***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 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 Bortezomib , a proteasome inhibitor with efficacy in multiple myeloma , is associated with thrombocytopenia , the cause and kinetics of which are different from those of st and ard cytotoxic agents . We assessed the frequency , kinetics , and mechanism of thrombocytopenia following treatment with bortezomib 1.3 mg/m2 in 228 patients with relapsed and /or refractory myeloma in 2 phase 2 trials . The mean platelet count decreased by approximately 60 % during treatment but recovered rapidly between treatments in a cyclic fashion . Among responders , the pretreatment platelet count increased significantly during subsequent cycles of therapy . The mean percent reduction in platelets was independent of baseline platelet count , M-protein concentration , and marrow plasmacytosis . Plasma thrombopoietin levels inversely correlated with platelet count . Murine studies demonstrated a reduction in peripheral platelet count following a single bortezomib dose without negative effects on megakaryocytic cellularity , ploidy , or morphology . These data suggest that bortezomib-induced thrombocytopenia is due to a reversible effect on megakaryocytic function rather than a direct cytotoxic effect on megakaryocytes or their progenitors . The exact mechanism underlying bortezomib-induced thrombocytopenia remains unknown but it is unlikely to be related to marrow injury or decreased thrombopoietin production Background High‐dose chemotherapy plus autologous stem‐cell transplantation has been the st and ard treatment for newly diagnosed multiple myeloma in adults up to 65 years of age . However , promising data on the use of combination therapy with lenalidomide , bortezomib , and dexamethasone ( RVD ) in this population have raised questions about the role and timing of transplantation . Methods We r and omly assigned 700 patients with multiple myeloma to receive induction therapy with three cycles of RVD and then consolidation therapy with either five additional cycles of RVD ( 350 patients ) or high‐dose melphalan plus stem‐cell transplantation followed by two additional cycles of RVD ( 350 patients ) . Patients in both groups received maintenance therapy with lenalidomide for 1 year . The primary end point was progression‐free survival . Results Median progression‐free survival was significantly longer in the group that underwent transplantation than in the group that received RVD alone ( 50 months vs. 36 months ; adjusted hazard ratio for disease progression or death , 0.65 ; P<0.001 ) . This benefit was observed across all patient subgroups , including those stratified according to International Staging System stage and cytogenetic risk . The percentage of patients with a complete response was higher in the transplantation group than in the RVD‐alone group ( 59 % vs. 48 % , P=0.03 ) , as was the percentage of patients in whom minimal residual disease was not detected ( 79 % vs. 65 % , P<0.001 ) . Overall survival at 4 years did not differ significantly between the transplantation group and the RVD‐alone group ( 81 % and 82 % , respectively ) . The rate of grade 3 or 4 neutropenia was significantly higher in the transplantation group than in the RVD‐alone group ( 92 % vs. 47 % ) , as were the rates of grade 3 or 4 gastrointestinal disorders ( 28 % vs. 7 % ) and infections ( 20 % vs. 9 % ) . No significant between‐group differences were observed in the rates of treatment‐related deaths , second primary cancers , thromboembolic events , and peripheral neuropathy . Conclusions Among adults with multiple myeloma  , RVD therapy plus transplantation was associated with significantly longer progression‐free survival  than RVD therapy alone , but overall survival did not differ significantly between the two approaches . ( Supported by Celgene and others ; IFM 2009 Study Clinical Trials.gov number , NCT01191060 . This multicenter phase I/II study investigated the maximum tolerated dose ( MTD ) , safety , and efficacy of low dose intravenous ( IV ) melphalan in combination with bortezomib for patients with relapsed multiple myeloma ( MM ) . Patients received bortezomib 1·3 mg/m2 on days 1 , 4 , 8 , and 11 and escalating doses of IV melphalan ( 2·5–10·0 mg/m2 ) on day 2 of a 28‐day cycle for a maximum of eight cycles . Dexamethasone 20 mg was added for progressive or stable disease . Fifty‐three patients were enrolled . The MTD was defined at melphalan 7·5 mg/m2 and bortezomib 1·3 mg/m2 . The overall response rate ( ORR ) was 68 % ( 23 % complete or near‐complete responses [ CR/nCR ] ) whilst at the MTD ( n = 33 ) the ORR was 76 % ( 34 % CR/nCR ) . After median follow‐up of 17 months , the median progression free survival was 10 months , rising to 12 months at the MTD ( P < 0·05 vs. non‐MTD regimens ) . The median overall survival was 28 months , but was not yet reached at the MTD . Grade 3/4 adverse events included thrombocytopenia ( 62 % ) , neutropenia ( 57 % ) , infection ( 21 % ) , and neuropathy ( 15 % ) . Bortezomib and low‐dose IV melphalan combination therapy is a safe and highly effective regimen for patients with relapsed MM . These data suggest further investigation of this combination is warranted Background and Objectives The proteasome inhibitor bortezomib is approved for the treatment of multiple myeloma ( MM ) and , in the US , for the treatment of mantle cell lymphoma following at least one prior therapy ; the recommended dose and schedule is 1.3 mg/m2 on days 1 , 4 , 8 and 11 of 21-day cycles , and the approved routes of administration in the US prescribing information are by intravenous and , following a recent up date , subcutaneous injection . Findings from a phase III study demonstrated that subcutaneous administration of bortezomib , using the same dose and schedule , result ed in similar efficacy with an improved systemic safety profile ( including significantly lower rates of peripheral neuropathy ) versus intravenous bortezomib in patients with relapsed MM . The objectives of this report were to present a comprehensive analysis of the pharmacokinetics and pharmacodynamics of subcutaneous versus intravenous bortezomib  , and to evaluate the impact of the subcutaneous administration site , subcutaneous injection concentration and demographic characteristics on bortezomib pharmacokinetics and pharmacodynamics . Patients and Methods Data were analysed from the pharmacokinetic sub study of the r and omized phase III MMY-3021 study and the phase I CAN-1004 study of subcutaneous versus intravenous bortezomib  in patients aged ≥18 ( MMY-3021 ) or ≤75 ( CAN-1004 ) years with symptomatic relapsed or refractory MM after 1–3 ( MMY-3021 ) or ≥1 ( CAN-1004 ) prior therapies . Patients received up to eight 21-day cycles of subcutaneous or intravenous bortezomib 1.3 mg/m2 on days 1 , 4 , 8 and 11 . Pharmacokinetic and pharmacodynamic ( 20S proteasome inhibition ) parameters  of bortezomib following subcutaneous or intravenous administration were evaluated on day 11 , cycle 1 .  Results Bortezomib systemic exposure was equivalent with subcutaneous versus intravenous administration in MMY-3021 [ mean area under the plasma concentration – time curve from time zero to the last quantifiable timepoint ( AUClast ) : 155 vs. 151 ng·h/mL ; geometric mean ratio 0.992 ( 90 % CI 80.18 , 122.80 ) ] and comparable in CAN-1004 ( mean AUClast : 195 vs. 241 ng·h/mL ) ; maximum ( peak ) plasma drug concentration ( Cmax ) was lower with subcutaneous administration in both MMY-3021 ( mean 20.4 vs. 223 ng/mL ) and CAN-1004 ( mean 22.5 vs. 162 ng/mL ) , and time to Cmax ( tmax ) was longer with subcutaneous administration in both studies ( median 30 vs. 2 min ) . Blood 20S proteasome inhibition pharmacodynamic parameters were also similar with subcutaneous versus intravenous bortezomib : mean maximum effect ( Emax ) was 63.7 versus 69.3 % in MMY-3021 and 57.0 versus 68.8 % in CAN-1004 , and mean area under the effect – time curve from time zero to 72 h was 1,714 versus 1,383 % · h in MMY-3021 and 1,619 versus 1,283 % · h in CAN-1004 . Time to Emax was longer with subcutaneous administration in MMY-3021 ( median 120 vs. 5 min ) and CAN-1004 ( median 120 vs. 3 min ) . Concentration of the subcutaneous injected solution had no appreciable effect on pharmacokinetic or pharmacodynamic parameters . There were no apparent differences in bortezomib pharmacokinetic and pharmacodynamic parameters between subcutaneous administration in the thigh or abdomen . There were also no apparent differences in bortezomib exposure related to body mass index , body surface area or age . ConclusionS ubcutaneous administration results in equivalent bortezomib plasma exposure to intravenous administration , together with comparable blood 20S proteasome inhibition pharmacodynamic effects . These findings , together with the non-inferior efficacy of subcutaneous versus intravenous bortezomib demonstrated in MMY-3021 , support the use of bortezomib via the subcutaneous route across the setting s of clinical use in which the safety and efficacy of intravenous bortezomib has been established This study shows that subcutaneous administration of bortezombib offers an alternative option to intravenous injection in patients with multiple myeloma . This phase I study compared pharmacokinetics and pharmacodynamics , and assessed safety and efficacy of intravenous and subcutaneous administration of bortezomib .  Relapsed or refractory multiple myeloma patients were r and omized to receive 
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Conclusion : The data presented so far consistently show that SC bortezomib has become a st and ard of care for patients with MM