Busulfan,Etoposide,and Cyclophosphamide Versus High-Dose Melphalan As A Conditioning Regimen For Autologous Hematopoietic Stem Cell Transplantation In Patients With Multiple Myeloma

Background:High dose melphalan(HDM)represents the standard conditioning regimen prior to autologous hematopoietic stem cell transplantation(autoHSCT)in multiple myeloma(MM).Despite improved response rates and survival rates for patients,relapse rates and regimen-related toxicities remain a challenge.Aim:The objective of this study is to compare the effects of conditioning regimen on toxicities and outcomes in patients who received busulfan,cyclophosphamide and etoposide(BVC)with patients who received HDM as the conditioning regimen followed by autoHSCT for MM.Methods:Inclusion criteria included adults(aged between 18-65 years)with MM who had a creatinine of less than 2.0 mg/dL,without active infections or severe obstructive and/or restrictive pulmonary disease determined by pulmonary function testing(i.e.,DLCO<50%and/or FEV1<50%and/or FVC<50%)and cardiac ejection fraction(EF)greater than 40%.The patients were first treated with several cycles of induction chemotherapy(generally 4-6 cycles)until the patient achieved a very good partial response(VGPR)or better,and then followed by stem cell mobilization and collection.Autologous peripheral blood hematopoietic stem cells(PBHSCs)were utilized as grafts in all patients.In approximately 2-3 months following adequate PBHSC collection patients received high-dose chemotherapy.Busulfan was administered intravenously at 0.8 mg/kg/day on days-7,-6 and-5.Etoposide was administered intravenously at 400 mg/m2/day on days-5 and-4,and cyclophosphamide was administered intravenously at 50 mg/m2/day on days-3 and-2.Outcomes and survival were compared with 41 patients who received melphalan intravenously at 200 mg/m2 on days-3 and-2 followed by autoHSCT.The effects of the conditioning regimen on toxicities that occurred in the transplant recipients to be assessed are as follows:a.Regimen-related toxicities;including hematological toxicities and non-hematological toxicities.b.Time to neutrophil and platelet engraftment.c.Duration of hospital stay.The outcomes to be analyzed are:a.Response status of the disease after transplantation.b.Relapse rate at 1 year of transplantation.c.Transplantation-related mortality(TRM)within 100 days of transplantation.d.Progression-free survival(PFS)at 1 year of transplantation.e.Overall survival(OS)at 1 year of transplantation.Data were analyzed and compared between the two groups using SPSS version 26.Descriptive statistics was used to report results including demographics,disease related factors,and transplant-related factors.Probabilities of PFS and OS were estimated using the Kaplan-Meier method and comparisons between groups were made with the Log-rank test.Multivariate analysis of OS,PFS and cumulative incidence of relapse were performed using Cox proportional hazards regression models which was used to estimate hazard ratios(HR)for BVC compared to HDM.Results:Between August 2015 and December 2020,patients aged 29-65 years(median age 52 years)with MM who received HDC using either HDM or BVC followed by autoHSCT from three centers(Qilu Hospital of Shandong University,Shandong First Medical University Provisional Hospital and First Hospital of Shandong Medical University)were retrospectively reviewed.The data were collected from the hospitals’ registry data for the analysis of 78 patients.Thirty seven patients had autoHSCT following conditioning with BVC,whereas 41 patients had autoHSCT following a conditioning regimen with HDM.Overall response rate(ORR),PFS,OS and cumulative incidence of relapse at 1 year were not significantly different between the BVC and HDM groups.Median follow-up was 540 days in the BVC group and 436 days in the HDM group.HDM conditioning was associated with increased incidence of pulmonary toxicities(36.6%versus 5.4%for BVC;P=0.002).Patients in the BVC group had significantly longer duration of hospitalization than patients in the HDM group(median 20 days,range:18-27 for BVC;versus median 18 days range:13-27 for HDM;P<0.0001).The median duration of neutropenia was significantly longer in the BVC group(7 days,range:4-12)than in the HDM group(6 days,range:(2-12);P=0.002.There were two cases of TRM,one in each group.In multivariate subgroup analysis,BVC conditioning was statistically similar to HDM conditioning in regard to PFS,OS and relapse.But,low-risk disease stages showed to predict PFS and cumulative incidence of relapse,with patients in ISS I and ISS II disease stages significantly had longer PFS;(ISS I:HR=0.186;P=0.006,and ISS II:HR=0.240;P=0.022);and delayed time to relapse;(ISS I:HR=0.220;P=0.013,ISS II:HR=0.262;P=0.036).Beta-2 microglobulin predicted OS,with pretreated elevated levels beta-2 microglobulin showed to significantly worsen the OS(HR=1.356;P=0.041).Age,gender,MM subtype,KPS,number of chemotherapy regimens/cycles used prior to transplantation,or disease status at the time of transplantation did not interact with PFS,OS or relapse rate in both groups.Conclusion:Although response rates and survival appear to be similar between the two regimens,the BVC regimen appear to be more superior compared to the HDM regimen in terms of nonhematological toxicities(pulmonary toxicity),but inferior in terms of hematological toxicities(cytopenia).BVC may offer a better alternative myeloblative conditioning regimen to HDM for patients with MM undergoing autoHSCT.Further prospective studies with large sample size are needed to be done to make definitive conclusions.