***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: The phase III MMY-3021 study compared safety and efficacy of subcutaneous versus intravenous administration of the proteasome inhibitor bortezomib in patients with relapsed myeloma . The initial report demonstrated non-inferior efficacy with subcutaneous versus intravenous bortezomib for the primary end point : overall response rate after four cycles of single-agent bortezomib . We report up date d outcome analyses after prolonged follow up . Best response rate ( after up to ten cycles of bortezomib ± dexamethasone ) remained 52 % in each arm , including 23 % and 22 % complete or near-complete responses with subcutaneous and intravenous bortezomib , respectively . Time to progression ( median 9.7 vs. 9.6 months ; hazard ratio 0.872 , P=0.462 ) , progression-free survival ( median 9.3 vs. 8.4 months ; hazard ratio 0.846 , P=0.319 ) , and overall survival ( 1-year : 76.4 % vs. 78.0 % , P=0.788 ) were comparable with subcutaneous versus intravenous bortezomib . Peripheral neuropathy rates remained significantly lower with subcutaneous versus intravenous bortezomib , with increased rates of improvement/resolution at the time of this analysis BACKGROUND Thalidomide plus dexamethasone ( TD ) is a st and ard induction therapy for myeloma . We aim ed to assess the efficacy and safety of addition of bortezomib to TD ( VTD ) versus TD alone as induction therapy before , and consolidation therapy after , double autologous stem-cell transplantation in newly diagnosed multiple myeloma . METHODS Patients ( aged 18 - 65 years ) with previously untreated symptomatic myeloma were enrolled from 73 sites in Italy between May , 2006 , and April , 2008 , and data collection continued until June 30 , 2010 . Patients were r and omly allocated ( 1:1 ratio ) by a web-based system to receive three 21-day cycles of thalidomide ( 100 mg daily for the first 14 days and 200 mg daily thereafter ) plus dexamethasone ( 40 mg daily on 8 of the first 12 days , but not consecutively ; total of 320 mg per cycle ) , either alone or with bortezomib ( 1·3 mg/m(2 ) on days 1 , 4 , 8 , and 11 ) . The r and omisation sequence was computer generated by the study coordinating team and was stratified by disease stage . After double autologous stem-cell transplantation , patients received two 35-day cycles of their assigned drug regimen , VTD or TD , as consolidation therapy . The primary endpoint was the rate of complete or near complete response to induction therapy . Analysis was by intention to treat . Patients and treating physicians were not masked to treatment allocation . This study is still underway but is not recruiting participants , and is registered with Clinical Trials.gov , number NCT01134484 , and with EudraCT , number 2005 - 003723 - 39 . FINDINGS 480 patients were enrolled and r and omly assigned to receive VTD ( n=241 patients ) or TD ( n=239 ) . Six patients withdrew consent before start of treatment , and 236 on VTD and 238 on TD were included in the intention-to-treat analysis . After induction therapy , complete or near complete response was achieved in 73 patients ( 31 % , 95 % CI 25·0 - 36·8 ) receiving VTD , and 27 ( 11 % , 7·3 - 15·4 ) on TD ( p<0·0001 ) . Grade 3 or 4 adverse events were recorded in a significantly higher number of patients on VTD ( n=132 , 56 % ) than in those on TD ( n=79 , 33 % ; p<0·0001 ) , with a higher occurrence of peripheral neuropathy in patients on VTD ( n=23 , 10 % ) than in those on TD ( n=5 , 2 % ; p=0·0004 ) . Resolution or improvement of severe peripheral neuropathy was recorded in 18 of 23 patients on VTD , and in three of five patients on TD . INTERPRETATION VTD induction therapy before double autologous stem-cell transplantation significantly improves rate of complete or near complete response , and represents a new st and ard of care for patients with multiple myeloma who are eligible for transplant . FUNDING Seràgnoli Institute of Haematology at the University of Bologna , Bologna , Italy The phase 3 VISTA study ( Clinical Trials.gov NCT00111319 ) in transplant‐ineligible myeloma patients demonstrated superior efficacy with bortezomib‐melphalan‐prednisone ( VMP ; nine 6‐wk cycles ) vs. melphalan‐prednisone ( MP ) but also increased toxicity . Health‐related quality of life ( HRQoL ; exploratory endpoint ) was evaluated using the European Organization for Research and Treatment of Cancer ( EORTC ) Quality of Life Question naire ( QLQ‐C30 ) Combinations of bortezomib ( V ) and dexamethasone ( D ) with either lenalidomide ( R ) or cyclophosphamide ( C ) have shown significant efficacy . This r and omized phase 2 trial evaluated VDC , VDR , and VDCR in previously untreated multiple myeloma ( MM ) . Patients received V 1.3 mg/m2 ( days 1 , 4 , 8 , 11 ) and D 40 mg ( days 1 , 8 , 15 ) , with either C 500 mg/m2 ( days 1 , 8) and R 15 mg ( days 1 - 14 ; VDCR ) , R 25 mg ( days 1 - 14 ; VDR ) , C 500 mg/m2 ( days 1 , 8 ; VDC ) or C 500 mg/m2 ( days 1 , 8 , 15 ; VDC-mod ) in 3-week cycles ( maximum 8 cycles ) , followed by maintenance with V 1.3 mg/m2 ( days 1 , 8 , 15 , 22 ) for four 6-week cycles ( all arms)≥very good partial response was seen in 58 % , 51 % , 41 % , and 53 % ( complete response rate of 25 % , 24 % , 22 % , and 47 % ) of patients ( VDCR , VDR , VCD , and VCD-mod , respectively ) ; the corresponding 1-year progression-free survival was 86 % , 83 % , 93 % , and 100 % , respectively . Common adverse events included hematologic toxicities , peripheral neuropathy , fatigue , and gastrointestinal disturbances . All regimens were highly active and well tolerated in previously untreated MM , and , based on this trial , VDR and VCD-mod are preferred for clinical practice and further comparative testing . No substantial advantage was noted with VDCR over the 3-drug combinations . This trial is registered at www . clinical trials.gov ( NCT00507442 ) In a r and omized , phase 3 study , superior complete/near-complete response ( CR/nCR ) rates and extended progression-free survival were demonstrated with bortezomib-thalidomide-dexamethasone ( VTD ) versus thalidomide-dexamethasone ( TD ) as induction therapy before , and consolidation after , double autologous stem cell transplantation for newly diagnosed myeloma patients ( intention-to-treat analysis ; VTD , n = 236 ; TD , n = 238 ) . This per- protocol analysis ( VTD , n = 160 ; TD , n = 161 ) specifically assessed the efficacy and safety of consolidation with VTD or TD . Before starting consolidation , CR/nCR rates were not significantly different in the VTD ( 63.1 % ) and TD arms ( 54.7 % ) . After consolidation , CR ( 60.6 % vs 46.6 % ) and CR/nCR ( 73.1 % vs 60.9 % ) rates were significantly higher for VTD-treated versus TD-treated patients . VTD consolidation significantly increased CR and CR/nCR rates , but TD did not ( McNemar test ) . With a median follow-up of 30.4 months from start of consolidation , 3-year progression-free survival was significantly longer for the VTD group ( 60 % vs 48 % for TD ) . Grade 2 or 3 peripheral neuropathy ( 8.1 % vs 2.4 % ) was more frequent with VTD ( grade 3 , 0.6 % ) versus TD consolidation . The superior efficacy of VTD versus TD as induction was retained despite readministration as consolidation therapy after double autologous transplantation . VTD consolidation therapy significantly contributed to improved clinical outcomes observed for patients r and omly assigned to the VTD arm of the study . The study is registered at www . clinical trials.gov as # NCT01134484 The Intergroupe Francophone du Myelome conducted a r and omized trial to compare bortezomib-dexamethasone ( VD ) as induction before high-dose therapy ( HDT ) and autologous stem cell transplantation ( ASCT ) to a combination consisting of reduced doses of bortezomib and thalidomide plus dexamethasone ( vtD ) in patients with multiple myeloma . Overall , a total of 199 patients were central ly r and omly assigned to receive VD or vtD. After 4 cycles , the complete response ( CR ) rate was the same in both groups ( 13 % in the vtD arm , 12 % in the VD arm , P = .74 ) . However , the CR plus very good partial response ( VGPR ) rate was significantly higher in the vtD arm ( 49 % vs 36 % , P = .05 ) . After ASCT , the CR plus VGPR rate was significantly higher in the vtD arm ( 74 % vs 58 % , P = .02 ) . The reduced doses of bortezomib and thalidomide translated into a reduced incidence of peripheral neuropathy ( PN ) : grade ≥ 2 PN were reported in 34 % in the VD arm versus 14 % in the vtD arm ( P = .001 ) . vtD , including reduced doses of bortezomib and thalidomide , yields higher VGPR rates compared with VD and can be considered a new effective triplet combination before HDT/ASCT Initial analysis of the Assessment of Proteasome Inhibition for Extending Remissions ( APEX ) trial of relapsed multiple myeloma patients showed significantly longer time to progression , higher response rate , and improved survival with single-agent bortezomib versus high-dose dexamethasone . In this up date d analysis ( median follow-up : 22 months ) , survival was assessed in both arms , and efficacy up date d for the bortezomib arm . Median survival was 29.8 months for bortezomib versus 23.7 months for dexamethasone , a 6-month benefit , despite substantial crossover from dexamethasone to bortezomib . Overall and complete response rates with bortezomib were 43 % and 9 % , respectively ; among responding patients , 56 % improved response with longer therapy beyond initial response , leading to continued improvement in overall quality of response . Higher response quality ( 100 % M-protein reduction ) was associated with longer response duration ; response duration was not associated with time to response . These data confirm the activity of bortezomib and support extended treatment in relapsed multiple myeloma patients tolerating therapy The Nordic Myeloma Study Group conducted an open r and omized trial to compare bortezomib as consolidation therapy given after high-dose therapy and autologous stem cell transplantation ( ASCT ) with no consolidation in bortezomib-naive patients with newly diagnosed multiple myeloma . Overall , 370 patients were central ly r and omly assigned 3 months after ASCT to receive 20 doses of bortezomib given during 21 weeks or no consolidation . The hypothesis was that consolidation therapy would prolong progression-free survival ( PFS ) . The PFS after r and omization was 27 months for the bortezomib group compared with 20 months for the control group ( P = .05 ) . Fifty-one of 90 patients in the treatment group compared with 32 of 90 controls improved their response after r and omization ( P = .007 ) . No difference in overall survival was seen . Fatigue was reported more commonly by the bortezomib-treated patients in self-reported quality -of-life ( QOL ) question naires , whereas no other major differences in QOL were recorded between the groups . Consolidation therapy seemed to be beneficial for patients not achieving at least a very good partial response ( VGPR ) but not for patients in the ≥ VGPR category at r and omization . Consolidation with bortezomib after ASCT in bortezomib-naive patients improves PFS without interfering with QOL . This trial was registered at www . clinical trials.gov as # NCT00417911 Objectives Thalidomide and bortezomib have been frequently used for second-line therapy in patients with myeloma relapsing after or refractory to initial melphalan-based treatment , but no r and omized trials have been published comparing these two treatment alternatives . Methods 
    Output:
    
Subgroup analyses by disease setting revealed improvements in all outcomes , whereas for therapy setting , an improved benefit for bortezomib was observed in all outcomes and subgroups except for OS following consolidation therapy .
This meta- analysis found that myeloma patients receiving bortezomib benefited in terms of OS , PFS and response rate compared to those who did not receive bortezomib .
This benefit was observed in trials of bortezomib versus no bortezomib with the same background therapy and in trials of bortezomib versus no bortezomib with different background therapy in each arm or compared to other agent(s ) .