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N Engl J Med. 2018 Feb 8;378(6):518-528. doi: 10.1056/NEJMoa1714678. Epub 2017 Dec 12.

Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma.

Collaborators (212)

Fantl D, Bar D, Riveros DA, Jarchum G, Enrico AI, Pavlovsky A, Jaksic W, Szer J, Murphy N, Sadawarte S, Forsyth C, Blum R, Ho J, Mills A, Horvath N, Bries G, Van Eygen K, Wu KL, Deeren D, Van Steenweghen S, Berneman ZN, Offner F, Mineur P, Schots R, Hungria V, Maciel J, Maiolino A, Braga W, Barbosa S, Kaufman J, Barreto W, Oliveira L, Fogliatto L, Castro N, Farias D, Santucci R, Hamerschlak N, Duarte F, Hadjiev E, Radinoff A, Tzvetkov N, Gercheva-Kyuchukova L, Mihaylov G, Yotov G, Raynov J, Sivcheva L, Goranov S, Kolonic SO, Skunca Z, Batinic J, Pejsa V, Spicka I, Gregora E, Scudla V, Maisnar V, Hajek R, Jungova A, Zodelava M, Gaprindashvili E, Fuhrmann S, Schleicher J, Jakob C, Dickinson JP, Hindahl H, Jacobs G, Chaidos A, Crawley C, Al-Rafaie F, Sahu S, Hamblin M, Makkuni S, Zhelyazkova A, Symeonidis A, Anagnostopoulos A, Pappa V, Anargyrou K, Zikos P, Illes A, Szomor A, Masszi T, Mikala G, Rosta A, Egyed M, Varga G, Rambaldi A, Boccadoro M, Palumbo A, Offidani M, Foa R, Rossi G, Cafro AM, Musto P, Fabbiano F, Corso A, di Raimondo F, Zambello R, Gobbi M, Nagafuji K, Iida S, Matsumoto M, Takezako N, Sunami K, Kosugi H, Ishikawa T, Izutsu K, Imada K, Kaneko H, Sugiura I, Shinagawa A, Onishi Y, Takamatsu H, Uchida T, Matsue K, Wake A, Aotsuka N, Lee WS, Eom HS, Kim KH, Kim S, Yoon DH, Lee JO, Kim JS, Lee JH, Min CK, Lee J, Stankovic S, Georgievski B, Chevreska L, Czyz J, Kloczko J, Jedrzejczak WW, Homenda W, Woszczyk D, Holojda J, Hus M, Hellmann A, Wrobel T, Walewski J, Martins J, Esteves G, Martins A, Gheorghita E, Borsaru G, Popov VM, Danaila CD, Lazaroiu M, Alekseev S, Samoilova O, Pristupa A, Udovitsa D, Rossiev V, Afanasyev B, Konstantinova T, Samarina I, Dunaev Y, Kaplanov K, Milanovic N, Marjanovic G, Marisavljevic D, Jovanovic D, Milojevic Z, Savic A, Hernandez Garcia MT, De La Rubia J, Couto Caro C, Perez de Oteyza J, Blade J, Gonzales Y, Oriol A, Rodriguez P, Martin Sanchez J, Sole M, de Arriba F, Sureda A, Martinez J, Alvarez Rivas MA, Gironella M, Casado Montero LF, Encinas C, Palomera L, Sastre Moral JL, Yagci M, Altuntas F, Ozet G, Ozsan GH, Vural F, Turgut M, Turgut B, Ferhanoglu B, Bolaman AZ, Besisik SK, Unal A, Beksac M, Pylypenko H, Samura B, Popovs’ka T, Masliak Z, Glushko N, Rekhtman G, Moezi M, de Lima M, Ehsan M, Vaughn C, Roman E, Schiller G, Jhangiani H, Wallace O, Holden V, Snider J, Noga S, Haile D, Alraws A.

Author information

1
From University Hospital of Salamanca-Instituto de Investigación Biomédica de Salamanca, Salamanca (M.-V.M.), and Clínica Universidad de Navarra-Centro de Investigación Médica Aplicada, Instituto de Investigación Sanitaria de Navarra, Centro de Investigación Biomédica en Red de Cáncer, Pamplona (J.S.-M.) - both in Spain; National and Kapodistrian University of Athens, Athens (M.A.D.); the Institute of Hematology, Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna (M. Cavo), and Azienda Ospedaliera "Santa Maria," Terni (A.M.L.) - both in Italy; Japanese Red Cross Medical Center, Department of Hematology, Tokyo (K.S.); University of Chicago Medical Center, Chicago (A.J.); Würzburg University Medical Center, Würzburg, Germany (S.K.); Université Catholique de Louvain (UCL), Centre Hospitalier Universitaire UCL Namur, Yvoir (C.D.), and Janssen Research and Development, Beerse (W.D.) - both in Belgium; Champalimaud Center for the Unknown, Lisbon, Portugal (P.L.); Semmelweis Egyetem, Budapest, Hungary (Z.N.); Dnepropetrovsk City Clinical Hospital #4, Dnepropetrovsk, Ukraine (P.K.); University Hospital Brno, Brno, Czech Republic (L.P.); University Hospitals Birmingham NHS Foundation Trust, Birmingham (M. Cook), and Leicester Royal Infirmary-Haematology, Leicester (M.G.) - both in the United Kingdom; the Department of Cancer Prevention, School of Public Health, Silesian Medical University, Katowice, Poland (S.G.); Clínica de Tratamento E, Cuiaba, Brazil (A.C.); Andrew Love Cancer Centre, Geelong, VIC, Australia (P.C.); Clinic of Professional Pathology, Saratov, Russia (T.S.); the Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea (S.-S.Y.); LTD "Medinvent" Institute of Health, Tbilisi, Georgia (G.I.); Matsuyama Red Cross Hospital, Matsuyama, Japan (T.F.); Janssen Research and Development, Spring House, PA (C.C., R.C., W.C., M.Q.); and Janssen Research and Development, Raritan, NJ (J.W., H.N.).

Abstract

BACKGROUND:

The combination of bortezomib, melphalan, and prednisone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. Daratumumab has shown efficacy in combination with standard-of-care regimens in patients with relapsed or refractory multiple myeloma.

METHODS:

In this phase 3 trial, we randomly assigned 706 patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation to receive nine cycles of bortezomib, melphalan, and prednisone either alone (control group) or with daratumumab (daratumumab group) until disease progression. The primary end point was progression-free survival.

RESULTS:

At a median follow-up of 16.5 months in a prespecified interim analysis, the 18-month progression-free survival rate was 71.6% (95% confidence interval [CI], 65.5 to 76.8) in the daratumumab group and 50.2% (95% CI, 43.2 to 56.7) in the control group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.38 to 0.65; P<0.001). The overall response rate was 90.9% in the daratumumab group, as compared with 73.9% in the control group (P<0.001), and the rate of complete response or better (including stringent complete response) was 42.6%, versus 24.4% (P<0.001). In the daratumumab group, 22.3% of the patients were negative for minimal residual disease (at a threshold of 1 tumor cell per 105 white cells), as compared with 6.2% of those in the control group (P<0.001). The most common adverse events of grade 3 or 4 were hematologic: neutropenia (in 39.9% of the patients in the daratumumab group and in 38.7% of those in the control group), thrombocytopenia (in 34.4% and 37.6%, respectively), and anemia (in 15.9% and 19.8%, respectively). The rate of grade 3 or 4 infections was 23.1% in the daratumumab group and 14.7% in the control group; the rate of treatment discontinuation due to infections was 0.9% and 1.4%, respectively. Daratumumab-associated infusion-related reactions occurred in 27.7% of the patients.

CONCLUSIONS:

Among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation, daratumumab combined with bortezomib, melphalan, and prednisone resulted in a lower risk of disease progression or death than the same regimen without daratumumab. The daratumumab-containing regimen was associated with more grade 3 or 4 infections. (Funded by Janssen Research and Development; ALCYONE ClinicalTrials.gov number, NCT02195479 .).

PMID:
29231133
DOI:
10.1056/NEJMoa1714678
[Indexed for MEDLINE]
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