***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 
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    Input: Between August 1990 and August 1995 , 231 patients ( median age 51 , 53 % Durie-Salmon stage III , median serum beta-2-microglobulin 3.1 g/L , median C-reactive protein 4 g/L ) with symptomatic multiple myeloma were enrolled in a program that used a series of induction regimens and two cycles of high-dose therapy ( " Total Therapy " ) . Remission induction utilized non-cross-resistant regimens ( vincristine-doxorubicin-dexamethasone [ VAD ] , high-dose cyclophosphamide and granulocyte-macrophage colony-stimulating factor with peripheral blood stem cell collection , and etoposide-dexamethasone-cytarabine-cisplatin ) . The first high-dose treatment comprised melphalan 200 mg/m2 and was repeated if complete ( CR ) or partial ( PR ) remission was maintained after the first transplant ; in case of less than PR , total body irradiation or cyclophosphamide was added . Interferon--2b maintenance was used after the second autotransplant . Fourteen patients with HLA-compatible donors underwent an allograft as their second high-dose therapy cycle . Eighty-eight percent completed induction therapy whereas first and second transplants were performed in 84 % and 71 % ( the majority within 8 and 15 months , respectively ) . Eight patients ( 3 % ) died of toxicity during induction , and 2 ( 1 % ) and 6 ( 4 % ) during the two transplants . True CR and at least a PR ( PR plus CR ) were obtained in 5 % ( 34 % ) after VAD , 15 % ( 65 % ) at the end of induction , and 26 % ( 75 % ) after the first and 41 % ( 83 % ) after the second transplants ( intent-to-treat ) . Median overall ( OS ) and event-free ( EFS ) survival duration s were 68 and 43 months , respectively . Actuarial 5-year OS and EFS rates were 58 % and 42 % , respectively . The median time to disease progression or relapse was 52 months . Among the 94 patients achieving CR , the median CR duration was 50 months . On multivariate analysis , superior EFS and OS were observed in the absence of unfavorable karyotypes ( 11q breakpoint abnormalities , -13 or 13-q ) and with low beta-2-microglobulin at diagnosis . CR duration was significantly longer with early onset of CR and favorable karyotypes . Time-dependent covariate analysis suggested that timely application of a second transplant extended both EFS and OS significantly , independent of cytogenetics and beta-2-microglobulin . Total Therapy represents a comprehensive treatment approach for newly diagnosed myeloma patients , using multi-regimen induction and t and em transplantation followed by interferon maintenance . As a result , the proportion of patients attaining CR increased progressively with continuing therapy . This observation is particularly important because CR is a sine qua non for long-term disease control and , eventually , cure Thalidomide ( Thal ) can overcome drug resistance in multiple myeloma ( MM ) but is associated with somnolence , constipation , and neuropathy . In previous in vitro studies , we have shown that the potent immunomodulatory derivative of thalidomide ( IMiD ) CC-5013 induces apoptosis or growth arrest even in resistant MM cell lines and patient cells , decreases binding of MM cells to bone marrow stromal cells ( BMSCs ) , inhibits the production in the BM milieu of cytokines ( interleukin-6 [ IL-6 ] , vascular endothelial growth factor [ VEGF ] , tumor necrosis factor-alpha [ TNF-alpha ] ) mediating growth and survival of MM cells , blocks angiogenesis , and stimulates host anti-MM natural killer ( NK ) cell immunity . Moreover , CC-5013 also inhibits tumor growth , decreases angiogenesis , and prolongs host survival in a human plasmacytoma mouse model . In the present study , we carried out a phase 1 CC-5013 dose-escalation ( 5 mg/d , 10 mg/d , 25 mg/d , and 50 mg/d ) study in 27 patients ( median age 57 years ; range , 40 - 71 years ) with relapsed and refractory relapsed MM . They received a median of 3 prior regimens ( range , 2 - 6 regimens ) , including autologous stem cell transplantation and Thal in 15 and 16 patients , respectively . In 24 evaluable patients , no dose-limiting toxicity ( DLT ) was observed in patients treated at any dose level within the first 28 days ; however , grade 3 myelosuppression developed after day 28 in all 13 patients treated with 50 mg/d CC-5013 . In 12 patients , dose reduction to 25 mg/d was well tolerated and therefore considered the maximal tolerated dose ( MTD ) . Importantly , no significant somnolence , constipation , or neuropathy has been seen in any cohort . Best responses of at least 25 % reduction in paraprotein occurred in 17 ( 71 % ) of 24 patients ( 90 % confidence interval [ CI ] , 52%-85 % ) , including 11 ( 46 % ) patients who had received prior Thal .  Stable disease ( less than 25 % reduction in paraprotein ) was observed in an additional 2 ( 8 % ) patients . Therefore , 17 ( 71 % ) of 24 patients ( 90 % CI , 52%-85 % ) demonstrated benefit from treatment . Our study therefore provides the basis for the evaluation of CC-5013 , either alone or in combination , to treat patients with MM at earlier stages of disease BACKGROUND In this trial of the treatment of newly diagnosed multiple myeloma , we compared a protocol that entailed a hematopoietic stem-cell autograft followed by an allograft from an HLA-identical sibling with a protocol of t and em autografts . METHODS We enrolled 162 consecutive patients with newly diagnosed myeloma who were 65 years of age or younger and who had at least one sibling . All patients were initially treated with vincristine , doxorubicin , and dexamethasone , followed by melphalan and autologous stem-cell rescue . Patients with an HLA-identical sibling then received nonmyeloablative total-body irradiation and stem cells from the sibling . Patients without an HLA-identical sibling received two consecutive myeloablative doses of melphalan , each of which was followed by autologous stem-cell rescue . The primary end points were overall survival and event-free survival . RESULTS After a median follow-up of 45 months ( range , 21 to 90 ) , the median overall survival and event-free survival were longer in the 80 patients with HLA-identical siblings than in the 82 patients without HLA-identical siblings ( 80 months vs. 54 months , P=0.01 ; and 35 months vs. 29 months , P=0.02 , respectively ) . Among patients who completed their assigned treatment protocol s , treatment-related mortality did not differ significantly between the double-autologous-transplant group ( 46 patients ) and the autograft-allograft group ( 58 patients , P=0.09 ) , but disease-related mortality was significantly higher in the double-autologous-transplant group ( 43 % vs. 7 % , P<0.001 ) . The cumulative incidence rates of grade s II , III , and IV graft-versus-host disease ( GVHD ) combined and of grade IV GVHD in the autograft-allograft group were 43 % and 4 % , respectively . Overall , 21 of 58 patients ( 36 % ) were in complete remission after a median follow-up of 38 months ( range , 10 to 72 ) after allografting . Of the 46 patients who received two autografts , 25 ( 54 % ) died . CONCLUSIONS Among patients with newly diagnosed myeloma , survival in recipients of a hematopoietic stem-cell autograft followed by a stem-cell allograft from an HLA-identical sibling is superior to that in recipients of t and em stem-cell autografts . ( Clinical Trials.gov number , NCT00415987 [ Clinical Trials.gov ] . ) BACKGROUND AND OBJECTIVES The Dutch-Belgian HOVON group performed a r and omized phase 3 trial to compare single non-myeloablative intensive treatment with double , intensive treatment in previously untreated patients with multiple myeloma ( MM ) . DESIGN AND METHODS Three hundred and three patients with stage II/III MM were r and omized after VAD induction chemotherapy  to receive two cycles of non-myeloablative intermediate-dose melphalan ( 70 mg/m2 ) ( single treatment ) or the same regimen followed by cyclophosphamide 120 mg/kg iv plus total body irradiation ( TBI ) 9 Gy and autologous stem cell transplantation ( double , intensive treatment ) . In both treatment arms interferon .IIa was given as maintenance until relapse/progression . RESULTS A significantly higher proportion of patients achieved a complete remission ( CR ) on protocol treatment with double , intensive therapy ( 32 % vs 13 % , p<0.001 ) . Double treatment produced better outcome in terms of event-free survival ( median 22 vs 21 months , 28 % vs 14 % at 4 years and 15 % vs 7 % at 6 years after r and omization ; logrank p=0.013 ; univariate HR 0.74 , 95 % CI , 0.58 - 0.94 ) , progression-free survival ( median 27 vs 24 months , 33 % vs 16 % at 4 years , and 17 % vs 9 % at 6 years after r and omization ; logrank p=0.006 ; HR=0.71 , 95 % CI 0.56 - 0.91 ) , but not overall survival ( median 50 vs 55 months , 52 % vs 56 % at 4 years and 39 % vs 36 % at 6 years after r and omization ; logrank p=0.51 ; HR=1.10 , 95 % CI 0.83 - 1.46 ) . The achievement of a CR had a favorable prognostic impact on event-free survival ( HR=0.60 , 95 % CI=0.44 -0.82 , p=0.001 ) and progression-free survival ( HR=0.62 , 95 % CI=0.45 -0.84 , p=0.002 ) . INTERPRETATION AND CONCLUSIONS Double , intensive treatment result ed in a better CR rate , event-free survival and progression-free survival but not overall survival compared to single non-myeloablative treatment in previously untreated patients with multiple myeloma BACKGROUND Autologous haemopoietic stem-cell transplantation ( HSCT ) improves survival in patients with multiple myeloma , but disease progression remains an issue . Allogeneic HSCT might reduce disease progression , but can be associated with high treatment-related mortality . Thus , we aim ed to assess effectiveness of allogeneic HSCT with non-myeloablative conditioning after autologous HSCT compared with t and em autologous HSCT . METHODS In our phase 3 biological assignment trial , we enrolled patients with multiple myeloma attending 37 transplant centres in the USA . Patients ( < 70 years old ) with adequate organ function who had completed at least three cycles of systemic antimyeloma therapy within the past 10 months were eligible for inclusion . We assigned patients to receive an autologous HSCT followed by an allogeneic HSCT ( auto-allo group ) or t and em autologous HSCTs ( auto-auto group ) on the basis of the availability of an HLA-matched sibling donor . Patients in the auto-auto group subsequently underwent a r and om allocation ( 1:1 ) to maintenance therapy ( thalidomide plus dexamethasone ) or observation . To avoid enrolment bias , we classified patients as st and ard risk or high risk on the basis of cytogenetics and β2-microglobulin concentrations . We used the Kaplan-Meier method to estimate differences in 3-year progression-free survival ( PFS ; primary endpoint ) between patients with st and ard-risk disease in the auto-allo group and the best results from the auto-auto group ( maintenance , observation , or pooled ) . This study is registered with Clinical Trials.gov , number NCT00075829 . FINDINGS Between Dec 17 , 2003 , and March 30 , 2007 , we enrolled 710 patients , of whom 625 had st and ard-risk disease and received an autologous HSCT . 156 ( 83 % ) of 189 patients with st and ard-risk disease in the auto-allo group and 366 ( 84 % ) of 436 in the auto-auto group received a second transplant . 219 patients in the auto-auto group were r and omly assigned to observation and 217 to receive maintenance treatment , of whom 168 ( 77 % ) completed this treatment . PFS and overall survival did not differ between maintenance and observation groups and pooled data were used . Kaplan-Meier estimates of 3-year PFS were 43 % ( 95 % CI 36 - 51 ) in the auto-allo group 
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Conclusion Despite higher complete remission rates , there is no improvement in OS with auto-allo HCT ; but this approach results in higher NRM in patients with newly diagnosed MM .