NE Oncology Issue – April 2016

Over the last 15 years, the overall survival (OS) of patients diagnosed with multiple myeloma (MM) has significantly improved.1 This can largely be attributed to the introduction of several new agents for the treatment of MM; most notably the proteasome inhibitor (PI), bortezomib, and the immunomodulatory agents (IMiDs), thalidomide and lenalidomide.1 However, even with these effective agents, most patients will relapse after therapy and with each line of therapy the duration of remission decreases.2 Outcomes are particularly poor for patients who become refractory to PIs and IMiDs and treatment options for these patients are limited. In a study by the International Myeloma Working Group, the median OS in patients who are refractory to bortezomib and at least one IMiD was reported to be 9 months.2 This highlights the current challenge in treating patients with relapsed and refractory disease and the need for new treatments in this setting.

Some of the options for salvage therapy in these relapsed and refractory patients include regimens containing next-generation PIs (e.g., carfilzomib) and IMiDs (e.g., pomalidomide).3 In addition, regimens containing the alkylating agent bendamustine may be an alternative option to cyclophosphamide- and melphalan-based regimens in the relapsed setting. As bendamustine shares structural similarities to both alkylating agents and purine analogs, it has a unique mechanism of action and has the advantage of being non–cross-resistant with other alkylating agents.4 Currently, bendamustine is licensed in Europe as front-line treatment for MM in combination with prednisolone for patients who are unsuitable for transplantation and who are contraindicated for thalidomide and bortezomib.4

New classes of agents with different mechanisms of action are also being investigated in patients with relapsed MM, such as histone deacetylase inhibitors (e.g., panobinostat) and monoclonal antibodies (e.g., elotuzumab, daratumumab).
Daratumumab is an immunoglobulin G1 kappa (IgG1κ) human monoclonal antibody that binds to CD38-expressing tumour cells and induces tumour cell death through a number of mechanisms.5 These include direct apoptosis, complement-mediated cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis. Daratumumab has demonstrated strong single-agent activity in patients with relapsed and/or refractory MM, as well as remarkable efficacy in combination with other agents, making it a promising new therapy option for patients with MM.5

Here we report the results of several studies, presented at the 57th Annual Meeting of the American Society of Hematology (ASH) in Orlando, which investigated the outcomes of patients after treatment with pomalidomide and dexamethasone, and evaluated the efficacy and safety of daratumumab in patients with relapsed and/or refractory MM:

  • In an analysis of the outcomes of patients treated with pomalidomide and dexamethasone in the IFM 2009-02 and IFM 2010-02 studies, patients who received a post-pomalidomide therapy showed further improved overall survival. (Fouquet G, et al. ASH 2015:1831)
  • In a combined analysis of the efficacy of daratumumab in the GEN501 and SIRIUS studies, single-agent daratumumab induced deep and durable responses in a heavily pretreated and highly refractory patient population. (Usmani SZ, et al. ASH 2015:29)
  • In a safety analysis of the ongoing phase II SIRIUS study, daratumumab showed a favourable safety profile, with infusion-related reactions that could be successfully managed with early interventions. (Voorhees P, et al. ASH 2015:1829)
  • Updated results from the phase II GEN503 study showed that daratumumab induced rapid, deep, and durable response in patients with relapsed or relapsed and refractory MM, when combined with lenalidomide and dexamethasone. (Plesner T, et al. ASH 2015:507)

References: 1. Rajkumar SV. Myeloma today: Disease definition and treatment advances. Am J Hematol 2016;92(1):90-100. 2. Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: A multicenter international myeloma working group study. Leukemia 2012;26:149-157. 3. Nooka AK, Kastritis E, Dimopoulos MA, et al. Treatment options for relapsed and refractory multiple myeloma. Blood 2015;125(20):3085-99. 4. Gentile M, Recchia AG, Mazzone C. et al. An old drug with a new future: bendamustine in multiple myeloma. Expert Opin Pharmacother 2013;14(16):2263-80. 5. Laubach JP and Richardson PG. CD38-targeted immunochemotherapy in refractory multiple myeloma: a new horizon. Clin Cancer Res 2015;21:2660–2.

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Canadian Perspectives

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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.

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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.

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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

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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.

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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.

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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

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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.

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Tony SK Mok, MD, FRCP(C), FRCP, FHKCP, FHKAM
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.

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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.

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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.