Efficacy And Safety Profile Of Generic Bortezomib In Multiple Myeloma And Prognosis Analysis Based On Surface CD28 And CD117 Expression

Objective:The current study was performed to evaluate the short-term efficacy,survival and adverse effects of the generic proteasome inhibitor Bortezomib in multiple myeloma(MM),and explore the prognostic relevance of surface CD28 and CD117 expression mode in MM.Methods:1.119 MM patients admitted to the our center(Department of Hematology,Affiliated Hospital of North Sichuan Medical College)were enrolled in this study from December 2017 to January 2021,who were all treated with BD+X induction/consolidative chemotherapy for at least 4 cycles.Clinical and laboratory data at diagnosis was collected.Response post 4 cycles and all induction/consolidation chemotherapy was evaluated based on the criteria of International Myeloma Working Group(IMWG),and the disease progression and survival status were followed up.Moreover,treatment-related adverse reactions were recorded.2.Among the 119 MM patient,104 patients underwent multi-parameter flow cytometry(FCM)detection at diagnosis,and the correlation of cell membrane CD28 and CD 117 with clinical prognosis were analyzed by univariate and multivariate COX proportional hazard regression models.Results:PartⅠ1.All 119 patients completed at least 4 cycles of induction chemotherapy.After 4 cycles of chemotherapy,94 patients(79%)achieved at least partial remission(≧PR),60 patients(50.4%)achieved at least very good partial remission(≧VGPR),and 32(26.9%)patients achieved complete remission or better response(≧CR);Amone the 56 patients who completed all planned 8-9 cycles of chemotherapy or 4-6 cycles of chemotherapy+autologous stem cell transplantation(ASCT),53 cases(94.6%)achieved≧PR,41 cases(73.2%)≧VGPR,and 26 patients(46.4%)≧CR.2.The median follow-up time was 19 months(4-55 months),and 24 patients died,and the median overall survival(OS)was not reached;46 patients had disease progression,and the median progression-free survival(PFS)was 27 months.Patients with ISS stage Ⅲ disease had shorter OS(P=0.002)and PFS(P=0.007)compared with patients with ISS stage Ⅰ-Ⅱ.Patients with HGB≥100g/L at diagnosis had better OS(P=0.018)and PFS(P=0.012)compared with those with HGB<100g/L.Patients with LDH≥1×upper limit of normal(ULN)at diagnosis had worse OS(P=0.039)and PFS(P=0.032)than those with LDH<1×ULN.However,no significant difference of OS or PFS was observed between patients with different gender,age(≧60 years or not),ECOG score(≧2 or not),BMPC%(≧30%or not),DS staging(stage Ⅲ or Ⅰ-Ⅱ),R-ISS staging(stage Ⅲ or Ⅰ-Ⅱ),Scr(≧177 μmol/L or not),β2-MG(≧5.5mg/L or not),ALB(≧35g/L or not),EMD(with or without),ASCT(with or without),high-risk cytogenetic abnormalities(with or without).3.Treatment-related adverse effects were observed,and grade 1-2 predominated.The most common hematological adverse effects was thrombocytopenia(12.6%),followed by neutropenia(8.4%)and anemia(6.7%);and the most common non-hematological adverse effects included peripheral neuropathy(64.7%),followed by constipation(59.7%),abdominal distension(42.9%),fatigue(20.2%),and herpes zoster virus infection(16.0%).Part Ⅱ1.The gene expression microarray of the dada set GSE9782 was acquired form Oncomine and GEO,which included 264 MM patients.We found the expression of CD28 and CD 117 mRNA was significantly different between dead(n=108)and alive patients(n=156)(P=0.0157,P=0.0017,rspectively).According to the optimal cut-off value determined with ROC curve,patients with lower CD28 expression(n=142)and higher CD28 expression group(n=122)were defined and patients with.lower CD28 expression had better OS than patients with higher expression(P=0.0008).Similarly,patients with higher CD 117 expression(n=197)had better OS than those with lower CD117 expression(n=67)(P=0.0035).Moreover,similar results were validated in in another data set GSE2658 including 414 MM patients,where the patients with lower CD28 mRNA expression(n=292)had significantly better OS than those with higher expression(n=122)(P=0.041),and patients with higher CD117 mRNA expression(n=115)had significantly better OS(P=0.021)than those with lower expression(n=299).2.In our cohort of 104 MM patients,55 patients(52.9%)were CD28 positive and 49 patients(47.1%)were negative.The proportion of patients with R-ISS stage III in the CD28+ group was higher than that in the CD28group(P=0.015).57 patients(54.8%)were CD117 positive and 47 were negative,and there was no significant difference between both groups in term of baseline characteristics.3.104 MM patients were further divided into three groups according to the expression mode of CD28 and CD117:30 patients(28.9%)of CD28-/CD117+,46(44.2%)of CD28-/CD117-or CD28+/CD117+,28(26.9%)of CD28+/CD117-,and The baseline clinical characteristics were not significantly different among the three groups.4.After 4 cycles of chemotherapy,24 patients(80.0%)in the CD28-/CD117+ group achieved a response of≧PR,20(66.7%)achieved≧VGPR,and 7(23.3%)achieved≧CR.While in the CD28-/CD117-or CD28+/CD117+ group,34 patients(73.9%)achieved ≧PR,18 patients(39.1%)achieved ≧VGPR,11 patients(23.9%)achieved ≧CR.In the CD28+/CD117-group,20 patients(71.4%)achieved ≧PR,13 patients(46.4%)achieved ≧VGPR,and 6 patients(21.4%)achieved ≧CR.The CD28-/CD117+ group was inclined to have a higher frequency of ≧VGPR than the other two groups(P=0.06).5.With a median follow-up of 16(4-46)months,CD28-patients obtained a better OS(P=0.04)than CD28+ patients,while the PFS was not significantly different(P=0.15).However,the OS(P=0.45)and PFS(P=0.53)in the CD117 groups did not show significant differences.Patients with CD28-/CD117+ had better OS(P=0.03)than those with other combinations(CD28+/CD177+ or CD28-/CD117-、CD28+/CD117-).6.Univariate analysis of Cox proportional hazard regression model showed that ISS stage Ⅲ,LDH>1×ULN were risk factors affecting OS,and multivariate analysis showed that ISS stage Ⅲ and CD28-/CD117+ mode were independent prognostic factors affecting OS.Conclusion:1.Generic bortezomib-based chemotherapy can induce a rapid remission in multiple myeloma,and the short-term response,survival and safety profiles are generally similar with historic reports of original bortezomib.2.In the era of novel anti-myeloma agents,the combinaton of CD28/CD117 immunophenotype remains prognostically relevant in MM patients treated with bortezomib-based chemotherapy.