Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma
Dimopoulos MA , Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, Rabin N, Orlowski RZ, Komarnicki M, Suzuki K, Plesner T, Yoon SS, Ben Yehuda D, Richardson PG, Goldschmidt H, Reece D, Lisby S, Khokhar NZ, O'Rourke L, Chiu C, Qin X, Guckert M, Ahmadi T, Moreau P; POLLUX Investigators.
From the National and Kapodistrian University of Athens, Athens (M.A.D.); Institut Català d'Oncologia, Institut Josep Carreras, Hospital Germans Trias I Pujol, Barcelona (A.O.), and Clínica Universidad de Navarra-Centro de Investigación Médica Aplicada, Instituto de Investigación Sanitaria de Navarra, Pamplona (J.S.-M.) - both in Spain; Karolinska Institute and the Department of Medicine, Division of Hematology, Karolinska University Hospital at Huddinge, Stockholm (H.N.); Tom Baker Cancer Centre, University of Calgary, Calgary, AB (N.J.B.), and the Cancer Clinical Research Unit, Princess Margaret Cancer Centre, Toronto (D.R.) - both in Canada; Levine Cancer Institute-Carolinas HealthCare System, Charlotte, NC (S.Z.U.); the Department of Haematology, University College London Hospitals NHS Trust, London (N.R.); the Department of Lymphoma-Myeloma, University of Texas M.D. Anderson Cancer Center, Houston (R.Z.O.); the Department of Hematology and Stem Cell Transplantation, Poznan University of Medical Sciences, Poznan, Poland (M.K.); the Department of Hematology, Japanese Red Cross Medical Center, Tokyo (K.S.); Vejle Hospital and University of Southern Denmark, Vejle (T.P.), and Genmab, Copenhagen (S.L.) - both in Denmark; the Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea (S.-S.Y.); the Hematology Department, Hadassah-Hebrew University Medical Center, Jerusalem (D.B.Y.); Dana-Farber Cancer Institute, Harvard Medical School, Boston (P.G.R.); University Hospital Heidelberg and the German Cancer Research Center, Heidelberg, Germany (H.G.); Janssen Research and Development, Spring House, PA (N.Z.K., L.O., C.C., X.Q., M.G., T.A.); and the Department of Hematology, University Hospital Hôtel-Dieu, Nantes, France (P.M.).
Background Daratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1-2 study involving patients with relapsed or refractory multiple myeloma.
Methods In this phase 3 trial, we randomly assigned 569 patients with multiple myeloma who had received one or more previous lines of therapy to receive lenalidomide and dexamethasone either alone (control group) or in combination with daratumumab (daratumumab group). The primary end point was progression-free survival.
Results At a median follow-up of 13.5 months in a protocol-specified interim analysis, 169 events of disease progression or death were observed (in 53 of 286 patients [18.5%] in the daratumumab group vs. 116 of 283 [41.0%] in the control group; hazard ratio, 0.37; 95% confidence interval [CI], 0.27 to 0.52; P<0.001 by stratified log-rank test). The Kaplan-Meier rate of progression-free survival at 12 months was 83.2% (95% CI, 78.3 to 87.2) in the daratumumab group, as compared with 60.1% (95% CI, 54.0 to 65.7) in the control group.
A significantly higher rate of overall response was observed in the daratumumab group than in the control group (92.9% vs. 76.4%, P<0.001), as was a higher rate of complete response or better (43.1% vs. 19.2%, P<0.001).
In the daratumumab group, 22.4% of the patients had results below the threshold for minimal residual disease (1 tumor cell per 105 white cells), as compared with 4.6% of those in the control group (P<0.001); results below the threshold for minimal residual disease were associated with improved outcomes.
The most common adverse events of grade 3 or 4 during treatment were neutropenia (in 51.9% of the patients in the daratumumab group vs. 37.0% of those in the control group), thrombocytopenia (in 12.7% vs. 13.5%), and anemia (in 12.4% vs. 19.6%). Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients and were mostly of grade 1 or 2.
Conclusions The addition of daratumumab to lenalidomide and dexamethasone significantly lengthened progression-free survival among patients with relapsed or refractory multiple myeloma. Daratumumab was associated with infusion-related reactions and a higher rate of neutropenia than the control therapy.
CITATION N Engl J Med. 2016 Oct 6;375(14):1319-1331