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Title: | Pembrolizumab plus lenalidomide and dexamethasone for patients with treatment-naive multiple myeloma (KEYNOTE-185): a randomised, open-label, phase 3 trial. | Authors: | Usmani S.Z.;Oriol A.;Karlin L.;Cavo M.;Rifkin R.M.;Hayek F.;Kirschner E.;Bharany N.;Overton L.;Mannem S.;Harroff A.;Atanackovic D.;Lee K.;Oliff I.;Lee W.;Bensinger W.;Lutzky J.;Baron A.;Jain S.;Roque T.;McIntyre K.;Yasencha C.K.;Houck W.;Schjesvold F.;Yimer H.A.;LeBlanc R.;Takezako N.;McCroskey R.D.;Lim A.B.M.;Suzuki K.;Kosugi H.;Grigoriadis G. ;Avivi I.;Facon T.;Jagannath S.;Lonial S.;Ghori R.U.;Farooqui M.Z.H.;Marinello P.;San-Miguel J.;Lim A. ;Walker T.;Nicol A.;Reece D.;Elemary M.;Boudreault Pedneault J.S.;Attal M.;Weisel K.;Engelhardt M.;Mackensen A.;Quinn J.;Cohen A.;Magen-Nativ H.;Benyamini N.;Larocca A.;Matsumoto M.;Iida S.;Ishikawa T.;Kondo Y.;Sunami K.;Ando K.;Teshima T.;Chou T.;Iwasaki H.;Miki H.;Matsumura I.;Onishi Y.;Izutsu K.;Kizaki M.;George A.;Blacklock H.;Simpson D.;Waage A.;Samoilova O.;Nikitin E.;Chagorova T.;McDonald A.;Patel M.;Oriol Rocafiguera A.;San Miguel Izquierdo J.;Mateos M.;Streetly M.;Forsyth P.;Jackson G.;Jenkins S.;Rifkin R.;Yimer H.;McCroskey R.;Martincic D.;Tarantolo S.;Larson S.;Faroun Y.;Vaughn J.;Baz R.;Saylors G.;Neppalli A.;Raptis A.;Fung H.;Janosky M.;Stevens D.;Coleman M.;Costa D.;Cross S.;Fanning S.;Berges D.F.;Harris T.;Zackon I. | Institution: | (Usmani) Levine Cancer Institute/Atrium Health, Charlotte, NC, United States (Schjesvold) Oslo Myeloma Center, Oslo University Hospital and KG Jebsen Center for B-Cell Malignancies, University of Oslo, Oslo, Norway (Oriol) Institut Catala d'Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Badalona, Spain (Karlin) Centre Hospitalier Lyon-Sud, Pierre-Benite, France (Cavo) Seragnoli Institute of Hematology, Bologna University School of Medicine, Bologna, Italy (Rifkin) Rocky Mountain Cancer Centers, Denver, CO, United States (Yimer) Texas Oncology, Tyler, TX, United States (LeBlanc) Centre Integre Universitaire de Sante et de Services Sociaux de l'Est de L'Ile de Montreal, University of Montreal, Montreal, QC, Canada (Takezako) Disaster Medical Center, Tokyo, Japan (McCroskey) Northwest Medical Specialties, PLLC, Puyallup, WA, United States (Lim) Austin Health, Austin Hospital, Heidelberg, VIC, Australia (Suzuki) Japanese Red Cross Medical Center, Tokyo, Japan (Kosugi) Ogaki Municipal Hospital, Ogaki, Japan (Grigoriadis) Monash Health, Melbourne, VIC, Australia (Avivi) Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel (Facon) Hopital Claude Huriez, Centre Hospitalier Regional Universitaire de Lille, Lille, France (Jagannath) Mount Sinai Hospital, New York, NY, United States (Lonial) Winship Cancer Institute, Emory University, Atlanta, GA, United States (Ghori, Farooqui, Marinello) Merck & Co, Inc, Kenilworth, NJ, United States (San-Miguel) Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada, Centro de Investigacion Biomedica en Red de Cancer, Instituto de Investigacion Sanitaria de Navarra, Pamplona, Spain | Issue Date: | 4-Sep-2019 | Copyright year: | 2019 | Publisher: | Elsevier Ltd | Place of publication: | United Kingdom | Publication information: | The Lancet Haematology. 6 (9) (pp e448-e458), 2019. Date of Publication: September 2019. | Abstract: | Background: Lenalidomide and dexamethasone has been a standard of care in transplant-ineligible patients with newly diagnosed multiple myeloma. The addition of a third drug to the combination is likely to improve treatment efficacy. KEYNOTE-185 assessed the efficacy and safety of lenalidomide and dexamethasone with and without pembrolizumab in patients with previously untreated multiple myeloma. Here, we present the results of an unplanned interim analysis done to assess the benefit-risk of the combination at the request of the US Food and Drug Administration (FDA). Method(s): KEYNOTE-185 was a randomised, open-label, phase 3 trial done at 95 medical centres across 15 countries (Australia, Canada, France, Germany, Ireland, Israel, Italy, Japan, New Zealand, Norway, Russia, South Africa, Spain, UK, and USA). Transplantation-ineligible patients aged 18 years and older with newly diagnosed multiple myeloma, Eastern Cooperative Oncology Group performance status of 0 or 1, and who were treatment naive were enrolled, and randomly assigned 1:1 to receive either pembrolizumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone alone using an interactive voice or integrated web response system. Patients received oral lenalidomide 25 mg on days 1-21 and oral dexamethasone 40 mg on days 1, 8, 15, and 22 of repeated 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The primary endpoint was progression-free survival, which was investigator-assessed because of early trial termination. Efficacy was analysed in all randomly assigned patients and safety was analysed in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT02579863, and it is closed for accrual. Finding(s): Between Jan 7, 2016, and June 9, 2017, 301 patients were randomly assigned to the pembrolizumab plus lenalidomide and dexamethasone group (n=151) or the lenalidomide and dexamethasone group (n=150). On July 3, 2017, the FDA decided to halt the study because of the imbalance in the proportion of death between groups. At database cutoff (June 2, 2017), with a median follow-up of 6.6 months (IQR 3.4-9.6), 149 patients in the pembrolizumab plus lenalidomide and dexamethasone group and 145 in the lenalidomide and dexamethasone group had received their assigned study drug. Median progression-free survival was not reached in either group; progression-free survival estimates at 6-months were 82.0% (95% CI 73.2-88.1) versus 85.0% (76.8-90.5; hazard ratio [HR] 1.22; 95% CI 0.67-2.22; p=0.75). Serious adverse events were reported in 81 (54%) patients in the pembrolizumab plus lenalidomide and dexamethasone group versus 57 (39%) patients in the lenalidomide and dexamethasone group; the most common serious adverse events were pneumonia (nine [6%]) and pyrexia (seven [5%]) in the pembrolizumab plus lenalidomide and dexamethasone group and pneumonia (eight [6%]) and sepsis (two [1%]) in the lenalidomide and dexamethasone group. Six (4%) treatment-related deaths occurred in the pembrolizumab plus lenalidomide and dexamethasone group (cardiac arrest, cardiac failure, myocarditis, large intestine perforation, pneumonia, and pulmonary embolism) and two (1%) in the lenalidomide and dexamethasone group (upper gastrointestinal haemorrhage and respiratory failure). Interpretation(s): The results from this unplanned, FDA-requested, interim analysis showed that the benefit-risk profile of pembrolizumab plus lenalidomide and dexamethasone is unfavourable for patients with newly diagnosed, previously untreated multiple myeloma. Long-term safety and survival follow-up is ongoing. Funding(s): Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc (Kenilworth, NJ, USA).Copyright © 2019 Elsevier Ltd | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1016/S2352-3026%2819%2930109-7 | PubMed URL: | 31327689 [http://www.ncbi.nlm.nih.gov/pubmed/?term=31327689] | ISSN: | 2352-3026 (electronic) | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/35895 | Type: | Article | Subjects: | pruritus/si [Side Effect] randomized controlled trial rash/si [Side Effect] respiratory failure/si [Side Effect] rhabdomyolysis/si [Side Effect] sepsis/si [Side Effect] Stevens Johnson syndrome/si [Side Effect] survival analysis systemic lupus erythematosus/si [Side Effect] toxic hepatitis/si [Side Effect] treatment duration adrenal insufficiency/si [Side Effect] aged anemia/si [Side Effect] article backache/si [Side Effect] cardiopulmonary insufficiency/si [Side Effect] chromosome analysis colitis/si [Side Effect] computer assisted tomography constipation/si [Side Effect] controlled study coughing/si [Side Effect] decreased appetite/si [Side Effect] dermatitis/si [Side Effect] diarrhea/si [Side Effect] disease exacerbation/si [Side Effect] drug efficacy drug eruption/si [Side Effect] drug safety drug withdrawal dry skin/si [Side Effect] dyspnea/si [Side Effect] erythema/si [Side Effect] erythema multiforme/si [Side Effect] fatigue/si [Side Effect] female fever/si [Side Effect] Food and Drug Administration health care quality heart arrest/si [Side Effect] heart failure/si [Side Effect] human hypersensitivity/si [Side Effect] hyperthyroidism/si [Side Effect] hypokalemia/si [Side Effect] hypothyroidism/si [Side Effect] infusion related reaction/si [Side Effect] insomnia/si [Side Effect] insulin dependent diabetes mellitus/si [Side Effect] intestine ischemia/si [Side Effect] intestine perforation/si [Side Effect] kidney failure/si [Side Effect] low drug dose lung embolism/si [Side Effect] major clinical study male mortality rate multicenter study *multiple myeloma/dt [Drug Therapy] myasthenia gravis/si [Side Effect] myocarditis/si [Side Effect] nausea/si [Side Effect] neutropenia/si [Side Effect] nuclear magnetic resonance imaging open study overall survival pancreatitis/si [Side Effect] peripheral edema/si [Side Effect] phase 3 clinical trial pneumonia/si [Side Effect] positron emission tomography priority journal progression free survival quality of life assessment upper gastrointestinal bleeding/si [Side Effect] upper respiratory tract infection/si [Side Effect] vomiting/si [Side Effect] *dexamethasone/ae [Adverse Drug Reaction] *dexamethasone/ct [Clinical Trial] *dexamethasone/cb [Drug Combination] *dexamethasone/dt [Drug Therapy] *dexamethasone/po [Oral Drug Administration] *dexamethasone/pv [Special Situation for Pharmacovigilance] *lenalidomide/ae [Adverse Drug Reaction] *lenalidomide/ct [Clinical Trial] *lenalidomide/cb [Drug Combination] *lenalidomide/dt [Drug Therapy] *lenalidomide/po [Oral Drug Administration] *lenalidomide/pv [Special Situation for Pharmacovigilance] *pembrolizumab/ae [Adverse Drug Reaction] *pembrolizumab/ct [Clinical Trial] *pembrolizumab/cb [Drug Combination] *pembrolizumab/dt [Drug Therapy] *pembrolizumab/iv [Intravenous Drug Administration] *pembrolizumab/pv [Special Situation for Pharmacovigilance] controlled study coughing / side effect decreased appetite / side effect dermatitis / side effect diarrhea / side effect disease exacerbation / side effect drug efficacy drug eruption / side effect drug safety drug withdrawal dry skin / side effect dyspnea / side effect erythema / side effect erythema multiforme / side effect fatigue / side effect female fever / side effect Food and Drug Administration health care quality heart arrest / side effect heart failure / side effect human hypersensitivity / side effect hyperthyroidism / side effect hypokalemia / side effect hypothyroidism / side effect infusion related reaction / side effect insomnia / side effect insulin dependent diabetes mellitus / side effect intestine ischemia / side effect intestine perforation / side effect kidney failure / side effect low drug dose lung embolism / side effect major clinical study male mortality rate multicenter study *multiple myeloma / *drug therapy myasthenia gravis / side effect myocarditis / side effect nausea / side effect neutropenia / side effect nuclear magnetic resonance imaging open study overall survival pancreatitis / side effect aged phase 3 clinical trial pneumonia / side effect positron emission tomography priority journal progression free survival pruritus / side effect quality of life assessment randomized controlled trial rash / side effect respiratory failure / side effect rhabdomyolysis / side effect sepsis / side effect Stevens Johnson syndrome / side effect survival analysis systemic lupus erythematosus / side effect toxic hepatitis / side effect treatment duration upper gastrointestinal bleeding / side effect upper respiratory tract infection / side effect vomiting / side effect adrenal insufficiency / side effect peripheral edema / side effect anemia / side effect Article backache / side effect cardiopulmonary insufficiency / side effect chromosome analysis colitis / side effect computer assisted tomography constipation / side effect |
Type of Clinical Study or Trial: | Randomised controlled trial |
Appears in Collections: | Articles |
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