Multiple Myeloma Treatment Selection And Minimal Residual Disease Monitoring Stud

Objective:Evidence on the prognostic value of autologous stem cell transplantation(ASCT)and minimal residual disease(MRD)dynamics of patients with newly diagnosed multiple myeloma(NDMM)in China is limited.Our objective in the current study was to understand the current care paradigm and outcomes of these patients.Methods:A total of 454 NDMM from three top-tier hematologic disease care hospitals were included.Induction treatment regimens[proteasome inhibitor(PI)-,immunomodulatory drug(IMiD)-,PI+IMiD-based,and conventional]and post-induction response,ASCT and MRD status,and survival outcomes and prognostic impactors were evaluated.Results:1.Study population:A total of 454 patients were enrolled in the study,including 267 from the IHBDH,138 from the SYSUCC,and 49 from the Shandong Provincial Hospital.The median[interquartile range(IQR)]of follow-up for the study population throughout the study period was 58.7[45.8-75.7]months,and the median[IQR]number of follow-up visits throughout the study period was 45[30-79.5].By the end of the follow-up period,4.2%of the study population were lost to follow-up and 165(36.3%)patients had died.2.Clinical characteristics:The median[range]age of the overall population at the time of diagnosis was 57[26,81]years and 59.0%were male.In total,119(26.2%)of the 454 patients received ASCT during the first-line of therapy,and the median[range]age was younger among patients who received ASCT treatment compared to patients who did not receive ASCT(50[32,67]vs.57[26,81],P<0.001).There were no significant differences in gender,type of M protein,presence of extramedullary lesions,and genetic abnormalities.3.Treatment options:The PI,IMID,PI+IMID,and conventional chemotherapy group had 291 patients(64.1%),62 patients(13.7%),32 patients(7.0%),and 69 patients(15.2%),respectively.Among the 453 patients with post-induction responses information,the ORRs were 91.0%,83.9%,90.6%,and 60.9%for patients who received PI-,IMiD-,PI+IMiDbased,and conventional regimens,respectively.The mPFS was 42.9 and 21.2 months among patients who received ASCT compared to patients who did not receive ASCT,respectively(P<0.001)and the mOS was NR and 65.8 months,respectively(P<0.001).4.The prognostic significance of dynamic MRD monitoring:Among the 404 patients who received regular MRD monitoring,88 had sustained MRD negativity,100 had loss of MRD negativity,and 216 had persistent MRD positivity.Among patients with sustained MRD negativity,loss of MRD negativity and persistent MRD positivity,the mPFS was 52.7,30.8.and 16.4 months(P<0.001)and the mOS was NR,71.5,and 56.6 months(P<0.001),respectively.Even among the 14 patients with HRCA,the survival of those who achieve MRD negativity is significantly better than those who do not achieve MRD negativity.5.Prognostic risk factors in NDMM patients:A multivariable analysis revealed that an elevated LDH level,ISS Ⅲ disease,and extra-medullary disease predicts significantly poor survival,while upfront ASCT appeared to be an independent protective factor for OS.Conclusions:1.Novel agents based induction therapy significantly improves the remission rate of induction therapy in patients with NDMM.2.In the era of novel agents therapy,first-line ASCT still significantly improves the survival of patients with NDMM.3.Sequential detection of MRD plays an important role in monitoring treatment response and evaluating prognosis in patients with MM.Achieving MRD negativity may overcome the poor prognostic impact of high-risk cytogenetic abnormalities.4.Multivariate analysis showed that elevated LDH levels,ISS Ⅲ disease,and extramedullary diseases were independent poor prognostic factors for NDMM patients.while upfront ASCT appeared to be an independent protective factor for OS.5.When compared to other nations,there is still a sizable gap in the clinical use of novel medicines and ASCT,therefore improving the survival of NDMM patients in China requires the combined efforts of domestic hematology colleagues.Objective:Currently,the minimal residual disease(MRD)kinetics in multiple myeloma(MM)were mostly based on the status of MRD(MRD negative and MRD positive)at two time points.In this real word study,we aimed to investigate the significance of quantitative MRD kinetics per log level by serial MRD monitoring in multiple myeloma.Methods:A total of 508 consecutive patients of NICHE-MM from January 2013 to January 2020 were included,all patients received proteasome inhibitor based regimen and have received at least one MRD assessment by multi-parameter flow cytometry(MFC)or next generation flow cytometry(NGF)(EuroFlow standard).We first evaluated the prognostic value of MRD remission depth per log level reduction in 508 patients,and then further evaluated the prognostic utility of quantitative MRD kinetics per log levels were further evaluated in 364 patients with serial MRD monitoring(≥3 timepoints)Finally,subgroup analysis and multivariate analysis COX proportional risk regression models were used to further test the prognostic utility of quantitative MRD kinetics.Results:Baseline characteristics and MRD monitoring:The median diagnostic age of 508 patients with NDMM was 57 years,including 290 males(57.1%).The median followup time of this population was 45.6 months.A total of 177 patients(34.8%)received upfront autologous stem cell transplantation(ASCT).At the time of diagnosis,91 patients(17.9%),185 patients(36.4%),and 232 patients(45.7%)had ISS stages Ⅰ,Ⅱ,and Ⅲ disease.The median PFS(mPFS)was 39.9 months,and the median OS(mOS)was 75.3 months.Median time to 1 st MRD detection was 2.13 months.Besides,median follow-up from the 1st MRD assessment was 37.8 months(range 3.4 to 96.4 months).MRD data were available at≥ 3 time points for 364 patients,2 time points for 62 patients,and 1 time point for 82 patients.Survival outcomes based on response level of MRD:Overall,a total of 280 out of 508(55.1%)patients achieved MRD negativity.mPFS was 53.7 months of MRD negative and 27.8 months of MRD positive patients,respectively(P<0.001);mOS was 89.3 months of MRD negative and 60.1 months of MRD positive patients,respectively(P<0.001).According to per log level reduction of MRD,120 patients(23.6%)achieved MRD negativity at≤10-5,160(31.5%)achieved MRD at 10-5-104,96(18.9%)achieved MRD at 10-4-10-3 and 132(26.0%)achieved MRD at>10-3,respectively.The mPFS were 63.9,46.0,35.3 and 21.6 months,respectively(P<0.0001),the mOS were NR,85.6,69.8 and 49.1,respectively(P<0.0001).Prognostic impacts of quantitative MRD kinetics per log levels:Four quantitative MRD kinetics patterns per log levels were identified:"Well educated","MRD relapse","Detectable decline" and "Stubborn".Survival analysis revealed that the mPFS were 88.3,30.9,NR and 20.6 months,respectively(P<0.001).The mOS were NR,66.9,NR,and 53.4 months,respectively(P<0.001).Multivariate COX analysis:Multivariate COX regression analysis verified the independent prognostic value of quantitative MRD kinetics.Conclusion:1.Patient’s achievement of per log depletion in flow MRD can increase PFS and for a year approximately,while OS increased about one to two years accordingly.2.Serial MRD measurements provide additional prognostic information compared to analyses conducted at just single time point or dual time points.3.For patients achieved MRD negativity,those with superior baseline characteristics and upfront ASCT treatment are prefer to be group of "well-educated" rather than"MRD relapse".4.Quantitative MRD kinetics depicted based on log level identified a group of patients with detectable but slowly declined residual tumor cells,whose baseline characteristics and prognosis better than those of patients in the stubborn group.5.Quantitative MRD kinetics per log levels under sequential MRD monitoring is an independent prognostic marker in NDMM.Objective:Sequential monitoring of minimal residual disease(MRD)in multiple myeloma(MM)patients at various points in time is useful for prognostic evaluation and clinical guidance.Nonetheless,the bone marrow flowcytometry based MRD monitoring technique of evaluation is invasive.We further to investigate the viability of monitoring MRD in MM patients by utilizing EasyM--a noninvasive mass spectrometry(MS)techniques for tracking serum M protein(MP).Methods:A total of 56 patients with NDMM visited the lymphoma department of our hospital from October 2013 to June 2019 were included in this study.Clinical information and survival outcomes of the patients were collected.All the patients have stored the peripheral blood serum samples(≥ 3 timepoints)at the time of initial diagnosis and after treatment in the pathological cell bank.We submitted the samples to Shanghai Kuaixu Biotechnology Co.,Ltd.for MP sequencing and targeted tracking by mass spectrometry(EasyM method).After that,we compared and analyzed the sensitivity of MS with other MRD monitoring protocols including flowcytometry.This study was approved by the institutional ethics committees.Results:1.Clinical characteristics:The median diagnostic age of 56 NDMM patients was 56 years old,including 34 males(60.7%).There were 38 patients with IgG type MP and 18 patients with IgA type MP.47 patients(83.9%)chose to receive proteasome inhibitor-based induction therapy,and a total of 44 patients(78.6%)received first-line ASCT treatment.2.Clonal peptide and targeted M protein monitoring:Among 56 MM patients,38 patients with IgG type MP can further identify IgG subclasses through mass spectrometry.Additionally,56 patients with MM have successfully used MS to identify their unique clonal peptides of MP.56 patients provided a total of 447 samples of serum and all sequential serum samples were successfully measured by using the MS method3.Sensitivity comparison between EasyM and flow MRD detection:EasyM MS has higher detection sensitivity than IFE.Beside,when the cutoff value of EasyM MS negativity is set to be less than 1.86%of the initially diagnosed MP quantification level,the comparative analysis of EasyM MS and NGF at the same time point revealed that,the EasyM MS had a detection sensitivity 95.8%and a specificity of 93.2%compared to NGF.4.Prognostic significance of mass spectrometry:Under the EasyM MS negativity cutoff value set to less than 1.86%of the initially diagnosed MP quantification level,the mPFS of the EasyM MS positive and negative group were 20.6 and 61.8 months,respectively(P<0.0001);The mOS was 55.7 months and NR,respectively(P<0.0001).Conclusion:1.Currently,for MM patients with IgG or IGA type MP and initial diagnosis MP>5g/L,EasyM MS detection can obtain patient specific MP clone peptides,which can be used for quantitative MRD monitoring by targeted tracking of subsequent MP.2.The sensitivity of EasyM MS detection is significantly higher than that of IFE and MFC.When the cutoff value of EasyM MS negative is set to less than 1.86%of the initial diagnosis of MP quantification level,the EasyM MS has good consistency with NGF.3.MM patients who achieve EasyM MS negative will benefit significantly from both PFS and OS.4.For MM patients,EasyM MS detection can be used as a minimally invasive MRD monitoring method based on peripheral blood in clinical practice.