***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 Histone deacetylase ( HDAC ) inhibitors are an important new class of therapeutics for treating multiple myeloma .  Ricolinostat ( ACY-1215 ) is the first oral selective HDAC6 inhibitor with reduced class I HDAC activity to be studied clinical ly . Motivated by findings from pre clinical studies showing potent synergistic activity with ricolinostat and lenalidomide , our goal was to assess the safety and preliminary activity of the combination of ricolinostat with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma . METHODS In this multicentre phase 1b trial , we recruited patients aged 18 years or older with previously treated relapsed or refractory multiple myeloma from five cancer centres in the USA . Inclusion criteria included a Karnofsky Performance Status score of at least 70 , measureable disease , adequate bone marrow reserve , adequate hepatic function , and a creatinine clearance of at least 50 mL per min . Exclusion criteria included previous exposure to HDAC inhibitors ; previous allogeneic stem-cell transplantation ; previous autologous stem-cell transplantation within 12 weeks of baseline ; active systemic infection ; malignancy within the last 5 years ; known or suspected HIV , hepatitis B , or hepatitis C infection ; a QTc Fridericia of more than 480 ms ; and substantial cardiovascular , gastrointestinal , psychiatric , or other medical disorders . We gave escalating doses ( from 40 - 240 mg once daily to 160 mg twice daily ) of oral ricolinostat according to a st and ard 3 + 3 design according to three different regimens on days 1 - 21 with a conventional 28 day schedule of oral lenalidomide ( from 15 mg [ in one cohort ] to 25 mg [ in all other cohorts ] once daily ) and oral dexamethasone ( 40 mg weekly ) . Primary outcomes were dose-limiting toxicities , the maximum tolerated dose of ricolinostat in this combination , and the dose and schedule of ricolinostat  recommended for further phase 2 investigation . Secondary outcomes were the pharmacokinetics and pharmacodynamics of ricolinostat in this combination and the preliminary anti-tumour activity of this treatment . The trial is closed to accrual and is registered at Clinical Trials.gov , number NCT01583283 . FINDINGS Between July 12 , 2012 , and Aug 20 , 2015 , we enrolled 38 patients . We observed two dose-limiting toxicities with ricolinostat 160 mg twice daily : one ( 2 % ) grade 3 syncope and one ( 2 % ) grade 3 myalgia event in different cohorts . A maximum tolerated dose was not reached . We chose ricolinostat 160 mg once daily on days 1 - 21 of a 28 day cycle as the recommended dose for future phase 2 studies in combination with lenalidomide 25 mg and dexamethasone 40 mg . The most common adverse events were fatigue ( grade 1 - 2 in 14 [ 37 % ] patients ; grade 3 in seven [ 18 % ] ) and diarrhoea ( grade 1 - 2 in 15 [ 39 % ] patients ; grade 3 in two [ 5 % ] ) . Our pharmacodynamic studies showed that at clinical ly relevant doses , ricolinostat selectively inhibits HDAC6 while retaining a low and tolerable level of class I HDAC inhibition . The pharmacokinetics of ricolinostat and lenalidomide were not affected by co-administration . In a preliminary assessment of antitumour activity , 21 ( 55 % [ 95 % CI 38 - 71 ] ) of 38 patients had an overall response . INTERPRETATION The findings from this study provide preliminary evidence that ricolinostat is a safe and well tolerated selective HDAC6 inhibitor , which might partner well with lenalidomide and dexamethasone to enhance their efficacy in relapsed or refractory multiple myeloma . FUNDING Acetylon Pharmaceuticals BACKGROUND We aim ed to assess efficacy and tolerability of vorinostat in combination with bortezomib for treatment of patients with relapsed or refractory multiple myeloma . METHODS In our r and omised , double-blind , placebo-controlled , phase 3 trial , we enrolled adults ( ≥18 years ) at 174 university hospitals in 31 countries worldwide . Eligible patients had to have non-refractory multiple myeloma that previously responded to treatment ( one to three regimens ) but were currently progressing , ECOG performance statuses of 2 or less , and no continuing toxic effects from previous treatment . We excluded patients with known resistance to bortezomib . We r and omly allocated patients ( 1:1 ) using an interactive voice response system to receive 21 day cycles of bortezomib ( 1·3 mg/m(2 ) intravenously on days 1 , 4 , 8 , and 11 ) in combination with oral vorinostat ( 400 mg ) or matching placebo once-daily on days 1 - 14 . We stratified patients by baseline tumour stage ( International Staging System stage 1 or stage ≥2 ) , previous bone-marrow transplantation ( yes or no ) , and number of previous regimens ( 1 or ≥2 ) . The primary endpoint was progression-free survival ( PFS ) in the intention-to-treat population . We assessed adverse events in all patients who received at least one dose of study drug . This study is registered with Clinical Trials.gov , number 00773747 . FINDINGS Between Dec 24 , 2008 , and Sept 8 , 2011 , we r and omly allocated 317 eligible patients to the  vorinostat group ( 315 of whom received at least one dose ) and 320 to the placebo group ( all of whom received at least one dose ) . Median PFS was 7·63 months ( 95 % CI 6·87 - 8·40 ) in the vorinostat group and 6·83 months ( 5·67 - 7·73 ) in the placebo group ( hazard ratio [ HR ] 0·77 , 95 % CI 0·64 - 0·94 ; p=0·0100 ) . 312 ( 99 % ) of 315 patients in the vorinostat group and 315 ( 98 % ) of 320 patients in the placebo group had adverse events ( 300 [ 95 % ] adverse events in the vorinostat group and 282 [ 88 % ] in the control group were regarded as related to treatment ) . The most common grade 3 - 4 adverse events were thrombocytopenia ( 143 [ 45 % ] patients in the vorinostat group vs 77 [ 24 % ] patients in the placebo group ) , neutropenia ( 89 [ 28 % ] vs 80 [ 25 % ] ) , and anaemia ( 53 [ 17 % ] vs 40 [ 13 % ] ) . INTERPRETATION Although the combination of vorinostat and bortezomib prolonged PFS relative to bortezomib and placebo , the clinical relevance of the difference in PFS between the two groups is not clear . Different treatment schedules of bortezomib and vorinostat might improve tolerability and enhance activity . FUNDING Merck Micro‐ Abstract We evaluated the combination of pegylated liposomal doxorubicin , bortezomib and vorinostat in 32 patients with relapsed/refractory multiple myeloma in a phase I study . The maximum tolerated dose of vorinostat with PLD/bortezomib was 400 mg on days 4 to 11 . Clinical activity was seen including in bortezomib‐refractory patients . However , hematologic , constitutional and gastrointestinal toxicity was common . Introduction / Background : Deacetylase inhibitors have synergistic activity in combination with proteasome inhibitors and anthracyclines in pre clinical models of multiple myeloma ( MM ) . We therefore evaluated the safety and efficacy of the deacetylase inhibitor vorinostat in combination with pegylated liposomal doxorubicin ( PLD ) and bortezomib in relapsed/refractory MM . Patients and Methods : Thirty‐two patients were treated with PLD and bortezomib in combination with escalating doses of vorinostat on days 4 to 11 or 1 to 14 . Results : The maximum tolerated dose  of vorinostat was 400 mg on days 4 to 11 . Neutropenia and thrombocytopenia attributable to protocol therapy were seen in 59 % and 94 % of patients , of which 37 % and 47 % were of grade 3 or higher severity , respectively . Constitutional and gastrointestinal adverse events of all grade s were common , the majority of which were less than grade 3 in severity . The overall response rate ( partial response rate or better ) was 65 % and the clinical benefit rate ( minimal response rate or better ) 74 % . The overall response rate was 83 % , 71 % , and 45 % for patients with bortezomib‐naive , ‐sensitive , and ‐refractory MM , respectively . The median progression‐free survival was 13.9 months and the 3‐year overall survival 77 % . Whole blood proteasome activity assays demonstrated a potential impact of vorinostat on the chymotryptic‐like activity of the proteasome . Conclusion : Further evaluation of PLD , bortezomib , and deacetylase inhibitor combinations is warranted , with special attention directed toward strategies to improve tolerability BACKGROUND Panobinostat is a potent oral pan-deacetylase inhibitor that in pre clinical studies has synergistic anti-myeloma activity when combined with bortezomib and dexamethasone . We aim ed to compare panobinostat , bortezomib , and dexamethasone with placebo , bortezomib , and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma . METHODS PANORAMA1 is a multicentre , r and omised , placebo-controlled , double-blind phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma who have received between one and three previous treatment regimens . Patients were r and omly assigned ( 1:1 ) via an interactive web-based and voice response system , stratified by number of previous treatment lines and by previous use of bortezomib , to receive 21 day cycles of placebo or panobinostat ( 20 mg ; on days 1 , 3 , 5 , 8 , 10 , 12 , orally ) , both in combination with bortezomib ( 1·3 mg/m(2 ) on days 1 , 4 , 8 , 11 , intravenously ) and dexamethasone ( 20 mg on days 1 , 2 , 4 , 5 , 8 , 9 , 11 , 12 , orally ) . Patients , physicians , and the investigators who did the data analysis were masked to treatment allocation ; crossover was not permitted . The primary endpoint was progression-free survival ( in accordance with modified European Group for Blood and Marrow Transplantation criteria and based on investigators ' assessment ) and was analysed by intention to treat . The study is ongoing , but no longer recruiting , and is registered at Clinical Trials.gov , number NCT01023308 . FINDINGS 768 patients were enrolled between Jan 21 , 2010 , and Feb 29 , 2012 , with 387 r and omly assigned to panobinostat , bortezomib , and dexamethasone and 381 to placebo , bortezomib , and dexamethasone . Median follow-up was 6·47 months ( IQR 1·81 - 13·47 ) in the panobinostat group and 5·59 months ( 2·14 - 11·30 ) in the placebo group . Median progression-free survival was significantly longer in the panobinostat group than in the placebo group ( 11·99 months [ 95 % CI 10·33 - 12·94 ] vs 8·08 months [ 7·56 - 9·23 ] ; hazard ratio [ HR ] 0·63 , 95 % CI 0·52 - 0·76 ; p<0·0001 ) . Overall survival data are not yet mature , although at the time of this analysis , median overall survival was 33·64 months ( 95 % CI 31·34-not estimable ) for the panobinostat group and 30·39 months ( 26·87-not estimable ) for the placebo group ( HR 0·87 , 95 % CI 0·69 - 1·10 ; p=0·26 ) . The proportion of patients achieving an overall response did not differ between treatment groups ( 235 [ 60·7 % , 95 % CI 55·7 - 65·6 ] for panobinostat vs 208 [ 54·6 % , 49·4 - 59·7 ] for placebo ; p 
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In conclusion , analysis of the pooled data revealed that panobinostat-containing regimens were effective and tolerable for patients with RRMM .
Furthermore , lenalidomide-refractory patients may derive greater benefits from these regimens .