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N Engl J Med. 2016 Aug 25;375(8):754-66. doi: 10.1056/NEJMoa1606038.

Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma.

Collaborators (138)

Spencer A, Estell J, Quach H, Horvath N, Murphy N, Augustson B, Lee C, Romeo M, de Lima V, Castro N, Hamerschlak N, Hungria V, Barreto W, Miguel CE, Capra M, Pour L, Maisnar V, Hajek R, Spicka I, Gregora E, Engelhardt M, Repp R, Teichmann M, Fenk R, Munder M, Langer C, Jung W, Binder M, Bassermann F, Weisel K, Vohringer M, Knop S, Schmidt-Hieber M, Altai E, Nagy Z, Szomor A, Gasztonyi Z, Illes A, Masszi T, Carella AM, Palumbo A, Foa R, Musto P, Cavo M, Corradini P, Di Raimondo F, Bosi A, Corso A, Ferrara F, Cascavilla N, Rambaldi A, Min C, Shin HJ, Kim B, Lee J, Park J, Mun YC, Yoon DH, Jo JC, Ovilla R, Gomez D, Te Boome L, Croockewit AJ, Bos G, Von Dem Borne PA, Vellenga E, Klein S, Levin MD, Westerman M, Grosicki S, Komarnicki M, Kyrcz-Krzemien S, Jurczyszyn A, Walewski J, Warzocha K, Samoilova O, Khuazheva N, Pristupa A, Rossiev V, Melnichenko V, Chagorova T, Serduk O, Udovitsa D, Vladimirov V, Proydakov A, De la Rubia J, Jarque I, Mateos MV, Martinez J, Gimenez E, Casado F, Blanchard MJ, Rivas JA, Lauri B, Forsberg K, Uggla B, Carlsson K, Hansson M, Ahlberg L, Strandberg M, Kragsbjerg P, Unal A, Beksac M, Kaya E, Hacihanefioglu A, Cagirgan S, Tuglular T, Besisik S, Pylypenko H, Samura B, Glushko N, Kaplan P, Masliak Z, Karamanesht E, Korenkova S, Skrypnyk I, Oliynyk H, Dyagil I, Bar M, Lentzsch S, Kyasa MJ, Lipe B, de Idiaquez D, Khan AC, Klein L, Bensinger W, Green DJ, Weiss B, Nooka A, Holland KH, Mark T, Voorhees PM, Winer E, Srkalovic G, Vescio R, Medvedova E, Cosgriff T, Laubach J.

Author information

1
From the Department of Hematology, University of Turin, Turin, Italy (A.P.); the Division of Hematology and Medical Oncology, Mayo Clinic Florida, Jacksonville (A.C.-K.); Universitaetsklinikum Tuebingen der Eberhard-Karls-Universitaet, Abteilung fuer Innere Medizin II, Tuebingen (K.W.), and University Medical Center of the Johannes Gutenberg-University, Third Department of Medicine, Mainz (M.M.) - both in Germany; Winship Cancer Institute, Emory University, Atlanta (A.K.N.); the Department of Hematology and Stem Cell Transplantation, St. László Hospital, Semmelweis University, Budapest, Hungary (T.M.); Ankara University, Department of Hematology, Ankara, Turkey (M.B.); Clinical Department of Hematology, 1st Medical Department, Charles University in Prague, Prague, Czech Republic (I.S.); Irmandade Da Santa Casa De Misericordia De São Paulo, São Paulo (V.H.); University Hospital of Salamanca-Instituto de Investigación Biomédica de Salamanca, Salamanca, Spain (M.V.M.); Weill Cornell Medical College, New York (T.M.M.); Janssen Research and Development, Spring House, PA (M.Q., X.Q., T.A.); Janssen Research and Development, Raritan, NJ (J.S., H.A.); Janssen Research and Development, Beerse, Belgium (W.D.); Malignant Haematology and Stem Cell Transplantation Service, Alfred Health-Monash University, Melbourne, VIC, Australia (A.S.); and the Department of Hematology, Erasmus MC, Rotterdam, the Netherlands (P.S.).

Abstract

BACKGROUND:

Daratumumab, a human IgGκ monoclonal antibody that targets CD38, induces direct and indirect antimyeloma activity and has shown substantial efficacy as monotherapy in heavily pretreated patients with multiple myeloma, as well as in combination with bortezomib in patients with newly diagnosed multiple myeloma.

METHODS:

In this phase 3 trial, we randomly assigned 498 patients with relapsed or relapsed and refractory multiple myeloma to receive bortezomib (1.3 mg per square meter of body-surface area) and dexamethasone (20 mg) alone (control group) or in combination with daratumumab (16 mg per kilogram of body weight) (daratumumab group). The primary end point was progression-free survival.

RESULTS:

A prespecified interim analysis showed that the rate of progression-free survival was significantly higher in the daratumumab group than in the control group; the 12-month rate of progression-free survival was 60.7% in the daratumumab group versus 26.9% in the control group. After a median follow-up period of 7.4 months, the median progression-free survival was not reached in the daratumumab group and was 7.2 months in the control group (hazard ratio for progression or death with daratumumab vs. control, 0.39; 95% confidence interval, 0.28 to 0.53; P<0.001). The rate of overall response was higher in the daratumumab group than in the control group (82.9% vs. 63.2%, P<0.001), as were the rates of very good partial response or better (59.2% vs. 29.1%, P<0.001) and complete response or better (19.2% vs. 9.0%, P=0.001). Three of the most common grade 3 or 4 adverse events reported in the daratumumab group and the control group were thrombocytopenia (45.3% and 32.9%, respectively), anemia (14.4% and 16.0%, respectively), and neutropenia (12.8% and 4.2%, respectively). Infusion-related reactions that were associated with daratumumab treatment were reported in 45.3% of the patients in the daratumumab group; these reactions were mostly grade 1 or 2 (grade 3 in 8.6% of the patients), and in 98.2% of these patients, they occurred during the first infusion.

CONCLUSIONS:

Among patients with relapsed or relapsed and refractory multiple myeloma, daratumumab in combination with bortezomib and dexamethasone resulted in significantly longer progression-free survival than bortezomib and dexamethasone alone and was associated with infusion-related reactions and higher rates of thrombocytopenia and neutropenia than bortezomib and dexamethasone alone. (Funded by Janssen Research and Development; ClinicalTrials.gov number, NCT02136134.).

PMID:
27557302
DOI:
10.1056/NEJMoa1606038
[Indexed for MEDLINE]
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