| Background and Objective: Multiple myeloma(MM)is the second most common hematological malignancy.It is characterized by significant heterogeneities in clinical manifestations and prognosis.The median overall survival(OS)for MM is about 4-5 years,but the OS is highly variable in different MM patients;some patients with aggressive disease courses may die in a few months after diagnosis,while other patients with indolent courses may live more than ten years.Exploring a useful prognostic system has been a topic of interest in the myeloma filed since the past forty years,and considerable progresses have been made now.In recent years,as the advent of targeted no drugs,such as thalidomide,bortezomib,lenalidomide,Monoclonal and other antibody come out,the continuous updating of treatment strategies has significantly improved the survival of MM patients,and the clinical prognostic stratification system has also been continuously changed.The International Staging System(ISS)was established by the International Myeloma Working Group(IMWG)in 2005.The revised ISS staging(R-ISS)system was developed in 2015 based on the original ISS staging system,combined with LDH and high-risk cytogenetics.The ISS and R-ISS staging system are the first line recommended systems in Chinese and IMWG guidelines.It is well known that ISS and R-ISS staging system are the most widely used MM staging systems for myeloma in China.However,the establishment of ISS system was based on the data of MM patients during the traditional treatment period,and the information of Chinese patients was not included in the initial data analysis.Subgroup analysis showed no significant difference in survival between ISS stage?and ?patients in the Asian patients.Therefore,whether the ISS and R-ISS systems are still applicable to myeloma patients in China is still controversial and needs further study.This study first examined the prognostic value of the ISS staging system in newly diagnosed myeloma patients in China.To further explore whether the R-ISS staging system is suitable for newly diagnosed myeloma patients in China.Serum free light chain(s FLC)ratios have been correlated with survival of myeloma patients.On the basis of the previous research,the Modified R-ISS(MR-ISS)staging system was established by combining R-ISS and s FLC to optimize the existing R-ISS staging system.Methods:In this study,the clinical data of 1016 myeloma patients who were treated at three multiple myeloma centers in China from 2008 to 2012 were retrospectively analyzed,and all patients received Bortezomib-based and/or Thalidomide-based first-line induction therapy.The mean overall survival(OS)and median disease-free progression(PFS)of patients with ISS system stage?/?/? were counted,and subgroup analysis was performed to analyze the overall survival of patients with ISS stage?/?/? in the Thalidomide-based group and Bortezomib-based group,and whether there was any significant difference in survival between the stage groups.To further investigate whether the revised ISS(R-ISS)staging system is applicable to Chinese myeloma patients during the novel agents,we retrospectively analyzed the clinical data of MM patients who attended our department from May 2010 to April 2015,of whom 202 patients with MM were treated with 4 courses of Bortezomib-based or Thalidomide-based regimens.Patients were grouped by using the R-ISS staging system,and the prognostic significance of the R-ISS staging system was analyzed using the original ISS staging system as control.Kaplan-Meier curve was used to analyze the difference of survival in patients with R-ISS staging system.The relative risk difference between the R-ISS staging group and the ISS staging group was compared.Subgroup analysis was performed based on age,whether bortezomib was used as the primary regimens,and whether transplantation was performed,to verify the prognostic value of R-ISS staging in Chinese myeloma patients in OS and PFS.Finally,based on the results of previous studies,an improved R-ISS staging system,namely MR-ISS staging system,was established by combining the two prognostic factors of R-ISS and s FLC.Retrospective analysis was performed on the data of 595 consecutive NDMM patients in our center from June 2010 to December 2016,to determine the MR-ISS staging criteria,and subgroup analysis was conducted to determine the applicable range of MR-ISS staging.The MR-ISS stage ?with the highest proportion of patients was further risk stratified.Finally,the prognostic value of MR-ISS staging was verified in an independent sample.Results(1)Clinical data of 1016 myeloma patients treated at three multiple myeloma centers in China from 2008 to 2012 were retrospectively analyzed.All patients received Bortezomib-based and/or Thalidomidome-based first-line induction therapy.The mean median survival(OS)of patients with ISS sage?/?/? was not achieved /55.4 /41.7months(P <0.001),and the median progression-free(PFS)was 30 /29.5 /25 months(P=0.072),respectively.In the subgroup analysis,the overall survival time of ISS stage?/?/? patients in the Thalidomide induction group was significantly different in each stage pair comparison.In the Bortezomib-based group,there was no statistically significant difference in overall survival between ISS stage?and ?.(2)Clinical data of newly diagnosed MM patients admitted to our department from May 2010 to April 2015 were retrospectively analyzed.All 202 MM patients received 4courses Bortezomib-based or Thalidomide-based therapy.202 cases were treated by combination of ISS,FISH and LDH R-ISS analysis system have shown that patients with stage?/?/? was 56 cases,108 cases,38 cases respectively;Compared to the original ISS staging system [patients with stage?/?/ ? was 62 cases,70 cases,70 cases],because some of the original ISS stage I and ? patients come into R-ISS stage?and the number of R-ISS stage?and ? patients decreased significantly.The OS in R-ISS stage?/?/? was not reached,61 and 38 months(P< 0.0001),respectively.Further Cox prognostic risk model analysis found that R-ISS prognosis ?vs?relative risk degree of HR: 9.606,significantly higher than in the ISS ? vs? in HR: 4.127,R-ISS with just the original ISS?vs?,HR increased almost twice as much,prompt R-ISS stage system can better evaluate the prognosis.In further subgroup analysis,R-ISS demonstrated its value in evaluating OS outcomes in younger patients who received Bortezomi-based regimens and those who did not receive transplants.However,R-ISS was better in PFS assessment in patients with R-ISS stage?than R-ISS stages II and ? in the first two years after diagnosis,and PFS was shorter in patients with R-ISS stage ?.However,the PFS of patients with R-ISS stage ?stabilized after two years and there was not statistically different compared with patients with R-ISS stage I.This may be related to the different salvage treatment regimens after the patients' disease progression,thus leading to a shift in staging.(3)Combining R-ISS and s FLC to establish a Modified R-ISS staging system(MR-ISS)can better classify patients into three subgroups with significant prognostic differences.The clinical data of 595 patients with NDMM were retrospectively analyzed to determine MR-ISS staging,with stage I as: R-ISS stage I with s FLC ratio <80(n=66),stage ? as: R-ISS stage ? with s FLC ratio?80(n=87);and stage II: all patients who did not meet stage I and ?(n=442).The median OS time is not reached for MR-ISS stage ?,48.67 months for MR-ISS stage ?,and 21.13 months for MR-ISS stage III(P<0.0001),while the median OS time was not reached for R-ISS stage I,47.67 months for R-ISS stage II,and 26.37 months for R-ISS stage ?(P<0.0001).The median PFS time is 50.97 for MR-ISS stage I,27.27 months for MR-ISS stage?,and 13.4 months for MRISS stage?,while the median PFS time was 30.97 months for R-ISS stage I,28.97 months for R-ISS stage?,and 14.23 months for R-ISS stage?.The overall survival(OS)of patients with MR-ISS stage I and ?was significantly different compared with those with R-ISS stage I and ?,and there was no statistically significant difference in PFS results between the two groups.The number of stage ?increased a high proportion with 74.3% and included a more heterogeneous population with a broad range of survival outcomes.We performed the univariable Cox analysis based on the various variables,and the adverse impact of MR-ISS stage ?on OS was associated with three risk factors including the elderly patients(HR,1.757),high-level LDH(HR,1.858),and renal dysfunction(HR,1.664).Based on this analysis,we constructed a new risk stratification model for MR-ISS stage ?consisting of the above prognostic factors.Specifically,elder patients,high-level LDH,and renal dysfunction were defined as adverse risk factors.Of the 442 patients,46.4% of patients were classified as low risk(0 factors),42.1% as intermediate risk(1 factor),and 11.5%were classified as high risk(?2 factors).The median OS for the corresponding risk groups was 59.2 months for low risk,43.5 months for intermediate risk,and 32 months for high risk,respectively.Finally,we again validated the prognostic assessment value of MR-ISS staging in an independent patient sample.Conclusion:The results of this study suggest that the current ISS staging system is still suitable for Chinese patients with multiple myeloma during the novel agents,and Borteomib may improve the poor prognosis of patients,especially in the middle and high stage of ISS staging.R-ISS staging system can better distinguish the overall survival time of patients,especially for the assessment of prognosis of myeloma patients who received Bortezomi-based treatment but did not receive transplantation,and it is suitable for the assessment of prognosis of MM patients in China.The improved R-ISS staging system(MR-ISS)allows for better clinical differentiation of patients into survival subgroups,particularly high-risk patients at risk for rapid progression and disease recurrence.The research shows that the MR-ISS staging system has higher predictive ability than the R-ISS staging system. |
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