A Single-center Retrospective Study And Basic Medical Research Of Primary Light Chain Amyloidosis

Part ⅠObjective:To summarize the clinical characteristics,treatment and prognosis of patients with primary light chain amyloidosis(pAL)in Chinese population.Methods:The clinical data of newly diagnosed pAL patients in our center from January 2007 to December 2019 were collected and analyzed retrospectively.Results:Among the 660 patients,from 2007 to 2014 and 2015 to 2019,a total of 168(25.5%)and 492(74.5%)patients were diagnosed,respectively,and the median time from onset to diagnosis was 13(1-363)and 9(1-231)months(P<0.001),respectively.Among the 660 patients,426(64.5%)were males.The median age of was 58(20-85)years old.The median number of organs involved was 2(1-6).73.6%,69.8%and 21.7%of patients was diagnosed with heart,kidney and liver involvement,respectively.The detection rates of monoclonal immunoglobulin(M protein)by serum immunofixation electrophoresis(sIFE),urine immunofixation electrophoresis(uIFE)and serum free light chain(sFLC)assay were 63.6%,80.6%and 86.1%,respectively.Positive rate of M protein could be increased to 98.1%when combining the three assays above mentioned.Before 2014,the first-line treatment of pAL patients in our hospital was mainly melphalan-based chemotherapy(28.6%)and autologous hematopoietic stem cell transplantation(13.1%).After 2014,the first-line treatment was mainly proteasome inhibitor-based chemotherapy(75.6%).After a median follow-up of 18.3(1.0-145.1)months,229 cases(34.7%)died.Median overall survival(OS)of patients with Mayo 2004 stage 1 has not yet been reached,and the median OS of stage 2 and 3 was 79.2 months and 16.2 months,respectively.The median OS of patients with Mayo 2012 stage 1 and stage 2 has not been reached,and the median OS of stage 3 and stage 4 was 37 months and 7.8 months,respectively.Multivariate analysis revealed that age>60 years old(P<0.001),≥3 organs involvement(P<0.001),Mayo 2004 stage(P<0.001)and percentage of bone marrow plasma cell(BMPC)≥ 10%(P<0.001)were independent risk factors for OS.≥ 3 organs involvement(P<0.001),Mayo 2004 stage(P<0.001)and BMPC≥ 10%(P<0.001)were independent risk factors for PFS.Conclusion:sIFE,uIFE combined with sFLC assays could significantly improve the detection rate of M protein in patients with pAL.Both of Mayo 2004 and 2014 staging systems had important prognostic value in Chinese patients with pAL.Age>60 years old,≥3 organs involvement,Mayo 2004 stage and BMPC≥ 10%were independent risk factors for OS in patients with pAL.≥ 3 organs involvement,Mayo 2004 staging and BMPC≥ 10%were independent risk factors for PFS in patients with pAL.Part ⅡObjective:To describe the gene mutation profile of patients with primary light chain amyloidosis(pAL)in Chinese population.Methods:Bone marrow plasma cells were sorted by anti-CD 138 magnetic microbeads,and target gene sequencing of 392 genes associated with plasma cell disorders were couducted.Results:Among the 74 patients,a total of 72 patients were identified for target gene mutations,involving 451 variants of 180 genes.The median number of mutations was 7(0-17)per patient.OBSCN(18%),followed by NEB(15%),DNAH9(14%),FAT1(14%),NCOR2(14%),ATXN1(12%),ASCC3(12%),TENM2(11%),DIS3(11%),KDM6B(11%)and ZFHX3(11%)were the most frequently mutated genes.Pathways were significantly enriched in the MAPK signaling pathway(14 genes),FoxO signal pathway(10 genes),NF-κB signal pathway(9 genes)and Notch signal pathway(6 genes),and 7 genes were involved in DNA repair pathway.At least one multiple myeloma(MM)-related driver genes was mutated in 44 patients(59.5%).DIS3(10.8%)and ATM(8.1%)were the most frequently mutated genes.After a median follow-up of 13.9 months,16 patients died.Compared with patients with less than 7 mutated genes,patients with more than 7 mutated genes showed a trend of worse prognosis(P<0.05).With mutation of genes in MAPK,FoxO,NF-κB,Notch or DNA damage repair pathway was not significantly correlated with prognosis.Patient with mutation of LRRK2(P=0.0028)or LYST(P<0.001)had worse outcome.Conclusion:There were evidence of MAPK signaling pathway,NF-κB signaling pathway,FoxO signaling pathway,Notch signaling pathway and DNA repair pathway alteration in pAL patients.pAL and MM may have similar gene profiles and similar pathogenesis.LRRK2 and LYST mutations may have certain prognostic value in patients with pAL.