| Objective:Multiple myeloma?MM?is a clonal plasma cell disorder,which remains incurable.The t?4;14?translocation is the second most common translocation in MM,affecting approximately 15%of MM patients with symptomatic disease.MM patients carrying t?4;14?translocation were resisted to traditional chemotherapy with short median overall survival.Despite recent therapeutic regimen such as bortezomib induction improves outcome of patients with t?4;14?,it still indicates a poor prognosis.The MM patients with t?4;14?is a heterogeneous group.The t?4;14?translocation deregulates two potential oncogenes,FGFR3 and WHSC1/MMSET.The role of FGFR3 and WHSC1/MMSET in MM development are not clear.Previous studies have shown that FGFR3 expression,which is lost in about 30%of t?4;14?MM,does not have a significant impact on patients'survival.However,The MMSET gene is overexpressed in almost all MM patients with t?4;14?.Thus,dysregulation of MMSET on der?4?might be a well-characterized event of t?4;14?.The MMSET gene encodes for a histone methyltransferase which is involved in genomic instability and tumor progression.Three major break-points within the 5'coding region of MMSET?MB4-1,MB4-2 and MB4-3?have been observed at 4p16 on chromosome der?4?.Each breakpoint overexpresses a specific IGH/MMSET fusion transcript.Hybrid transcripts from MB4-1 patients encode the full-length MMSET protein,while hybrid transcripts from MB4-2 and MB4-3patients lack the first or first and second translated exons of MMSET,respectively.The aim of this study was to clarify whether expression of FGFR3 and the overexpression of full-length?MB4-1?or truncated forms?MB4-2 and MB4-3?of MMSET influence the prognosis of MM patients with t?4;14?.Methods:A total of 53 newly diagnosed symptomatic t?4;14?posos MM patients from 2011to 2016 were retrospectively analyzed.The last follow-up date was December 31,2016.Of all patients,the median follow-up time was 18.83 months from the diagnosis.1.In all cases,RT-PCR was performed using cDNA from purified CD138+bone marrow plasma cells at diagnosis to analyze expression of FGFR3 and the IGH-MMSET fusion transcripts resulting from the three different breakpoints MB4-1,MB4-2 and MB4-3.2.CD138+plasma cells sorted were also assessed using DNA probes specific for the following chromosomal aberrations:del?13q14?,del?17p?and amp?1q21?.3.We further analyzed FGFR3 expression,MB4 breakpoint and other risk factors that might affect the prognosis of this series of patients.According to prognostic variables in univariate analysis,we further made multivariate analysis to select the powerful independent adverse factor for PFS and OS.Impact of MMSET breakpoints on the outcome of patients with t?4;14?and other cytogenetic high-risk factors were also analyzed.Finally,We compared the prognosis of MB4-1 and MB4-2/MB4-3 subgroups after being treated with induction therapy of bortezomib-based regimen.Results:1.Of the 53 t?4;14?POS patients,25?47.2%?had the MB4-1 breakpoint,while 12?22.6%?and 16?30.2%?had the MB4-2 and MB4-3 breakpoints,respectively.2.FGFR3 expression was detected in 22?88%?,21?75%?of MB4-1,MB4-2/MB4-3breakpoints,respectively?P=0.302?.However,FGFR3 expression or not had no prognosis significance in the present study?P>0.05?.3.Based on the univariate analysis,patients with serum calcium higher than 2.8mmol/L?P<0.001?,del?17p??P=0.001?and high-risk genetic abnormality?P=0.028?had inferior PFS than the corresponding control group.Furthermore,patients with MB4-2/MB4-3 breakpoint?P=0.001?,ISS stage III?P=0.001?,Lactate dehydrogenase?LDH?higher than 245 U/L?P=0.033?,Creatinine?Cr?higher than 176umol/L?P=0.03?,?2-MG higher than 5.5mg/L?P=0.039?,del?17p??P=0.013?,amp?1q21??P=0.028?and high-risk genetic abnormality?P=0.003?had inferior OS than the corresponding control group.4.In multivariate analysis,when adjusted to the above prognostic variables,t?4;14?grouped according to breakpoint into MB4-1 and MB4-2/MB4-3 subgroup remained the powerful independent adverse factor for PFS?HR 2.74,95%CI:1.24–6.09,P=0.013?and OS?HR 4.37,95%CI:1.17–16.33,P=0.029?.Another independent factors in OS were del?17p??HR 3.65,95%CI:1.2–11.14,P=0.023?,ISS III stage?HR 3.76,95%CI:1.19–11.9,P=0.024?and LDH?HR 2.86,95%CI:1–8.19,P=0.05?.The other independent factor in PFS was serum calcium?HR 11.54,95%CI:3.7–36,P<0.001?.5.Overall,del?17p?was detected in 11 out of 53 cases?20.8%?.Amp?1q21?was found in 32 out of 53 cases?60.4%?.MB4-1 without del?17p?subgroup had longer PFS than the rest three subgroups?P=0.002,0.036,0.002,respectively?.MB4-1 without del?17p?subgroup had longer OS than MB4-2/MB4-3 with/without del?17p??P<0.001and P=0.002?,however,MB4-1 without del?17p?subgroup had similar OS with MB4-1with del?17p?subgroup?P=0.259?.MB4-2/MB4-3 with amp?1q21?subgroup had shorter PFS than MB4-1 without amp?1q21??P=0.047?,but similar with the rest two subgroups?P=0.234 and 0.326?.MB4-2/MB4-3 with amp?1q21?subgroup had shorter OS than MB4-1 with or without amp?1q21??P=0.024 and 0.002?,but similar with MB4-2/MB4-3without amp?1q21?subgroup?P=0.61?.6.ORR of patients in MB4-1 subgroup was superior to those in MB4-2/MB4-3subgroup after being treated with induction therapy of bortezomib-based regimen?P=0.035?.In bortezomib-based chemotherapy group,the median PFS and OS of patients with MB4-2/MB4-3 breakpoint were 13.67 vs.29.2 months?P=0.004?and 22.9 vs.NS?P=0.00?when compared to patients with MB4-1 breakpoint.In addition,in patients with MB4-1 breakpoint,the median PFS and OS of patients treated with bortezomib-based chemotherapy were 29.2 vs.12.37 months?P=0.03?and not reached vs.41.73 months?P=0.048?when compared to patients treated with other chemotherapy.Accordingly,in patients with MB4-2/MB4-3 breakpoint,no statistically significant difference between bortezomib-based and other chemotherapy groups was observed?PFS:P=0.074;OS:P=0.266?.Conclusion:No prognosis significance of FGFR3 expression was observed in the present study.In this study,MB4-2/MB4-3 breakpoint and serum calcium?2.8mmol/L were independent factors in PFS.MB4-2/MB4-3 breakpoint,ISS III stage,del?17p?positive and LDH?245 U/L were independent factors in OS.Our results supported that MB4-2/MB4-3 breakpoint with truncated forms of MMSET,defines a subset of t?4;14?MM with poor prognosis.MB4-1 without del?17p?subgroup might be a subset of t?4;14?MM with superior prognosis.Bortezomib-based therapy significantly improve the survival of patients with MB4-1 subgroup but could not overcome the negative impact of MB4-2/MB4-3 breakpoint. |
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