Minimal Residual Disease In Multiple Myeloma

Objective:The depth of response in patients with multiple myeloma(MM)is closely related to survival.It has been proved that obtaining minimal residual disease(MRD)negative can be transformed into long-term survival,but the relationship between MRD dynamics and prognosis remains to be clarified.The purpose of this study was to explore the prognostic significance of MRD dynamic monitoring in MM patients.Methods:579 newly diagnosed multiple myeloma(NDMM)in our hospital from January 2013 to December 2019 were included,and the demographic information,laboratory results and medical records were collected.MRD negative was defined as at least 2×105 events detected by bone marrow flow cytometry and fewer than 20 events(0.01%,10-4)in phenotypically abnormal clonal plasma cells.Survival analysis was performed by Kaplan Meier method to explore the prognostic significance of MRD dynamics,and the prognostic significance of MRD negative in different subgroups of MM patients.Finally,we also explored the clinical characteristics of MGUS-like MM patients.Results:1.The prognosis of MRD negative patients was significantly better than that of MRD positive patients:the median follow-up time was 45.2 months,the median progress free survive(PFS)of all patients was 39.9(35.3-44.5)months and the median overall survival(OS)was 73.5(67.3-79.7)months.MRD negative patients were significantly better than MRD positive patients both in terms of PFS(median PFS 55.0 months vs 24.2 months,P=0.000)and OS(median OS 89.3 months vs 58.7 months,P=0.000);2.The prognosis of patients was significantly correlated with the depth of remission(<10-5,10-5～10-4,10-4～10-2,≥10-2).For each logarithm of the depth of remission of MRD,patients had better survival benefits;3.The speed of MRD turning negative was not related to prognosis:the prognosis of the four groups with MRD negative acquisition time<0.5 years,0.5～1 years,1～2 years and≥2 years showed no significant difference in PFS or OS;in patients receiving ASCT,the timing of MRD negative acquisition(before transplantation,3 months after transplantation and maintenance treatment)was not related to the prognosis;4.MRD negative duration time:the PFS of patients with MRD negative≥3 years was significantly better than that of patients in the 2～3 years group,1～2 years group,and<1 year group(median PFS was 64.3 vs 36.4 vs 25.1 vs 25.3 months,P=0.000).In terms of OS,there was no significant difference between patients with MRD negative duration≥3 years and patients with 2～3 years(median OS was not reached vs 89.3 months,P=0.402),which were significantly better than patients in 1～2 years and<1 year group(median OS was 56.4 and 66.7 months,respectively)(P=0.000).In addition,there was no significant difference in PFS or OS between MRD positive patients and MRD negative duration 1～2 years group and<1 year group;5.The dynamic pattern of MRD in patients receiving ASCT:the prognosis of patients in MRD persistent negative group and MRD positive to negative group was the same,which was significantly better than MRD persistent positive group and MRD negative to positive group.Notably,in terms of OS,the prognosis of patients in MRD negative to positive group was even worse than that in MRD persistent positive group(P=0.039);6.The prognostic significance of MRD negativity in different subgroups of patients:among MRD negative patients,the prognosis of high risk cytogenetic aberrations(HRCA)vs standard risk CA,age≥65 years vs<65 years and R-ISS stage Ⅰ/Ⅱ vs stage Ⅲ patients was similar.The prognostic significance of MRD negative was independent of cytogenetics,age and disease stage.Among MRD positive patients,the prognosis of HRCA patients was significantly worse than that of standard risk CA patients,the prognosis of patients with R-ISS Ⅲ was significantly worse than that of patients with R-ISS Ⅰ/Ⅱ.The prognostic significance of HRCA and R-ISS was limited to MRD positive patients.MRD negative could overcome the poor prognosis of high-risk patients;7.Monoclonal gammopathy of unknown significance(MGUS)-like MM:The MM patients with MRD positive≥5 years and progression-free was defined as MGUS-like MM patients.Survival analysis showed that among the patients without progression in 5 years,the prognosis of MRD negative and MRD positive patients was the same,which was significantly better than that of patients with disease progression in 5 years.Compared to other patients,MGUS-like MM patients showed earlier disease stage,lower tumor load and fewer genetic abnormalities.Conclusion:1.MRD negative is the most important dynamic prognostic factor of MM;2.The depth of MRD remission is significantly correlated with prognosis;3.The speed of MRD turning negative is not related to the prognosis;4.The duration time of MRD negative is also very important for the prognosis of MM patients,and 2 years should be taken as the time interval of MRD negative persistence;5.The prognostic significance of MRD negative is independent of cytogenetics,age and disease stage;MRD negative can overcome the poor prognosis of high-risk patients;6.MGUS-like MM is usually characterized by early disease stage,low tumor load and less genetic abnormal events.For these patients,it may be unnecessary to obtain negative MRD.Objective:With the application of new drugs,the treatment response depth of patients with multiple myeloma(MM)is significantly deepened.With the combined application of three or four drugs,more and more patients can obtain minimal residual disease(MRD)negative after induction treatment,and the remission of MRD has been proved to be significantly related to the good prognosis of MM patients.On this basis,the necessity of MM patients receiving autologous hematopoietic stem cell transplantation(ASCT)has been questioned.The purpose of this study was to investigate the necessity of ASCT after early induction therapy.Methods:After screening,407 newly diagnosed multiple myeloma patients treated in our department from January 2013 to December 2019 who were suitable for transplantation(age≤65 years),received new drug treatment and had MRD test results after early induction treatment(4-6 courses)were included.The characteristics and outcomes of patients with MRD negative ± ASCT and MRD positive± ASCT were compared.Results:1.The prognosis of patients in MRD negative+ASCT group[median progression free survival(PFS)88.3 months,median overall survival(OS)90.6 months]was significantly better than that of patients in MRD negative+non-ASCT group(median PFS 46.0 months,median OS 76.4 months),MRD positive+ASCT group(median PFS 42.8 months,median OS 78.8 months)and MRD positive+non-ASCT group(median PFS 22.7 months,median OS 52.3 months);2.Among MRD negative patients,the PFS of ASCT group was significantly better than that of non-ASCT group in different age groups,1 high-risk cytogenetic abnormalities(HRCA)group,2+HRCA group and R-ISS stage Ⅲ patients,but there was no significant difference in the prognosis between 0 HRCA group,R-ISS stage Ⅰ or Ⅱ patients.In terms of OS,ASCT group was better than non-ASCT group in different subgroups,but the difference was statistically significant only in R-ISS stage Ⅲ patients and 2+HRCA group;3.Among the patients with MRD negative,the duration of MRD negative in ASCT group was significantly longer than that in non-ASCT group(median time 58.1 months vs 33.5 months,P=0.000);89.1%(57/64)of patients in ASCT group had MRD negative duration≥2 years,while only 49.1%(28/57)of patients in non-ASCT group(P=0.000).Further analysis of different HRCA subgroups showed that ASCT mainly improved the rate of the MRD negative duration≥2 years in patients with 1 HRCA group(90.6%vs 38.9%,P=0.000)and 2+HRCA group(88.2%vs 35.3%,P=0.001),but not 0 HRCA group(86.7%vs 68.2%,P= 0.198);4.The importance of persistent MRD negativity:The prognosis of patients with MRD negativity duration≥2 years was significantly better than that of patients<2 years.In patients with MRD-negative duration≥2 years and<2 years,the prognosis of ASCT group and non-ASCT group was comparable;5.Uni variate and multivariate analysis of the factors affecting the negative duration of MRD showed that non-ASCT,1q21 amplification and anemia were the high-risk factors causing the shortening of MRD duration;ASCT(HR=0.30,95%Cl 0.16-0.56,P=0.000)was an independent factor affecting the duration of negative MRD.Conclusion:1.It is still necessary to do ASCT for MM patients with early MRD negative after induction therapy,especially for patients with high-risk cytogenetic abnormalities and R-ISS stage Ⅲ;2.Continuous remission of MRD is a more important prognostic factor than negative MRD;3.ASCT is an independent factor to prolong the duration of MRD negative,and ASCT is especially important for prolonging the duration of MRD negativity in high-risk patients.Objective:To explore the clinical value of oligoclonal bands(OB)in patients with multiple myeloma(MM).Methods:We retrospectively analyzed the baseline data of 624 newly diagnosed MM patients admitted to our department from January 2013 to December 2019,including 30 patients with OB,and the clinical characteristics,treatment effects and survival of OB and non-OB patients were compared.Results:OB occurred in 11.8%(22/187)of patients who received ASCT and only 1.8%(8/437)of patients who did not receive ASCT(P=0.000).The median time from ASCT to the appearance of OB was 3.2 months(0.6-10.5 months).The M protein types of OB mainly include IgG κ,IgG λ,IgM λ and λ light chains.In the presence of OB,90%of patients were evaluated as complete remission(CR)and above.There were no statistically significant differences in disease stage,tumor burden,and genetic abnormalities between OB and non-OB patients.Among the overall patients,the prognosis of OB patients was significantly better than that of non-OB patients,and OB patients showed deeper disease remission(significantly higher CR rate and MRD negative rate,and longer MRD negative duration),which may be the reason for their better prognosis.Among patients who underwent ASCT,OB patients showed earlier immune recovery,but the depth of treatment response and survival outcomes were similar between OB and non-OB patients.Although OB patients showed earlier immune reconstitution,this did not translate into better survival,suggesting that the better prognosis of OB patients was mainly related to deeper and durable remission rather than early immune reconstitution.Further analysis in patients who received ASCT and obtained MRD negative indicated that there was no additional survival benefit in patients with OB.Conclusion:The better prognosis of OB patients may be related to the deeper treatment response,but not to the early immune reconstitution.The appearance of OB is only a sign of deep remission and early immune reconstitution in patients,it cannot be translated into survival benefit of MM patients.