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Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study
N. Raje, E. Terpos, W. Willenbacher, K. Shimizu, R. García-Sanz, B. Durie, W. Legieć, M. Krejčí, K. Laribi, L. Zhu, P. Cheng, D. Warner, GD. Roodman,
Jazyk angličtina Země Anglie, Velká Británie
Typ dokumentu klinické zkoušky, fáze III, srovnávací studie, časopisecké články, multicentrická studie, randomizované kontrolované studie, práce podpořená grantem
Nursing & Allied Health Database (ProQuest) od 2000-09-01 do Před 2 měsíci
Health & Medicine (ProQuest) od 2000-09-01 do Před 2 měsíci
Public Health Database (ProQuest) od 2000-09-01 do Před 2 měsíci
Odkazy
PubMed
29429912
DOI
10.1016/s1470-2045(18)30072-x
Knihovny.cz E-zdroje
- MeSH
- antitumorózní látky škodlivé účinky terapeutické užití MeSH
- časové faktory MeSH
- denosumab škodlivé účinky terapeutické užití MeSH
- doba přežití bez progrese choroby MeSH
- dvojitá slepá metoda MeSH
- fraktury spontánní etiologie mortalita patologie prevence a kontrola MeSH
- inhibitory kostní resorpce škodlivé účinky terapeutické užití MeSH
- komprese míchy etiologie mortalita patologie prevence a kontrola MeSH
- kyselina zoledronová škodlivé účinky terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- mnohočetný myelom komplikace farmakoterapie mortalita patologie MeSH
- nádory kostí komplikace mortalita prevence a kontrola sekundární MeSH
- rizikové faktory MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- srovnávací studie MeSH
BACKGROUND: Multiple myeloma is characterised by monoclonal paraprotein production and osteolytic lesions, commonly leading to skeletal-related events (spinal cord compression, pathological fracture, or surgery or radiotherapy to affected bone). Denosumab, a monoclonal antibody targeting RANKL, reduces skeletal-related events associated with bone lesions or metastases in patients with advanced solid tumours. This study aimed to assess the efficacy and safety of denosumab compared with zoledronic acid for the prevention of skeletal-related events in patients with newly diagnosed multiple myeloma. METHODS: In this international, double-blind, double-dummy, randomised, active-controlled, phase 3 study, patients in 259 centres and 29 countries aged 18 years or older with symptomatic newly diagnosed multiple myeloma who had at least one documented lytic bone lesion were randomly assigned (1:1; centrally, by interactive voice response system using a fixed stratified permuted block randomisation list with a block size of four) to subcutaneous denosumab 120 mg plus intravenous placebo every 4 weeks or intravenous zoledronic acid 4 mg plus subcutaneous placebo every 4 weeks (both groups also received investigators' choice of first-line antimyeloma therapy). Stratification was by intent to undergo autologous transplantation, antimyeloma therapy, International Staging System stage, previous skeletal-related events, and region. The clinical study team and patients were masked to treatment assignments. The primary endpoint was non-inferiority of denosumab to zoledronic acid with respect to time to first skeletal-related event in the full analysis set (all randomly assigned patients). All safety endpoints were analysed in the safety analysis set, which includes all randomly assigned patients who received at least one dose of active study drug. This study is registered with ClinicalTrials.gov, number NCT01345019. FINDINGS: From May 17, 2012, to March 29, 2016, we enrolled 1718 patients and randomly assigned 859 to each treatment group. The study met the primary endpoint; denosumab was non-inferior to zoledronic acid for time to first skeletal-related event (hazard ratio 0·98, 95% CI 0·85-1·14; pnon-inferiority=0·010). 1702 patients received at least one dose of the investigational drug and were included in the safety analysis (850 patients receiving denosumab and 852 receiving zoledronic acid). The most common grade 3 or worse treatment-emergent adverse events for denosumab and zoledronic acid were neutropenia (126 [15%] vs 125 [15%]), thrombocytopenia (120 [14%] vs 103 [12%]), anaemia (100 [12%] vs 85 [10%]), febrile neutropenia (96 [11%] vs 87 [10%]), and pneumonia (65 [8%] vs 70 [8%]). Renal toxicity was reported in 85 (10%) patients in the denosumab group versus 146 (17%) in the zoledronic acid group; hypocalcaemia adverse events were reported in 144 (17%) versus 106 (12%). Incidence of osteonecrosis of the jaw was not significantly different between the denosumab and zoledronic acid groups (35 [4%] vs 24 [3%]; p=0·147). The most common serious adverse event for both treatment groups was pneumonia (71 [8%] vs 69 [8%]). One patient in the zoledronic acid group died of cardiac arrest that was deemed treatment-related. INTERPRETATION: In patients with newly diagnosed multiple myeloma, denosumab was non-inferior to zoledronic acid for time to skeletal-related events. The results from this study suggest denosumab could be an additional option for the standard of care for patients with multiple myeloma with bone disease. FUNDING: Amgen.
Cedars Sinai Medical Center Los Angeles CA USA
Center for Multiple Myeloma Massachusetts General Hospital Cancer Center Boston MA USA
Department of Hematology Centre Hospitalier Le Mans Le Mans France
Hospital Universitario de Salamanca Salamanca Spain
Indiana University School of Medicine Indianapolis IN USA
Innsbruck University Hospital and OncoTyrol Center of Personalized Cancer Medicine Innsbruck Austria
Medical University of Lublin Lublin Poland
National Hospital Organization Higashi Nagoya National Hospital Nagoya Japan
University Hospital Brno Department of Internal Medicine Hematology and Oncology Brno Czech Republic
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