| Background and objectiveMultiple myeloma(MM)is a malignancy from clonal plasmocytes,which is the second common hematological malignancies after lymphoma,especially in the elderly over 60 years.With the aggravating trend of aging population in China,the incidence of MM increases rapidly and has become one of the important diseases threatening people’s health.Typically,multiple myeloma shows obvious heterogeneity and different prognosis,along with some clinical manifestations including hypercalcemia,anemia,bone destruction,renal insufficiency and other symptoms caused by terminal organ dysfunction.Over the past two decades,the availability of proteasome inhibitors(PIs)and immunomodulatory agents(IMi Ds)based trsatments has increased the median survival of patients.However,MM remains an incurable disease,and almost all patients have to face the relapse and progression of the disease.Immunoglobulin D(IgD)myeloma is a rare isotype that comprises 1–2% of MM patients,which has significantly inferior survival for a median overall survival(OS)between 13 and 21 months.Given the knowledge about IgD myeloma is obtained mostly from isolated case reports and single center case series,lacking of large cohort assessment,we carried out a multicenter retrospective study with 356 IgD myeloma patients from 14 centers of Asian Myeloma Network(AMN),to evaluate the prevalence,clinical features,response to traeatment,survival outcome,prognostic factors,and to develop a prognostic model for evidence-based treatment of IgD myeloma.Methods1.Sample collectionThis multicenter study conducted in fourteen centers from three countries(China,Korea,and Singapore)in AMN,data from 356 newly diagnosed and symptomatic IgD myeloma patients was collected from 2002 to 2019.Clinical and laboratory data were retrospectively collected from medical records,included age at diagnosis,gender,stage(DS,ISS,R-ISS),percentage of plasma cells in BM,light chain restriction,hemoglobin level,platelet count,LDH,serum creatinine level,serum calcium level,serum free light chian(s FLC),extramedullary plasmacytoma,FISH abnormalities,treatment modality,ASCT,respons to treatment and survival.2.Comparison of clinical featuresIn order to get accurate clinical features of IgD MM,we firstly compare data between IgD and non-IgD patients,and within different centers.To further identified the relationship between IgD and other subtypes,we compared IgD myeloma patients with Ig G,Ig A,and light chain patients,respectively.Categorical variables were tested by the Fisher’s exact test,and the Mann-Whitney U test for continuous variables.All data were considered statistically significant at P < 0.05.3.Development of the predictive model and validationTo avoid data bias,we split existing 356 patients from 14 centers to three parts,namely training cohort(Shanghai XX Hospital,n = 212),validation cohort 1(Beijing XX Hospital and Beijing XX Hospital,n = 81),and validation cohort 2(11 centers from Korea and Singapore,n = 63).LASSO Cox regression model were performed to build a predictive model.The quality of the prediction model was measured with the concordance index(C-index)and areas under the time-dependent receiver-operating characteristics(ROC)curves(AUCs).A bootstrap with 1000 re-samples was used for internal validation.SAS 9.4 and R 3.5.1 were used for the statistical analysis.Results1.Patients’ characteristics in IgD myelomaIgD myeloma patients accounted for 2-8.8% in NDMM,over 5% prevalence of three Chinese centers,which is significantly higher than foreign reports.Compared with non-IgD MM,IgD myeloma patients shows characteristics with a younger age,a higher frequency in male(67.7%)and lambda light chain(88.8%).In addition,patiens with ISS Ⅲ(62.4%),R-ISS Ⅲ(32.3%),hypercalcemia(23.9% vs.14.7%),renal insufficiency(38.5% vs.18.4%),elevated LDH(38.2% vs.24.9%),thrombocytopenia(22.3% vs.12.8%),and plasma cells in BM≥50%(41.9% vs 20.1%)were more outstanding in IgD myeloma.Compared with common subtypes,the median age at diagnosis was younger in Ig G,Ig A,and light chain patients(56 : 61 : 62 : 60 years,P < 0.001,respectively).Compared to Ig G myeloma,male dominance was still significant in IgD myeloma(67.7% vs.59.3% P =0.02).2.Chromosome abnormalities in IgD myelomaFISH was available in 301 patients(301/356),while the 1q21 probe was only performed in 270 patients.The frequency of 1q21+,13q-,17p-,t(11;14),t(4;14)and t(14;16)was 33.7%,25.6%,11.6%,29.2%,1.3% and 1.0%,respectively.Among the 88 IgD patients harbored t(11;14),the most frequent CA coupled with t(11;14)were 13q-(31.8%),1q21+(30.7%),and followed with 17p-(11.4%).Compared with non-IgD MM,the frequency of t(11;14)in patients with IgD myeloma was significantly higher than other subtypes(P < 0.001),while 13q-、1q21+、t(4;14)was lower than others(P<0.05).According to the definition of ‘double-hit’ by Mayo m SMART3.0,IgD myeloma patients were identified at 5.6% which was lower than non-IgD patients.Further analysis shows that 13q-,17p-,1q21+,t(4;14),t(11;14),t(14;16)did not exhibit additional impacts on OS(P > 0.05).Compared with common subtypes,the frequency of t(11;14)in patients with IgD myelom was significantly higher than Ig G and Ig A subtypes(P < 0.001),but was a slight higher than light chain subtype(P = 0.302),while 13q-、1q21+、t(4;14)was lower than other subtypes(P<0.05).‘Double-hit’ phenotype was however lower in IgD myelomas(5.6%)than Ig G(20.6%,P < 0.001),Ig A(20%,P < 0.001),and light chain(12.4%,P =0.073).3.Response of different initail treatment and survivalFor 356 patients,168(47.2%)patients received with bortezomib-based regimen,62(17.4%)with IMi Ds-based,67(18.8%)with the combination with IMi Ds and PIs,and the remaining 59(16.6%)with traditional alkylating agent regimen,and the median OS were37 months,46 months,34 months and 36 months.Patients received IMi Ds showed a longer median OS than other agents,however,not untranslated into a significant survival benefit(P = 0.17).Overall,85 patients(23.9%)received ASCT.Although patients received ASCT had a median OS of 46 months which was a slightly longer than 35 months for non-ASCT patients,there was no significant difference survival(P = 0.404).Evaluable response rate were available in 215 patients,the overall response rate(ORR)of initail treatment was 88.8% and very good partial response(VGPR)or better were 58.6%.4.Prognostic factor for OS in IgD MMLASSO Cox regression model was usde to build a predictive model.Five variables,including lambda light chain,plasma cells in BM≥50%,hemoglobin<100g/L,LDH≥ 245U/L,and extramedullary plasmacytoma,were identified as an independent risk for OS in univariate and multivariate analysis.5.Development of a predictive model and validationIn this study,LASSO Cox regression model was usde to build a predictive model.By the analysis of nomogram,we got IgD MM risk score as follows: 0.9215×lambda light chain + 0.6376×plasma cells in BM(≥50%)+ 0.5203×anemia(<100g/L)+ 0.6864×LDH(≥245U/L)+ 0.4484×extramedullary plasmacytoma(variable present = 1,absent = 0).The accuracy of this nomogram was validated with C-index and ROC curve.In the training cohort,the predictive accuracy for OS calculated using the C-index was 0.705(95% CI,0.663～0.747).In the internal validation,the corrected C-index of OS was 0.696.Similarly,the C-index for OS in validation cohort 1 was 0.690(95% CI,0.612～ 0.768)and 0.703(95% CI,0.608～0.798)in validation cohort 2.On the basis of the distribution of the risk scores and the 3-year survival probability,two categories of risk were created with the cut-off point at 1.56: standard risk(risk score ≤ 1.56,n = 156)and high risk subgroup(risk score﹥1.56,n = 200).We further identified the validity of the prediction model,which showed a significant advantage in prognostic value,and not affected by treatment regiments.Further research confirms that,ASCT could benefit patients with high risk,but did not improve the survival of patients in the standard risk group.ConclusionsIn this study,we described the clinical characteristics of 356 patients with IgD myeloma,developed and validated a predictive model,which included five clinical variables.By validated in training and validation cohorts,and subgroups received different treatment regiments,we found that this prognostic model has good prognostic value,which can not only provide guidance for the treatment of IgD myeloma,but also provide a better reference for the risk stratification treatment strategies for IgD myeloma. |
PDF Full Text Request