The research mission in myeloma

Letters to the Editor 422 E Cornet1, JF Lesesve2, H Mossafa3, G Sébahoun4, V Levy5, F Davi6 and X Troussard1, and the Groupe Français d’Hématologie Cellulaire (GFHC) 1 Laboratoire d’Hématologie, CHU de Caen, Registre Régional des Hémopathies Malignes de Basse-Normandie and UPRES EA 3919, Caen, France; 2 Laboratoire d’Hématologie Biologique, CHU de Nancy, Vandoeuvre, France; 3 Laboratoire Pasteur-Cerba, Laboratoire de Cytogénétique, Cergy-Pontoise, France; 4 Laboratoire d’Hématologie, Hôpital Nord, Marseille, France; 5 CIC 9504, Hôpital Saint Louis, APHP, Université Paris 7 and INSERM U717, Paris, France and 6 Laboratoire d’Hématologie, Hôpital Pitié-Salpêtrière et Université Pierre et Marie Curie, Paris, France E-mail: [email protected] References 1 Gordon DS, Jones BM, Browing SW, Spira TJ, Laurence DN. Persistent polyclonal lymphocytosis of B-lymphocytes. New Engl J Med 1982; 307: 232–236. 2 Mossafa H, Malaure H, Maynadie M, Valensi F, Schillinger F, Garand R, et al., and the Groupe Française d’Hématologie Cellulaire (GFHC). Persistent polyclonal B lymphocytosis with binucleated lymphocytes: a study of 25 cases. Br J Haematol 1999; 104: 486–493. 3 Lawlor E, Murray M, O’Brian DS, Blaney C, Foroni L, Sarsfield P et al. Persistent polyclonal B lymphocytosis with Epstein–Barr virus antibodies and subsequent malignant pulmonary blastoma. J Clin Pathol 1991; 44: 341–342. 4 Roy J, Ryckman C, Bernier V, Whittom R, Delage R. Large cell lymphoma complicating persistent polyclonal B cell lymphocytosis. Leukemia 1998; 12: 1026–1030. 5 Chan MA, Benedict SH, Carstairs KC, Francombe WH, Gelfand EW. Expansion of B-lymphocytes with an unusual immunoglobulin rearrangment associated with atypical lymphocytosis and cigarette smoking. Am J Respir Cell Mol Biol 1990; 2: 549–552. 6 Delage B, Darveau A, Jacques L, Huot A, Delage JM. Chronic B-cell lymphocytosis of the young woman: clinical, phenotypic, and molecular studies. Blood 1992; 80 (Suppl 1): 447a. 7 Feugier P, Kennel de March A, Lesesve JF, Monhoven N, Dorvaux V, Braun F et al. Intravascular bone marrow accumulation in persistent polyclonal lymphocytosis: a misleading feature for B-cell neoplasm. Mod Pathol 2004; 17: 1087–1096. 8 Troussard X, Valensi F, Debert C, Maynadie M, Schillinger F, Bonnet P et al. Polyclonal lymphocytosis with binucleated lymphocytes: a genetic predisposition. Br J Haematol 1994; 88: 275–280. 9 Mossafa H, Tapia S, Flandrin G, Troussard X and the groupe français d’hématologie cellulaire (GFHC). Chromosomal instability and ATR amplification gene in patients with persistent polyclonal B-cell lymphocytosis (PPBL). Leuk Lymphoma 2004; 45: 1401–1406. 10 Smith L, Liu SJ, Goodrich L, Jacobson D, Degnin C, Bentley N et al. Duplication of ATR inhibits MyoD, induces aneuploidy and eliminates radiation-induced G1 arrest. Nat Genet 1998; 19: 39–46. 11 van Dongen JJ, Langerak AW, Brüggemann M, Evans PA, Hummel M, Lavender FL et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 concerted action BMH4-CT98-3936. Leukemia 2003; 17: 2257–2317. The research mission in myeloma Leukemia (2009) 23, 422–423; doi:10.1038/leu.2008.209; published online 7 August 2008 We have read with interest the editorial by Dr Bergsagel that accompanies the original article by Arzoumanian et al, which explores the complex relationship between cytogenetic abnormalities and clinical outcome in the treatment of patients with multiple myeloma, utilizing the ‘Total Therapy’ approach advocated by Barlogie et al.1,2 We agree that the pursuit of improved patient outcome utilizing the least toxic therapy while maintaining efficacy is a key goal of new drug development in the field, and this goal has come closer to reality over the last decade, primarily through the development of thalidomide, bortezomib and lenalidomide. We also agree that the heterogeneity encountered in myeloma remains a major barrier in dissecting who benefits best from what, with the use of more sensitive and specific tools, such as immunophenotyping, molecular diagnostics and imaging to assess response a priority for ongoing research. We would concur that achievement of complete response (CR) was rare until the introduction of high-dose therapy followed by autologous stem cell transplant, and this has generally been associated with prolongation in survival. Similarly, clinical trials of novel agents combined with conventional therapy suggest that patients who achieve a CR with these drugs receive clinical benefit. Thus, it is not apparent how improvements in CR rates with novel agents can therefore be Leukemia considered ‘cosmetic,’ when they have led to significant prolongation in overall survival, as confirmed in multiple randomized trials.3–8 Further, we do not agree that pursuing ‘ever higher complete responses’ by combining novel agents with conventional agents and/or transplant is unwarranted, especially as historical analyses of survival before and after the introduction of novel agents in clinical practice are showing a positive impact on patient survival, which is the first time in the last 20 years that such a change has been seen.9,10 In the second part of the editorial, the commentary is much less clear. First, contrasts are drawn between the E4A03 and VISTA studies, which lack merit.3,4 Specifically, the statement that ‘the increase in the CR (in the VISTA trial) was not accompanied by an equally dramatic prolongation of overall survival’ is not correct, as overall survival for patients receiving VMP versus MP has been significantly superior for the VMP arm at every protocol-specified follow-up point to date. Importantly, the 2-year probabilities of the experimental arms in both studies (VISTA and E4AO3) are identical; are both markedly superior to their respective comparators, and constitute encouraging advances for the treatment of newly diagnosed disease. In our view, the correct conclusion from these trials is that there are now important new therapeutic platforms to build upon, incorporating both bortezomib and lenalidomide, and this is very good news for our patients. Unfortunately, the text next implies that research clinicians are driven by alternative motives and are overly influenced by corporate rhetoric rather than by a desire to cure the disease. Letters to the Editor This suggests that clinician choices can be directed by the promotion of company data, and potentially calls into question a clinician’s choice for his or her patient in the context of a clinical trial. To then link this to the success or otherwise of an individual investigator’s career is simply wrong. It is in this context that the language surrounding the corporations manufacturing these agents and the use of the figure demonstrating their relative stock price is both inappropriate and irrelevant to the scientific discussion at hand.1 In myeloma over the last 5 years, we have been fortunate to see the rapid translation of bench-to-bedside research with a constructive partnership between academia, patient advocacy, the National Cancer Institute, the Food and Drug Administration and the pharmaceutical industry. Hard work coupled with a strong sense of collaboration, integrity and the unanimous goal of improving patient survival has underpinned this effort. It is important to recognize that, while great progress has been made in multiple myeloma, the disease remains fatal and a great deal still needs to be done. This will require continued team work if progress is to be maintained. The initial part of the editorial addresses an important scientific debate as part of this ongoing research. In contrast, the remainder conveys a message that is at odds with both the reality and goal of our collective mission. PG Richardson1, J San-Miguel2, S Lonial3, D Reece4, A Jakubowiak5, M Hussein6, S Jagannath7, CS Mitsiades1, N Raje8, J Kaufman3, D Avigan9, I Ghobrial1, RL Schlossman1, N Munshi1, W Dalton6 and KC Anderson1 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; 2 Department of Hematology, Hospital Universitario de Salamanca, Salamanca, Spain; 3 Department of Hematology Oncology, Winship Cancer Center, Emory University, Atlanta, GA, USA; 4 Department of Medicine, Division of Hematology, Princess Margaret Hospital, Toronto, Canada; 5 Division of Medical Oncology, Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA; 6 Department of Hematologic Malignancies, H Lee Moffitt Cancer Center, Tampa, FL, USA; 7 Department of Medical Oncology, St Vincent’s Hospital, New York, NY, USA; 8 423 Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center, Boston, MA, USA and 9 Division of Hematology Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA E-mail: [email protected] References 1 Bergsagel PL. A kinder, gentler way: control of the proliferative tumor compartment, not cosmetic complete response, should be the goal of myeloma therapy. Leukemia 2008; 22: 673–675. 2 Arzoumanian V, Hoering A, Sawyer J, van Rhee F, Bailey C, Gurley J et al. Suppression of abnormal karyotype predicts superior survival in multiple myeloma. Leukemia 2008; 22: 850–855. 3 Rajkumar SV, Jacobus S, Callander N, Fonseca R, Vesole D, Williams M et al. A randomized trial of lenalidomide plus highdose dexamethasone (RD) versus lenalidomide plus low-dose dexamethasone (Rd) in newly diagnosed multiple myeloma (E4A03): a trial coordinated by the eastern cooperative oncology group. Blood 2007; 110: 74. 4 San Miguel JF, Schlag R, Khuageva N, Shpilberg O, Dimopoulos M, Kropff M et al. MMY-3002: a phase 3 study comparing bortezomibmelphalan-prednisone (VMP) with melphalan-prednisone (MP) in newly diagnosed multiple myeloma. Blood 2007; 110: 76. 5 Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer EA, Facon T et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005; 352: 2487–2498. 6 Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, et al., Multiple Myeloma (009) Study Investigators. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America.. N Engl J Med 2007; 357: 2133–2142. 7 Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, et al., Multiple Myeloma (010) Study Investigators. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007; 357: 2123–2132. 8 Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol 2007; 25: 3892–3901. 9 Jawed I, Lee CM, Tward JD, Macdonald OK, Martincic D, Vudarla N et al. Survival outcomes for multiple myeloma over three decades: a surveillance, epidemiology, and end results (SEER) analysis. J Clin Oncol 2007; 25 (18s): 8019. 10 Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008; 111: 2516–2520. Reply to the research mission in myeloma by Richardson et al. Leukemia (2009) 23, 423–424; doi:10.1038/leu.2008.211; published online 7 August 2008 Although by definition the purpose of editorials is to provoke discussion, I share the authors’ indignation1 with the implications regarding research clinicians’ motivations and the influence of corporate rhetoric they have surmized my editorial to contain.2 This was not what I intended to convey, and I am grateful that they have taken the time to correct these misconceptions. In response I acknowledge here the fact that not only research clinicians, but all interested health care professionals (including those in the pharmaceutical industry, regulatory agencies, philanthropic organizations and medical education companies) involved in myeloma clinical trials have a common, unifying and over-riding goal of helping patients. I agree with the authors that in many recent trials a higher complete response (CR) rate is associated with a survival advantage.3–8 I share the view that the introduction of new agents in myeloma has significantly improved overall survival. The concern I meant to raise was that the relationship between CR and improved overall survival (OS) is not consistent, and this becomes more apparent when one considers trials in which a higher response is associated with a higher early mortality, and/ or at best, no improvement in survival.8–15 Finally, and unfortunately the statement ‘the increase in the CR (in the VISTA trial) (odds ratio 11) was not accompanied by an equally dramatic prolongation of OS (hazard ratio 0.6)’ is Leukemia