Management of Double-Refractory Multiple Myeloma
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MULTIPLE MYELOMA (R NIESVIZKY, SECTION EDITOR)
Management of Double-Refractory Multiple Myeloma Jason P. Meadows & Tomer M. Mark
Published online: 23 August 2013 # Springer Science+Business Media New York 2013
Abstract Widespread use of the novel agents bortezomib and lenalidomide has improved outcomes in multiple myeloma (MM). Despite remarkable progress, patients will eventually relapse after exhausting treatment with these drugs. Management of myeloma that is refractory to both bortezomib and lenalidomide (double-refractory MM, DRMM) is complicated due to disease, patient, and treatment-related factors and new therapies for these patients are required. A review of the unique challenges of treating DRMM, recently FDA-approved therapeutic agents, and selected novel drugs under active clinical investigation, is presented below. Keywords Myeloma . Multiple myeloma . Relapsed . Refractory . Double-refractory . Carfilzomib . Pomalidomide . Bortezomib . Lenalidomide . Panobinostat . Daratumumab . Elotuzumab . Ixazomib
Introduction Multiple myeloma (MM) comprises 1 % of all cancers and 10 % of newly diagnosed hematologic malignancies in the United States. It is the second most common hematologic malignancy with 21,700 new cases diagnosed and 10,900 deaths in 2012 [1]. Treatment of MM has changed dramatically, starting with the discovery of the anti-myeloma activity of thalidomide in the late 1990s [2, 3]. The subsequent development of thalidomide analogues as a new class of J. P. Meadows Department of Internal Medicine, University of Hawaii, 1356 Lusitana St. 7th Floor, Honolulu, HI 96813, USA e-mail: [email protected] T. M. Mark (*) Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York Presbyterian Hospital-Cornell Medical Center, 428 East 72nd Street, Suite 300, New York, NY 10021, USA e-mail: [email protected]
antineoplastic agents called the immunomodulatory drugs (IMiDs®) led to significantly improved survival in myeloma patients [4]. In June 2006, lenalidomide became the first IMiD® to be FDA approved [5]. Research in the early 1990s demonstrated the increased levels of proteosomal mRNA in cancer [6]. Aiming to exploit this feature, bortezomib was developed as a first-in-class proteasome inhibitor (PI). It was first approved for relapsed/ refractory disease in 2003 and later approved for treatmentnaïve MM (2008) [7]. Thalidomide, lenalidomide, and bortezomib were called the “novel agents” and have led to significant improvement in survival outcomes and have become a mainstay of myeloma treatment [8–10]. Despite the advances in treatment, MM still is considered an incurable disease and patients eventually become refractory to even the novel agents. After relapse, patients are left with limited options for treatment and face a grim overall prognosis. Retrospective review has shown persons with myeloma that has progressed after prior lenalidomide and bortezomib treatment have a median overall survival of 9 months and an event-free survival of 5 months
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