***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: 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 BACKGROUND Lenalidomide is an immunomodulatory drug that is also currently used in transplant-eligible patients with multiple myeloma . Previous studies have suggested a negative impact of lenalidomide on the mobilization of CD34 + cells . No data are available regarding the more detailed composition of blood grafts after lenalidomide . STUDY DESIGN AND METHODS In a multicenter , prospect i ve study , we analyzed the mobilization of CD34 + cells , graft cellular composition , and post-transplant hematologic recovery in 26 patients with multiple myeloma after lenalidomide-based induction and in 34 lenalidomide-naive controls with multiple myeloma . All patients were mobilized with low-dose cyclophosphamide plus granulocyte-colony-stimulating factor . The cellular composition of the grafts was analyzed from thawed , cryopreserved sample s with flow cytometry . Graft function was evaluated by engraftment data and by complete blood counts until 12 months after the graft infusion . RESULTS Patients in the lenalidomide arm had lower median peak CD34 + counts and approximately 40 % lower CD34 + cell yields from the first apheresis session , but these differences were not significant . The median total number of CD34 + cells collected was comparable ( 6.4 vs. 7.5 × 106 /kg ) . The number of apheresis sessions was higher in the lenalidomide group ( 2 vs. 1 ; p = 0.039 ) . The blood graft composition was comparable between the groups . Hematologic recovery within 12 months post-transplant did not differ between the groups . CONCLUSION Lenalidomide-based induction seems to have an impact on the number of aphereses performed , but not on the total yields of the CD34 + cells in the graft . Neither cellular composition of the grafts nor post-transplant recovery was affected by the limited pre-transplant exposure to lenalidomide This follow‐up extension of a r and omised phase II study assessed differences in long‐term outcomes between bortezomib‐thalidomide‐dexamethasone ( VTD ) and VTD‐cyclophosphamide ( VTDC ) induction therapy in multiple myeloma . Newly diagnosed patients ( n = 98 ) were r and omised 1:1 to intravenous bortezomib ( 1·3 mg/m2 ; days 1 , 4 , 8 , 11 ) , thalidomide ( 100 mg ; days 1–21 ) , and dexamethasone ( 40 mg ; days 1–4 , 9–12 ) , with/without cyclophosphamide ( 400 mg/m2 ; days 1 , 8) , for four 21‐day cycles before stem‐cell mobilisation/transplantation .  After a median follow‐up of 64·8 months , median time‐to‐next therapy was 51·8 and 47·9 months with VTD and VTDC , respectively . Type of subsequent therapy was similar in both arms . After adjusting for asymmetric censoring , median time to progression was not significantly different between VTD and VTDC [ 35·7 vs. 34·5 months ; Hazard ratio ( HR ) 1·26 , 95 % confidence interval : 0·76–2·09 ; P = 0·370 ] . Five‐year survival was 69·1 % and 65·3 % with VTD and VTDC , respectively . When analysed by minimal residual disease ( MRD ) status , overall survival was longer in MRD‐negative versus MRD‐positive patients with bone marrow‐confirmed complete response ( HR 3·66 , P = 0·0318 ) . VTD induction followed by transplantation provides long‐term disease control and , consistent with the primary analysis , there is no additional benefit from adding cyclophosphamide . This study was registered at Clinical Trials.gov ( NCT00531453 ) Mixed treatment comparison ( MTC ) meta- analysis is a generalization of st and ard pairwise meta- analysis for A vs B trials , to data structures that include , for example , A vs B , B vs C , and A vs C trials . There are two roles for MTC : one is to strengthen inference concerning the relative efficacy of two treatments , by including both ' direct ' and ' indirect ' comparisons . The other is to facilitate simultaneous inference regarding all treatments , in order for example to select the best treatment . In this paper , we present a range of Bayesian hierarchical models using the Markov chain Monte Carlo software WinBUGS . These are multivariate r and om effects models that allow for variation in true treatment effects across trials . We consider models where the between-trials variance is homogeneous across treatment comparisons as well as heterogeneous variance models . We also compare models with fixed ( unconstrained ) baseline study effects with models with r and om baselines drawn from a common distribution . These models are applied to an illustrative data set and posterior parameter distributions are compared . We discuss model critique and model selection , illustrating the role of Bayesian deviance analysis , and node-based model criticism . The assumptions underlying the MTC models and their parameterization are also discussed Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more PURPOSE Bortezomib-thalidomide-dexamethasone ( VTD ) is an effective induction therapy in multiple myeloma ( MM ) . This phase II , noncomparative study sought to determine whether addition of cyclophosphamide to this regimen ( VTDC ) could further increase efficacy without compromising safety . PATIENTS AND METHODS Patients age 18 to 70 years with previously untreated , measurable MM , who were eligible for high-dose chemotherapy-autologous stem-cell transplantation ( HDCT-ASCT ) , were r and omly assigned to bortezomib 1.3 mg/m(2 ) , thalidomide 100 mg , and dexamethasone 40 mg , with ( n = 49 ) or without ( n = 49 ) cyclophosphamide 400 mg/m(2 ) for four 21-day cycles , followed by HDCT-ASCT . The primary end point was postinduction combined rate of near-complete response ( nCR ) or better ( including complete response [ CR ] with normalized serum κ : λ free light chain ratio , CR , and nCR ) . RESULTS Postinduction , 51 % ( VTD ) and 44 % ( VTDC ) of patients achieved combined CR/nCR , with bone marrow-confirmed CR in 29 % and 31 % , overall response rates of 100 % and 96 % , respectively , and very good partial response or better rates of 69 % per arm . Post-HDCT-ASCT , combined CR/nCR rates were 85 % ( VTD ) and 77 % ( VTDC ) . In all , 35 % ( VTD ) and 27 % ( VTDC ) of patients were negative for minimal residual disease ( MRD ) during induction and postinduction . Three-year overall survival was 80 % ( both arms ) . Grade 3 to 4 adverse events ( AEs ) and serious AEs were observed in 47 % and 22 % ( VTD ) and 57 % and 41 % ( VTDC ) of patients , respectively . The primary health-related quality of life end point ( European Organisation for Research and Treatment of Cancer Quality of Life Question naire C30 [ EORTC QLQ-C30 ] Global Health score ) steadily increased with VTD during induction and reached a clinical ly relevant difference post-transplantation versus baseline . CONCLUSION Both VTD and VTDC are highly active induction regimens producing high combined CR/nCR and MRD-negative rates ; however , VTDC was associated with increased toxicity and suggestion of transient decreases in Global Health score , without an increase in activity Pegylated liposomal doxorubicin has pharmacologic and safety advantages over conventional doxorubicin Whilst infusional vincristine , adriamycin and dexamethasone ( VAD ) is an effective treatment for patients with multiple myeloma ( MM ) , administration may be complicated by line‐associated infections and thromboses . The oral regime , Z‐Dex ( idarubicin and dexamethasone ) has been shown to be efficacious in MM . We conducted a r and omized study comparing Z‐Dex with VAD as induction therapy in newly diagnosed MM patients . A total of 106 patients ( median age , 56 years ; range : 37–73 ; Durie‐Salmon stage II/III ) were r and omized to receive four to six cycles of Z‐Dex or VAD . Central line complications were reported in 38 patients on 57 cycles , primarily because of infection . Neutropenia ( all grade s ) was more common in the Z‐Dex arm ( P = 0·009 ) although grade III/IV neutropenia was not significantly different between the treatment groups ( P = 0·06 ) . Infections ( all grade s ) were more commonly seen in the VAD arm ( P = 0·001 ) although grade III/IV infections were not significantly different between the two groups ( P = 0·081 ) . The responses to therapy ( complete/partial response ) in evaluable patients were : VAD 74 % vs. Z‐Dex 58 % , with an estimated difference in response of 16 % ( 95 % CI −2–33 , P =  0·075 ) . VAD recipients ( 15 % ) suffered early treatment‐related mortality compared with 12 % of Z‐Dex recipients . Overall , 45 patients have died : disease progression  ( Z‐Dex n = 13 , VAD n = 10 ) , regimen‐related toxicity  ( Z‐Dex n = 2 , VAD n = 2 ) , infection  ( Z‐Dex n = 0 , VAD n = 3 ) , other causes ( Z‐Dex n = 7 , VAD n = 2 ) , unknown ( Z‐Dex n = 3 , VAD n = 2 ) . This study demonstrated that Z‐Dex might be a suitable oral alternative to VAD for treating newly diagnosed MM patients , although definitive evidence for equivalence is not provided The phase 3 trial HOVON-50 was design ed to evaluate the effect of thalidomide during induction treatment and as maintenance in patients with 
    Output:
    
Bortezomib/thalidomide regimens were not superior to lenalidomide , considering these outcomes .
Risk of thrombotic events was higher with TAD ( thalidomide-doxorubicin-dexamethasone ) , neurological with PAD ( bortezomib-doxorubicin-dexamethasone ) , infectious with Dex , hematological with Z-Dex , gastrointestinal with VTD , and cardiac with PAD regimens .
Our study endorses current recommendations on combined immunomodulatory drugs and proteasome inhibitors frontline regimens ( in triplets ) in transplant-eligible multiple myeloma patients , but also formally demonstrates the favorable performance of lenalidomide in overall and progression-free survival , when compared with bortezomib/thalidomide protocol