer link,etc.were searched.Relative references were also searched through other means such as websites of the magazines.The deadline was 03/01/2020.The literature was screened by title and abstract according to the PICOS principle.The data table was designed to extract the key information of the included literatures.The Revman 5.3 software was used to analyze the efficacy and safety of the monoclonal antibody-based three-drug regimens of the patients with relapsed and refractory multiple myeloma.Subgroup analysis was performed to analyze the heterogeneity.Finally,conclusions were received.Results:A total of 2783 relevant literature records were gotten.After manual check,2427 literature records were obtained.After screening,6 literatures were included(all are randomized controlled trials).The included studies were all clinically registered,open-label,multi-center randomized controlled trials,and the research spanned across multiple clinical centers in Europe,America,and Asia Pacific.The study enrollments began in June 2011(Lonial 2015)and ended in February 2018(Attal 2019).A total of2289 patients with relapsed and refractory multiple myeloma were included,including1149 in the test group and 1140 in the control group who had received at least one treatment before.The median ages were between 64-69 years.As for the research protocols,the test group consisted of Isatuximab + Pomalidomide + Dexamethasone,Daratumumab + Lenalidomide + Dexamethasone,Elotuzumab + Pomalidomide +Dexamethasone,Elotuzumab + Bortezomib + Dexamethasone,Elotuzumab +Lenalidomide + Dexamethasone,Daratumumab + Bortezomib + Dexamethasone.The patients were 1: 1 randomly divided into two groups by interactive response technology.All studies reported reasons for exiting or losing follow-ups.Because they were all open-labeled,no blind method was used.The methodological quality of the included studies was high,and the overall risk of bias was low with high credibility.In terms of progression-free survival analysis,after the risk ratio being analyzed using a random effects model,the result was meaningless and not heterogeneous.Twosubgroups were analyzed according to the monoclonal antibody target: the anti-CS1 monoclonal antibody subgroup(containing Elotuzumab)and the anti-CD38 monoclonal antibody subgroup(containing Daratuzumab,Isatuximab).The result of the anti-CS1 monoclonal antibody subgroup was meaningless.The 5 studies were divided into three subgroups according to the monoclonal antibody: the Daratumumab subgroup,the Isatuximab subgroup and the Elotuzumab subgroup.The results of the Isatuximab group and the Elotuzumab group were meaningless.The studies were divided into two subgroups according to age: <65-year-old subgroup and ?65-year-old subgroup.The results of both subgroups were meaningful and the heterogeneity between the studies were small.According to ISS staging,the studies were divided into two groups: the stage? or ? subgroup,and the stage ? subgroup.The result of the stage ? or ? subgroup was meaningful and the heterogeneity was small while that of the ? subgroup was not.According to the lines of treatment,the studies were divided into two subgroups: the ?3lines subgroup and the >3 lines subgroup.The result of the ?3 lines subgroup was meaningful,and the heterogeneity was small while that of the >3 lines subgroup was not meaningful.The result of the total response rate was significant,but the heterogeneity was large.After the Attal 2019 group being removed,the heterogeneity decreased to moderate level.In terms of adverse effects,the result of any level of hematological adverse effects was meaningless.The result of grade 3-4 was not meaningless and the heterogeneity was high.Only the lymphopenia subgroup was meaningful.The results of the thrombocytopenia subgroup and the anemia subgroup were not meaningful.The result of non-hematological adverse effects of any level was meaningful,especially that of the constipation subgroup.The result of grade 3-4 was not meaningful.Conclusion:The monoclonal antibody-based three-drug regimens are effective for the treatment of relapsed and refractory multiple myeloma,and they are benefit for patients achieving progression-free survival and response without increasing the overall incidence ofhematological adverse effects.But the incidence of lymphopenia of grade 3-4 may increase.The incidence of any level of non-hematological adverse effects may increase,especially of the constipation subgroup,and the rate of non-hematological adverse reactions of grade 3-4 would not increase compared with the two-drug regimens.Relapsed and refractory multiple myeloma is still a challenging problem to clinical physicians,requiring a large amount of basic and clinical researches to explore the use of new drugs and new protocols which is exactly the ongoing work of many researchers.A monoclonal antibody-based three-drug regimen is a good choice for the relapsed and refractory multiple myeloma patient.