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Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial

San-Miguel, JF and Hungria, VT and Yoon, SS and Beksac, M and Dimopoulos, MA and Elghandour, A and Jedrzejczak, WW and Gunther, A and Nakorn, TN and Siritanaratkul, N and Corradini, P and Chuncharunee, S and Lee, JJ and Schlossman, RL and Shelekhova, T and Yong, K and Tan, D and Numbenjapon, T and Cavenagh, JD and Hou, J and LeBlanc, R and Nahi, H and Qiu, L and Salwender, H and Pulini, S and Moreau, P and Warzocha, K and White, D and Blade, J and Chen, W and de la Rubia, J and Gimsing, P and Lonial, S and Kaufman, JL and Ocio, EM and Veskovski, L and Sohn, SK and Wang, MC and Lee, JH and Einsele, H and Sopala, M and Corrado, C and Bengoudifa, BR and Binlich, F and Richardson, PG (2014) Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncology. pp. 1195-1206.

Abstract

BACKGROUND: Panobinostat is a potent oral pan-deacetylase inhibitor that in preclinical studies has synergistic anti-myeloma activity when combined with bortezomib and dexamethasone. We aimed 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, randomised, 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 randomly 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 ClinicalTrials.gov, number NCT01023308. FINDINGS: 768 patients were enrolled between Jan 21, 2010, and Feb 29, 2012, with 387 randomly 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=0.09); however, the proportion of patients with a complete or near complete response was significantly higher in the panobinostat group than in the placebo group (107 [27.6%, 95% CI 23.2-32.4] vs 60 [15.7%, 12.2-19.8]; p=0.00006). Minimal responses were noted in 23 (6%) patients in the panobinostat group and in 42 (11%) in the placebo group. Median duration of response (partial response or better) was 13.14 months (95% CI 11.76-14.92) in the panobinostat group and 10.87 months (9.23-11.76) in the placebo group, and median time to response (partial response or better) was 1.51 months (1.41-1.64) in the panobinostat group and 2.00 months (1.61-2.79) in the placebo group. Serious adverse events were reported in 228 (60%) of 381 patients in the panobinostat group and 157 (42%) of 377 patients in the placebo group. Common grade 3-4 laboratory abnormalities and adverse events (irrespective of association with study drug) included thrombocytopenia (256 [67%] in the panobinostat group vs 118 [31%] in the placebo group), lymphopenia (202 [53%] vs 150 [40%]), diarrhoea (97 [26%] vs 30 [8%]), asthenia or fatigue (91 [24%] vs 45 [12%]), and peripheral neuropathy (67 [18%] vs 55 [15%]). INTERPRETATION: Our results suggest that panobinostat could be a useful addition to the treatment armamentarium for patients with relapsed or relapsed and refractory multiple myeloma. Longer follow up will be necessary to determine whether there is any effect on overall survival. FUNDING: Novartis Pharmaceuticals

Item Type: Article
Additional Information: NIBR author: Bengoudifa, BR institute: NIBR contributor address: Clinica Universidad de Navarra-CIMA, Pamplona, Spain. Electronic address: sanmiguel@unav.esSanta Casa de Misericordia de Sao Paulo Hospital, Sao Paulo, BrazilSeoul National University Hospital, Seoul, South KoreaAnkara University School of Medicine, Ankara, TurkeyUniversity of Athens School of Medicine, Athens, GreeceAlexandria University, Alexandria, EgyptMedical University of Warsaw, Warsaw, PolandUniversity of Kiel, Kiel, GermanyChulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, ThailandSiriraj Hospital, Bangkok, ThailandFondazione IRCCS Istituto Nazionale dei Tumori, University of Milan, Milan, ItalyRamathibodi Hospital, Bangkok, ThailandChonnam National University Hwasun Hospital, Hwasun, South KoreaDana-Farber Cancer Institute, Boston, MA, USAClinic of Professional Pathology and Haematology, Saratov State Medical University, Saratov, RussiaUCL Cancer Institute, University College London, London, UKSingapore General Hospital, SingaporePhramongkutklao Hospital, Bangkok, ThailandSt Bartholomew's Hospital, Barts Health NHS Trust, London, UKChang Zheng Hospital, Shanghai, ChinaMaisonneuve-Rosemont Hospital and University of Montreal, Montreal, QC, CanadaKarolinska University Hospital, Stockholm, SwedenState Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, ChinaAsklepios Clinic Altona, Hamburg, GermanySpirito Santo Hospital, Pescara, ItalyNantes University Hospital, Nantes, FranceInstitute of Haematology and Transfusion Medicine, Warsaw, PolandQueen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, NS, CanadaHospital Clinic de Barcelona, Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, SpainBeijing Chaoyang Hospital, Capital Medical University, Beijing, ChinaUniversity Hospital La Fe and Universidad Catolica San Vicente Martir, Valencia, SpainRigshospitalet and University of Copenhagen, Copenhagen, DenmarkDepartment of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USADepartment of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USAUniversity Hospital and Cancer Research Center, University of Salamanca-Instituto de Investigacion Biomedica de Salamanca, Instituto de Biologia Molecular y Celular del Cancer, Salamanca, SpainSahlgrenska University Hospital, Goteborg, SwedenKyungpook National University, Daegu, South KoreaKaohsiung Chang Gung Memorial Hospital, Kaohsiung, TaiwanGachon University Gil Medical Center, Incheon, South KoreaUniversity Hospital Wurzburg, Wurzburg, GermanyNovartis Pharma AG, Basel, SwitzerlandNovartis Pharma AG, Basel, SwitzerlandNovartis Pharma AG, Basel, SwitzerlandNovartis Pharma SAS, Rueil-Malmaison, FranceDana-Farber Cancer Institute, Boston, MA, USA
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/24248

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