***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: This subgroup analysis of the phase III APEX ( Assessment of Proteasome Inhibition for Extending Remissions ) trial examined whether prior exposure to specific therapies affected the relative efficacy of bortezomib versus dexamethasone in relapsed/refractory myeloma .  Time to progression and overall survival were superior with bortezomib in all subgroups , with no evidence of interaction between any prior therapies and assignment to study therapy . Patients with prior thalidomide exposure had worse outcomes overall , but neither prior thalidomide nor prior autologous stem cell transplantation affected the relative efficacy of bortezomib versus dexamethasone . These results confirm the superiority of bortezomib over dexamethasone , regardless of prior exposure to specific therapies ( clinical trials.gov : NCT00048230 ) Recently , cereblon ( CRBN ) expression was found to be essential for the activity of thalidomide and lenalidomide . In the present study , we investigated whether the clinical efficacy of thalidomide in multiple myeloma is associated with CRBN expression in myeloma cells . Patients with newly diagnosed multiple myeloma were included in the HOVON-65/GMMG-HD4 trial , in which postintensification treatment in 1 arm consisted of daily thalidomide ( 50 mg ) for 2 years . Gene-expression profiling , determined at the start of the trial , was available for 96 patients who started thalidomide maintenance . In this patient set , increase of CRBN gene expression was significantly associated with longerprogression-free survival ( P = .005 ) . In contrast , no association between CRBN expression and survival was observed in the arm with bortezomib maintenance . We conclude that CRBN expression may be associated with the clinical efficacy of thalidomide . This trial has been registered at the Nederl and s Trial Register ( www.trialregister.nl ) as NTR213 ; at the European Union Drug Regulating Authorities Clinical Trials ( EudraCT ) as 2004 - 000944 - 26 ; and at the International St and ard R and omized Controlled Trial Number ( IS RCT N ) as 64455289 Immunoglobulin production by myeloma plasma cells depends on the unfolded protein response for protein production and folding . Recent studies have highlighted the importance of IRE1alpha and X box binding protein 1 ( XBP1 ) , key members of this pathway , in normal B-plasma cell development . We have determined the gene expression levels of IRE1alpha , XBP1 , XBP1UNSPLICED ( XBP1u ) , and XBP1SPLICED ( XBP1s ) in a series of patients with myeloma and correlated findings with clinical outcome . We show that IRE1alpha and XBP1 are highly expressed and that patients with low XBP1s/u ratios have a significantly better overall survival . XBP1s is an independent prognostic marker and can be used with beta2 microglobulin and t(4;14 ) to identify a group of patients with a poor outcome . Furthermore , we show the beneficial therapeutic effects of thalidomide in patients with low XBP1s/u ratios . This study highlights the importance of XBP1 in myeloma and its significance as an independent prognostic marker and as a predictor of thalidomide response OBJECTIVE To study the clinical course of patients with multiple myeloma ( MM ) that relapses after initial therapy . PATIENTS AND METHODS Patients with MM , seen at the Mayo Clinic in Rochester , Minn , between January 1 , 1985 , and December 31 , 1998 , were identified from a prospect ively maintained data base . Our study population consisted of 578 patients with newly diagnosed MM who were followed up and monitored throughout their clinical course at our institution . RESULTS The median age of the 578 patients with MM was 65 years ( range , 26 - 92 years ) ; 228 patients ( 39 % ) were women . The median follow-up of 71 surviving patients was 55 months ( range , 0 - 202 months ) . The overall survival ( OS ) for the 578 patients at 1 , 2 , and 5 years was 72 % , 55 % , and 22 % , respectively ; the median OS from initial therapy was 28.4 months . The median OS of 355 patients who experienced relapse after initial treatment was 17.1 months from initiation of the second therapy , and 84 % died within 5 years . The duration of response decreased consistently with each successive regimen . Patients with a high plasma cell labeling index ( > or = 1.0 % ) , low platelet count ( < 150 x 10(9)/L ) , high creatinine level ( > or = 2.0 mg/dL ) , and low albumin level ( < 3.0 g/dL ) had a poorer prognosis . CONCLUSIONS Our study revealed decreasing response duration with increasing number of salvage regimens , probably reflecting acquired drug resistance and an increasing proliferative rate of the myeloma cells . Patients who experienced relapse after initial treatment and received salvage therapy had a median survival of nearly 1.5 years . This must be remembered when making treatment decisions for these patients and must be factored in when assessing the efficacy of new therapies The potential synergistic anti-myeloma effect for thalidomide combining with interferon alpha was not yet clear clinical ly . From March 2001 to January 2004 , a total of 28 heavily pretreated multiple myleoma ( MM ) patients were enrolled in this open-labeled , r and omized Phase II study . Patients with refractory MM were r and omized to receive either thalidomide alone ( 200 mg/day up to the maximum dose 800 mg/day , arm B ) or the combination of thalidomide and interferon alpha ( 3 MIU/m2 subcutaneous injection 3 times weekly , arm A ) . The objective of this study was to compare the safety and efficacy of thalidomide alone to combined regimen . The patients ' characteristics were similar between the 2 arms . However , the average treatment duration was significantly longer in the arm B than the arm A ( 236 days versus 101 days , p = 0.029 ) . Serum levels of paraprotein decline ≥ 25 percent were obtained in 6 of 12 patients ( 50.0 percent ) treated with arm B and 3 of the 16 patients ( 18.8 percent ) treated with arm A. The estimated time to event was 7.9 months ( 95 percent confidence interval [ 95%CI ] , 0.5–15.4 ) for arm B and 1.5 months ( 95%CI , 0.0–3.4 ) for arm A ( log-rank test , p = 0.0193 ) . The major adverse events in both arms consisted of neutropenia , anemia , thrombocytopenia , constipation , somnolence , and skin rash . Our study showed that thalidomide alone was effective and tolerated in patients with relapsed or refractory MM . The thalidomide combined with interferon alpha result ed in a lower frequency of paraprotein response , shorter treatment- duration and 25 percent of patients ' refusing rate . It may be concluded that the combined regimen is not well tolerated in our patients and needed to be further evaluated in the future PURPOSE This phase III international study compared the efficacy and safety of a combination of pegylated liposomal doxorubicin ( PLD ) plus bortezomib with bortezomib monotherapy in patients with relapsed or refractory multiple myeloma . PATIENTS AND METHODS Six hundred forty-six patients were r and omly assigned to receive either intravenous bortezomib 1.3 mg/m(2 ) on days 1 , 4 , 8 , and 11 of an every 21-days cycle , or the same bortezomib regimen with PLD 30 mg/m(2 ) on day 4 . RESULTS Median time to progression was increased from 6.5 months for bortezomib to 9.3 months with the PLD + bortezomib combination ( P = .000004 ; hazard ratio , 1.82 [ monotherapy v combination therapy ] ; 95 % CI , 1.41 to 2.35 ) . The 15-month survival rate for PLD + bortezomib was 76 % compared with 65 % for bortezomib alone ( P = .03 ) . The complete plus partial response rate was 41 % for bortezomib and 44 % for PLD + bortezomib , a difference that was not statistically significant . Median duration of response was increased from 7.0 to 10.2 months ( P = .0008 ) with PLD + bortezomib . Grade 3/4 adverse events were more frequent in the combination group ( 80 % v 64 % ) , with safety profiles consistent with the known toxicities of the two agents . An increased incidence in the combination group was seen of grade 3/4 neutropenia , thrombocytopenia , asthenia , fatigue , diarrhea , and h and -foot syndrome . CONCLUSION PLD with bortezomib is superior to bortezomib monotherapy for the treatment of patients with relapsed or refractory multiple myeloma . The combination therapy is associated with a higher incidence of grade 3/4 myelosuppression , constitutional symptoms , and GI and dermatologic toxicities 
    Output:
    
Overall , the results of comparisons between monotherapy and combined therapy in individual trials were differentiated , and some combinations were not more effective than monotherapy ( bortezomib plub bevacizumab vs. bortezomib and thalidomide plus INFα vs. thalidomide ) which emphasizes the role of individualized therapy in relapsed/refractory MM especially in the elderly or patients with significant comorbidities .
Conclusions The results of this meta- analysis showed that combined therapy is superior to monotherapy only in some end points and it is less tolerated in patients with relapsed/refractory MM .
Thus , the overall superiority of complex therapy to monotherapy depends on the combination of the targeted agents