***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: Adverse prognostic factors in multiple myeloma include advanced age , number of prior therapies , and higher International Staging System ( ISS ) disease stage . In the international , r and omised , phase‐3 Assessment of Proteasome Inhibition for Extending Remissions ( APEX ) study , bortezomib demonstrated significantly longer time to progression ( TTP ) , higher response rates and improved survival compared with high‐dose dexamethasone in patients with relapsed multiple myeloma following one to three prior therapies . In this APEX subgroup analysis , efficacy of bortezomib and dexamethasone was compared in elderly ( age ≥65 years ) and high‐risk ( > 1 prior line of therapy ; ISS stage II/III ; refractory to prior therapy ) patients . Bortezomib demonstrated substantial clinical activity in these patients . Response rate ( 34–40 % vs. 13–19 % ) , including complete response rate ( 5–8 % vs. 0–1 % ) , was significantly higher with bortezomib versus dexamethasone in all four subgroups . Similarly , median TTP was significantly longer with bortezomib versus dexamethasone , and 1‐year survival probability was significantly higher in all subgroups . As in the total APEX population , rates of grade 3/4 adverse events were higher in bortezomib‐ versus dexamethasone‐treated patients aged ≥65 years and with > 1 prior line , while rates of serious adverse events were similar ; toxicities generally proved manageable . Bortezomib should be considered an appropriate treatment for elderly and high‐risk patients with relapsed multiple myeloma 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 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 ) 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 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  Thalidomide- and bortezomib-naïve patients with melphalan refractory myeloma were r and omly assigned to low-dose thalidomide + dexamethasone ( Thal-Dex ) or bortezomib + dexamethasone ( Bort-Dex ) . At progression on either therapy , the patients were offered crossover to the alternative drug combination . An estimated 300 patients would be needed for the trial to detect a 50 % difference in median PFS between the treatment arms . Results After inclusion of 131 patients , the trial was prematurely closed because of low accrual . Sixty-seven patients were r and omized to Thal-Dex and 64 to Bort-Dex . Progression-free survival was similar ( median , 9.0 months for Thal-Dex and 7.2 for Bort-Dex ) . Response rate was similar ( 55 % for Thal-Dex and 63 % for Bort-Dex ) , but time to response was shorter ( P < 0.05 ) and the VGPR rate higher ( P < 0.01 ) for Bort-Dex . Time-to-other treatment after crossover was similar ( median , 13.2 months for Thal-Dex and 11.2 months for Bort-Dex ) , as was overall survival ( 22.8 months for Thal-Dex and 19.0 for Bort-Dex ) . Venous thromboembolism was seen in seven patients and cerebrovascular events in four patients in the Thal-Dex group . Severe neuropathy , reactivation of herpes virus infections , and mental depression were more frequently observed in the Bort-Dex group . In the quality -of-life analysis , no difference was noted for physical function , pain , and global quality of life . Fatigue and sleep disturbances were significantly more prevalent in the Bort-Dex group . Conclusions Thalidomide ( 50–100 mg daily ) in combination with dexamethasone seems to have an efficacy comparable with that of bortezomib and dexamethasone in melphalan refractory myeloma . However , the statistical strength of the results in this study is limited by the low number of included patients Renal impairment is associated with poor prognosis in multiple myeloma ( MM ) . This subgroup analysis of the phase 3 Assessment of Proteasome Inhibition for Extending Remissions ( APEX ) study of bortezomib vs high-dose dexamethasone  assessed efficacy and safety in patients with relapsed MM with varying degrees of renal impairment ( creatinine clearance ( CrCl ) < 30 , 30–50 , 51–80 and > 80 ml min−1 ) . Time to progression ( TTP ) , overall survival ( OS ) and safety were compared between subgroups with CrCl ⩽50 ml min−1 ( severe-to-moderate ) and > 50 ml min−1 ( no/mild impairment ) . Response rates  with bortezomib were similar ( 36–47 % ) and time to response rapid ( 0.7–1.6 months ) across subgroups . Although the trend was toward shorter TTP/OS in bortezomib patients with severe-to-moderate vs no/mild impairment , differences were not significant . OS was significantly shorter in dexamethasone patients with CrCl ⩽50 vs > 50 ml min−1 ( P=0.003 ) , indicating that bortezomib is more effective than dexamethasone in overcoming the detrimental effect of renal impairment . Safety profile  of bortezomib was comparable between subgroups . With dexamethasone  , grade 3/4 adverse events ( AEs ) , serious AEs and discontinuations for AEs were significantly elevated in patients with CrCl ⩽ 
    Output:
    
RESULTS The CCO HDSG recommends the use of bortezomib-based combinations in previously untreated patients with multiple myeloma who are c and i date s for autologous stem cell transplantation and in individuals who are ineligible for autologous stem cell transplantation .
The evidence did not establish a subgroup of patients with myeloma that should be uniquely targeted for therapy with bortezomib .
Qualifying statements by the HDSG address alternative dosing options , the management of cytopenias and the prevention of toxicities , including herpes zoster reactivation .
CONCLUSIONS Bortezomib alone or in combination with other agents can be recommended for both previously untreated or relapsed/refractory patients with multiple myeloma .