| Objective:Multiple myeloma(MM)is characterized by genetic heterogeneity.Chromosome 1q21 aberrations in MM have attracted much attention for a long time.The objective of this study is to clarify the prognostic value of gain(1q)and explore the best therapeutic strategy for patients with gain(1q).Methods:From January 2008 to December 2016,947 newly diagnosed MM patients in BDH-02/03 clinical trial were enrolled in this study.Baseline characteristics,laboratory detections,therapeutic regimens and outcome of the patients were collected.Cytogenetic aberrations were detected by by fluorescence in situ hybridization in CD138-positive mononuclear cells.Clinical features,cytogenetic abnormalities,and treatment choice were evaluated by univariate analysis.Factors with independent prognostic value were included in multivariate analysis.Results:1.Prognostic threshold:The copy number of 1q21 ranged from two to nine,55.9%of patients had two copies of 1q21.28.2%of patients had three copies of 1q21?and 15.9%of patients had at least four copies.Patients with 1q21 gain had significantly shorter PFS and OS than those without(PFS:23.1 months vs 37.5 months,P<0.001;OS:40.0 months vs 89.4 months,P<0.001).There was no significant difference in the survival of patients with three copies and at least four copies of 1q21.20%of 1q21 gain clone was necessary to distinguish high-risk patients.The clone size of I q21 gain was positively correlated to copy number.2.Clinical characteristics:Gain(1q)positive patients were not significantly different from negative patients in gender,extramedullary lesions,and treatment options.In the gain(lq)positive subgroup,patients older than 65 year were slightly more common(P=0.045),hemoglobin levels were lower(P<0.001),IgD and IgA types were more common(P<0.001),and the proportion of patients with ISS 3 increased significantly(P=0.002).3.Genetic characteristics:Gain(1q)was concurrent with t(4;14)or del(13q).The median PFS and OS of patients with both gain(1q)and t(4;14)were 22.1 months and 38.8 months,respectively.The median PFS and OS of patients with both gain(1 q)and del(13q)was 21.5 months and 36.5 months,respectively.Patients of gain(1q)with the above two co-occurrent cytogenetic abnormalities had no significant difference in survival compared with patients without t(4;14)or del(13q).Gain(1q)and del(17p)seldom appeared concurrently.The median PFS of gain(1q)and del(17p)double negative,single positive and double positive patients was 45.0 months,23.9 months and 15.9 months(P<0.001),respectively.The median OS of the three groups was 89.4 months,50.1 months and 31.0 months(P<0.001),respectively.4.Treatment options:In patients with gain(1q),the median PFS of patients accepted frontline hematopoietic stem cell transplantation(HSCT)was 43.7 months,and the median OS was not reached.The median PFS of the non-HSCT group was 25.3 months,and the median OS was 36.5 months(P=0.027,P<0.001).In non-HSCT patients with gain(1q),thalidomide and bortezomib based treatment had no significant effect on survival.Gain(1 q)positive patients could not benefit more from bortezomib,compared to thalidomide.The median OS of gain(1q)patients treated in prolonged bortezomib subgroup(?6 cycles)or non-prolonged subgroup(<6 cycles)was 66.2 months and 41.4 months(P=0.091),respectively.Conclusion:1.Gain(1q)was an independent high-risk factor of MM.Three copies of 1q21 and 20%of MM cells might be the optimal cut-off value to distinguish adverse outcome of patients.2.Gain(1q)was concurrent with t(4;14)or del(13q).The patients with concurrent t(4;14)or del(13q)had inferior outcome than those with sole gain(1q).Bortezomib overcame the inferior effect of t(4;14),but not gain(1 q).In the era of bortezomib,gain(1q)might be more important than t(4;14)in prognostic staging.3.The patients with gain(1 q)were encouraged to accept ASCT during the 1st-line therapy,as bortezomib showed no advantage on survival,compared to thalidomide.Prolonged bortezomib treatment might not bring extra benefit to patients with 1q21 gain.Objective:Age is an important prognostic factor in multiple myeloma.The risk of progression from MGUS and SMM to symptomatic MM steadily increased with age.Young and old MM patients have different clinical manifestations and cytogenetic characteristics.The purpose of this study is to explore the potential in adding age to the prognostic staging system,and evaluate the explained variation of prognostic factors in age stratified subgroups.Methods:The study enrolled 947 patients who were treated in our hospital from January 2008 to December 2016.The Kruskal-Wallis test was used to evaluate the significance on continuous variables.The Fisher's exact test was used for categorical variables.Kaplan-Meier method was used to calculate the median overall survival(OS)and progression-free survival(PFS).The difference between the survival groups was compared by the log-rank test.Cox proportional-hazards model was developed to assess the variables with significant effects on PFS and OS.The explained variation of prognostic factors was analyzed by Stata/MP 16.0(Stata Corp.,TX,USA)software,and the str2ph model was used to calculate the R2 value.Results:1.Baseline characteristics:Among 778 patients with complete data,59.5%(463/778)of patients were younger than 60 years old,3 1.4%(244/778)of patients were 61-70 years old,only 9.1%(71/778)of patients were over 71 years old.The median glomerular filtration rate of the three groups was 89.1,74.0 and 66.4 ml/min(P<0.001),respectively.The ?2-microglobulin level gradually increased with age(P<0.001),along with the proportion of patients with ISS 3 stage.Patients? 71 years old had a higher proportion of ECOG PS score 3-4,twice than that of patients?60 years old.The incidence of high-risk IgH translocation decreased with age,and was 25.4%,21.3%and 14.3%across age groups.The incidence of gain(1q)increased with age,and was 43.9%,47.1%and 54.8%,respectively.The incidence of del(17p)and del(13q)seldom changed with age.2.Prognosis of patients at different ages:The median PFS of patients in?60,61-70 and?71 year subgroups was 36.3,32.6 and 23.1 months,respectively.(P<0.001)The median OS in the three age groups was 86.2,60.7 and 34.9 months,respectively.(P<0.001)3.The explained variation of high-risk factors at different ages:With age increasing,the weight of the number of high-risk cytogenetic abnormalities did not change significantly,accounting for about 50%in each age group.The weight of ISS gradually decreased with age,accounting for 36%,27%,and 14%in the?60,61-70 and ?71 year subgroup,respectively.The weight of the ECOG PS score gradually increased with age,accounting for 10%,17%,and 36%in the three subgroups,respectively.4.Treatment options of elderly high-risk patients:The overall response rate of both bortezomib and thalidomide arms gradually decreased with age,and were 90.2%,81.9%,and 69.2%,respectively(P<0.001).Elderly patients with impaired renal function or high-risk cytogenetic abnormalities?2 benefited more from bortezomib based treatment than young patients.Conclusion:1.Age is an important prognostic factor in multiple myeloma.The risk of progression or death steadily grows with age.After adjusting for ISS stage,LDH,and high-risk cytogenetic abnormalities,age remained independent prognostic significance in multiple myeloma.2.The prognostic impact of ISS decreased,whereas the impact of physical status on prognosis gradually increased with age.3.High-risk elderly patients benefit from bortezomib based treatment,and should be positively treated with proteasome inhibitor-based regimens. |
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