Attal M, et al. ASCO 2016:8001

Background

Lenalidomide maintenance therapy after autologous stem cell transplant (ASCT) in patients with newly diagnosed multiple myeloma reduces the risk of progression or death by approximately 50% compared to ASCT alone.1–4 However, none of the phase III studies conducted to date were designed with overall survival (OS) as the primary endpoint. The objective of this study was to assess the effect of post-ASCT lenalidomide maintenance on OS using a pooled analysis of primary-source patient data.5

Study design

  • A meta-analysis was prospectively planned prior to pooling data.
  • Inclusion criteria for this analysis were:
    • A lenalidomide maintenance arm vs. a control arm (placebo or no maintenance) after ASCT;
    • Database lock had previously occurred for primary efficacy analysis; and
    • Primary-source patient data were available.
  • Three studies fulfilled all criteria: IFM 2005-02, CALGB 100104 (Alliance), and GIMEMA-RVMM-PI-209.
  • The primary analysis was a log-rank test and Cox model stratified by study to assess the impact of lenalidomide maintenance on OS.
  • There were enough events that a March 2015 cutoff allowed for targeting a 20-month improvement in median OS (HR = 0.78; median: 70–90 months).
  • Heterogeneity (quantitative or qualitative) across studies was tested and reasons for heterogeneity were explored.
  • The three studies intended for lenalidomide maintenance to be given until progression; however, a second primary malignancy (SPM) signal was detected at the end of 2010 in the IFM and CALGB studies.
    • The NCI supported the Alliance electing to continue lenalidomide maintenance until progression; GIMEMA also elected to continue lenalidomide maintenance until progression.
    • IFM elected to discontinue lenalidomide maintenance.

Study Design

Study Design

Key findings

Baseline characteristics and disposition

  • Baseline characteristics were similar between the lenalidomide and control arms in the pooled population (lenalidomide: n = 605, control: n = 604).
  • The median age was 58 years in both groups.
  • Many patients achieved a complete response or very good partial response after ASCT (53% in the lenalidomide arm and 56% in the control arm).
  • Patients in the lenalidomide arm had a slightly higher incidence of stage III disease at diagnosis, using the International Staging System (19% vs. 15% in the control arm), and a slightly higher incidence of deletion 17p and translocation (4; 14) (15% vs. 10% in the control arm of the IFM and GIMEMA studies only).

Efficacy

  • After a median follow-up of 80 months, median OS was not reached in the lenalidomide arm and was 86.0 months in the control arm (HR = 0.74, 95% CI: 0.62–0.89, p = 0.001). (Figure 1)
  • Lenalidomide maintenance led to a 26% reduction in the risk of death, representing an estimated 2.5-year increase in median survival.
    • The median OS for the lenalidomide arm was extrapolated to be 116 months based on the median OS of the control arm and the HR.
  • The majority of subgroup analyses showed an OS benefit in the lenalidomide arm, including subgroups for age (< and ≥60 years), sex, response after ASCT, prior induction therapy, and renal function after ASCT (creatinine clearance < and ≥50 mL/min).
  • Individual HRs for each study were in the same direction, favouring lenalidomide maintenance; thus all studies contributed to the positive results of the meta-analysis. (Figure 2)
  • No qualitative heterogeneity was found (p = 0.75 by Gail-Simon test); however, quantitative heterogeneity was observed (p = 0.047 by Pignon test).
    • This was related to the difference in magnitude of the treatment effect between studies (primarily between the CALGB and IFM studies).
  • Potential reasons for heterogeneity included:
    • Imbalances in pre-study characteristics between treatment arms within the individual studies;
    • Different induction regimens and pre-transplant consolidations;
    • Differences in study conduct after unblinding; and
    • Differences in frequency and type of second-line therapy.
  • The mean treatment duration of maintenance in the CALGB study was 30 months for the lenalidomide arm, 13 months for the control arm, and 25 months for non-progressing patients who crossed over to the lenalidomide arm.
  • In the IFM study, the mean treatment duration of maintenance was 25 months in the lenalidomide arm and 20 months in the control arm.
    • Over 50% of patients received maintenance therapy for more than two years in both studies.

Figure 1. Overall survival

Figure 1. Overall survival

Figure 2. Overall survival hazard ratios

Figure 2. Overall survival hazard ratios

Safety

  • Patients in the lenalidomide arm were at increased risk of SPMs. (Figure 3)
  • This included both hematologic malignancies and solid tumour malignancies.

Figure 3. Cumulative incidence of second primary malignancies

Figure 3. Cumulative incidence of second primary malignancies

Key conclusions

  • Lenalidomide maintenance significantly prolongs OS post-ASCT, and is feasible for long-term disease control after ASCT.
  • The OS benefit of lenalidomide maintenance outweighs the risk of developing an SPM.
  • Lenalidomide maintenance after ASCT can be considered a standard of care for newly diagnosed patients with multiple myeloma..

References: 1. Palumbo A, Cavallo F, Gay F, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med 2014;371:895–905. 2. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 2012;366:1770–81. 3. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 2012;366:1782–91. 4. Palumbo A, Hajek R, Delforge M, et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med 2012;366:1759–69. 5. Attal M, Palumbo A, Holstein SA, et al. Lenalidomide maintenance after high-dose melphalan and autologous stem cell transplant in multiple myeloma: a meta-analysis of overall survival. J Clin Oncol (ASCO Annual Meeting) 2016;34(Suppl):abstr 8001.

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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.