NE Oncology Issue – April 2016

Usmani SZ, et al. ASH 2015:29


In the GEN5011 and SIRIUS2 (MMY2002) clinical studies, daratumumab monotherapy has demonstrated remarkable efficacy and good tolerability in heavily treated patients with relapsed and refractory (R/R) multiple myeloma (MM). At ASH 2015, a combined analysis of the efficacy of daratumumab 16 mg/kg in these two studies was presented.3

Study design

  • The GEN501 study was an open-label, multicentre, phase I/II dose-escalation and dose expansion study in patients with MM who relapsed from or were refractory to ≥2 prior lines of therapy including proteasome inhibitors (PI) and immunomodulatory agents (IMiDs).
  • The SIRIUS study was an open-label, multicentre, phase II study in patients who had received ≥3 prior lines of therapy, including a PI and an IMiD, or who were double refractory to a PI and an IMiD.
  • Eligibility criteria included patients ≥18 years of age with:
    • An Eastern Cooperative Oncology Group performance status ≤2;
    • An absolute neutrophil count ≥1,000 cells/mm3;
    • A hemoglobin level of ≥7.5 g/dL;
    • A platelet count of ≥75 x 109/L (GEN501) or ≥50 x 109/L (SIRUIS); and
    • An alanine aminotransferase level ≤3.5 (GEN501) or ≤2.5 (SIRIUS) times the upper limit of normal.
  • In part 2 of the GEN501 study (n = 42), the first 16 mg/kg daratumumab was infused followed by a 3-week rest period, then was given once weekly for 7 weeks, once every 2 weeks for 14 weeks, and once every 4 weeks thereafter.
  • In the SIRIUS study (n =106), 16 mg/kg daratumumab was infused once weekly for 8 weeks, followed by once every 2 weeks for 16 weeks, and once every 4 weeks thereafter.


Key findings

  • In the combined population (N = 148), the median age of patients was 64 years (range: 31–84), with 46% of patients being ≥65 years of age.
  • The median time since diagnosis was 5.1 years (range: 0.8–23.8).
  • The median number of prior lines of therapy was 5 (range: 2–14), with 76% of patients having >3 prior lines of therapy.
  • Overall, 91% of patients were refractory to their last line of therapy, 86% of patients were refractory to both a PI and an IMiD, 39% of patients were refractory to carfilzomib, and 55% of patients were refractory to pomalidomide.
  • In the combined dataset, the median duration of treatment was 3.4 months (range: 0–20) and the median number of infusions was 12 (range: 1–33).
  • Treatment was discontinued in 127 patients, with the most common reason for treatment discontinuation being progressive disease (114/148 patients, 77%).
  • Fourteen patients died within 30 days of the last dose of treatment: 11 patients (7%) due to progressive disease and 3 patients (2%) due to adverse events (AEs).
  • The combined treatment-emergent AEs are listed in Table 1.
    • AEs were consistent with the individual studies and no new safety signals were identified.
  • Infusion-related reactions occurred in 48% of patients; 46%, 4%, and 3% occurred during the first, second, and subsequent infusions, respectively.
  • The median duration of response was 7.6 months (95% CI: 5.6–not evaluable [NE]).
  • In many patients, responses deepened with daratumumab treatment.
  • Overall response rate was 31% (95% CI: 23.7–39.2) and 19 patients (13%) achieved a very good partial response or better. (Table 2)
  • Overall response was consistent in subgroups including age, number of prior lines of therapy, refractory status, or renal function.
  • At a median follow-up of 14.8 months:
    • Fifty percent of responders were progression-free at 12 months (95% CI: 33.6–63.9); and
    • Forty of the 46 responders were still alive.
  • The median progression-free survival was not reached in the group of patients who responded to daratumumab and was 3.2 months in patients with minimal response and stable disease. (Figure 1)
  • The median overall survival (OS) was not reached for the group of responders and was 17.5 months in patients with minimal response and stable disease. (Figure 2)
  • The median OS for the combined analysis was 19.9 months (95% CI: 15.1–NE).
  • The one-year OS rate was 69% (95% CI: 60.4–75.6).

Key conclusions

  • Single-agent daratumumab induced rapid, deep, and durable responses in a heavily pretreated and highly refractory patient population.
  • A remarkable depth of response was observed in patients who were refractory to newer agents, including pomalidomide and carfilzomib.
  • Daratumumab conferred an OS benefit even in patients who achieved minimal response or stable disease.
  • This updated analysis of the combined dataset of the GEN501 and SIRIUS studies did not identify any new safety signals.
  • Daratumumab has immune-mediated and immunomodulatory mechanisms that may be contributing to a survival benefit

References: 1. Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med 2015;373(13):1207-19. 2. Lonial S, Weiss BM, Usmani SZ et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet 2015. In press. 3. Usmani SZ, Weiss BM, Bahlis NJ, et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. ASH Annual Meeting Abstracts 2015:29.

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Canadian Perspectives

Carolyn Owen, MD
Dr. Carolyn Owen completed postgraduate training in internal medicine and hematology at the University of Ottawa and the University of British Columbia, respectively, followed by a research fellowship in molecular genetics at Barts and the London School of Medicine and Dentistry in London, UK. Her research focused on familial myelodysplasia and acute myeloid leukemia. She is currently an Assistant Professor at the Foothills Medical Centre & Tom Baker Cancer Centre, and her clinical interests are low-grade lymphoma and chronic lymphocytic leukemia. She is also the local principal investigator in Calgary for several clinical trials in these areas.

Graeme Fraser, MD, MSc, FRCPC
Dr. Graeme Fraser graduated from the University of Western Ontario (UWO) and completed post-graduate training in Internal Medicine and Hematology at UWO and McMaster University, respectively. His training in malignant hematology was supported by a National Cancer Institute of Canada–Terry Fox Foundation Clinical Research Fellowship. Dr. Fraser is a hematologist at the Juravinski Cancer Centre/Hamilton Health Sciences in Hamilton, Ontario, and he is an Associate Professor in the Department of Oncology. His research interests include the care of adolescent and young adult cancer patients, clinical trials in chronic lymphocytic leukemia, lymphoma, and myeloma, and practice guideline development as a member of the Cancer Care Ontario Program in Evidence-Based Care.

Laurie H. Sehn, MD, MPH
Dr. Laurie H. Sehn is a Clinical Assistant Professor at the BC Cancer Agency and the University of British Columbia in Vancouver. She has been a medical oncologist and clinical investigator with the Lymphoma Tumour Group since 1998. Dr. Sehn has served on the Board of Directors of Lymphoma Canada (LC) since 2002 and is now Director of Research Fellowships for LC. Her research interests include the lymphoid cancers with particular focus on the biology and treatment of large-cell
lymphoma, the application of new imaging techniques such as PET scanning to lymphoma management, and innovative new approaches to treatment.

Investigator Commentaries

Alessandra Tedeschi, MD
Dr. Alessandra Tedeschi obtained her medical degree from the University of Bologna, Italy and subsequently trained in hemato-oncology at the University of Ancona, Italy. She completed two research stages on lymphoproliferative disorders in the Department of Hematology at the Niguarda Hospital in Milan, Italy. Dr. Tedeschi has been a consultant in Hematology at the Niguarda Cancer Center, Niguarda Hospital in Milan, Italy since 1999. Her clinical work focuses on the treatment of patients with indolent lymphoproliferative disorders and her research interests include the study of chronic lymphocytic leukemia (CLL) and Waldenström’s macroglobulinemia. Dr. Tedeschi is a principal and co-investigator on many national and international trials in CLL. She has published over 60 peer-reviewed research articles.

Veronique Leblond, MD
Dr. Veronique Leblond is a Professor and Head of the Department of Hematology at Pitié–Salpêtrière Hospital, Paris, France. She is the chair of the French Innovative Leukemia Group (FILO), focusing on acute leukemia, chronic lymphocytic leukemia (CLL), and Waldenström’s macroglobulinemia (WM), which includes more than 90 centres in France and Belgium. Dr. Leblond is responsible for a rare tumour network (K-VIROGREF) dedicated to the management of transplant recipients with virus-induced tumours, funded by the French National Cancer Institute (INCA) in 2012, and she is the head of GRECHY (Groupe de Recherche Clinique Hémopathie Lymphoïde) at the Pierre and Marie Curie University in Paris, France. She is also a member of the French Society of Hematology and the American Society of Hematology. Dr. Leblond was the principal investigator of several biological and clinical trials in WM and CLL. She received the Robert Kyle award in 2008 and the Waldenström award in 2012. Dr. Leblond is connected to several very active patient associations and charities including Laurette Fugain, SiLLC (Soutien et Information à la Leucémie Lymphoïde Chronique et la Maladie de Waldenström), International WM Foundation, and Waldenström France. She is an author of over 280 research articles, books, and book chapters.

Simon Rule, MD
Dr. Simon Rule is a Professor in Hematology at the Institute of Translational & Stratified Medicine, Plymouth University Peninsula Schools of Medicine & Dentistry, and a Hematologist at the Derriford Hospital in Plymouth, United Kingdom (UK). He has been a member of the National Cancer Research Network (NCRN) Lymphoma Committee since 2000 and serves as Chair of the NCRN Low Grade Lymphoma Clinical Studies Group. Dr. Rule’s clinical research interests are in non-Hodgkin lymphoma (NHL) and new drug development, with a specific interest in mantle cell lymphoma. Dr. Rule has been an author of over 70 publications in peer-reviewed journals. Over the last five years, Dr. Rule has been the Chief Investigator on 12 National studies and Principal Investigator on over 40 studies, mostly involving NHL. Within the UK, Dr. Rule runs all of the national clinical trials for mantle cell lymphoma.

Expert Commentary

Clemens-Martin Wendtner, MD
Dr. Clemens-Martin Wendtner is a Professor of Medicine and the Director of the Department of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases and Tropical Medicine at the Klinikum Schwabing, Munich — an academic hospital of the University of Munich. He completed his MD at the University of Münster in 1993. Thereafter, he received postdoctoral training at the Max-Planck-Institute in Martinsried, Germany and at the National Institutes of Health (NIH) in Bethesda, U.S.A., until 1995. After a clinical fellowship at the University of Munich, he gained his German and U.S.A. licence (ECFMG) in Internal Medicine before specializing as a hematologist and oncologist at the same institution. Dr. Wendtner received his postdoctoral lecture qualification at the University of Munich in 2002, and since 2004, has been a full professor of Internal Medicine, Hematology, and Medical Oncology at the University of Cologne. Dr. Wendtner is a member of multiple national and international societies in the field of Medicine and has won several research awards, including first prize at the 6th International Symposium on Biological Therapy of Cancer in Munich, and a merit award from the American Society of Clinical Oncology. As a founding member of the German CLL Study Group (GCLLSG), he participates on the Steering Committee and is Secretary of the GCLLSG. He has been principal investigator for numerous phase I–III clinical studies, and his interests focus on the development of new therapies in the field of CLL.

Professor Tony Mok studied medicine at the University of Alberta and subsequently completed his fellowship training at the Princess Margaret Hospital in Toronto. After practising oncology and internal medicine for seven years in Toronto, he returned to Hong Kong in 1996 to pursue an academic career. Prof. Mok is a Li Shu Fan Medical Foundation Named Professor and Chairman of Clinical Oncology at The Chinese University of Hong Kong, Hong Kong. His main research interest focuses on biomarker and molecular targeted therapy in lung cancer. He co-founded the Lung Cancer Research Group, and has led a number of important multinational clinical trials, which include the IPASS (IRESSA Pan-Asia Study), a landmark study that established the role of first-line gefitinib in patients with EGFR mutation. Prof. Mok is the Past President of the International Association for the Study of Lung Cancer (IASLC), Past Chair of the American Society of Clinical Oncology (ASCO) International Affairs Committee, a member of the ASCO Publications Committee and Vice Secretary of the Chinese Society of Clinical Oncology (CSCO). Prof. Mok has contributed to over 200 articles in international peer-reviewed journals, including the New England Journal of Medicine, Science, Lancet, and Journal of Clinical Oncology, and contributed to multiple editorials and textbooks. He is an Editor on Thoracic Oncology for the Journal of Clinical Oncology. He has also authored eight books in Chinese and hosted three television series in Hong Kong.

Barbara Melosky, MD, FRCP(C)
Dr. Barbara Melosky is a Clinical Associate Professor of Medicine at the University of British Columbia and a medical oncologist at the BC Cancer Agency in Vancouver. She graduated from medical school at the University of Manitoba, and did a residency in internal medicine and an oncology fellowship at the University of British Columbia. Dr. Melosky is currently working in the fields of lung and gastrointestinal malignancies with a special interest in the side effects of targeted therapy. She sits on the Executive Committee for the Lung Disease Site NCIC Clinical Trials Group and is the annual Chair of the Canadian Lung Cancer Conference.

Sandeep Sehdev, MD
Dr. Sandeep Sehdev is an Assistant Professor (adjunct) at McMaster University in Hamilton and a medical oncologist serving the William Osler Health System in Brampton and Etobicoke and the Headwaters Healthcare Centre in Orangeville. He graduated from medical school at the University of Ottawa and completed a residency in oncology at the University of Toronto and Princess Margaret Hospital. Dr. Sehdev is currently a general community oncologist and continuing health education lead for oncology with a special interest in advocacy, community oncology and patient education, and applications of technology in learning. He has been involved in multiple multicentre clinical trials.