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Hematological Malignancies Carfilzomib—A Selective Proteasome Inhibitor for the Treatment of Relapsed and/or Refractory Multiple Myeloma David S Siegel, MD, PhD, 1 Ravi Vij, MD 2 and Ruben Niesvizky, MD 3 1. Chief, Division of Multiple Myeloma, John Theurer Cancer Center, Hackensack University, Hackensack, New Jersey; 2. Associate Professor of Medicine, Washington University School of Medicine, St Louis, Missouri; 3. Director, Multiple Myeloma Center and Associate Professor of Medicine, Departments of Medicine and Hematology/Oncology, Weill Cornell Medical College, New York, NY, US Abstract Multiple myeloma (MM) is a plasma cell malignancy characterized by overproduction of monoclonal immunoglobulins, hypercalcemia, renal injury, anemia, and osteolytic lesions. Despite markedly improved clinical outcomes since the introduction of first-generation immunomodulatory drugs and proteasome inhibitors, survival is very short in patients who relapse and are refractory to these therapies. Carfilzomib is a selective proteasome inhibitor currently being developed for the treatment of MM. In clinical studies, carfilzomib has achieved durable responses in relapsed and/or refractory MM and demonstrated acceptable tolerability with minimal peripheral neuropathy and no evidence of cumulative toxicity. Herein we summarize the key clinical data for single-agent carfilzomib in the relapsed and/or refractory disease setting and provide an overview of the current clinical development of the drug, both as monotherapy and in combinations. Keywords Multiple myeloma, proteasome inhibitor, relapsed/refractory, selective, safety, tolerability Disclosure: David S Siegel, MD, PhD, has been consultant for, received honoraria from, and served as a Board of Directors or Advisory Committee member for Millennium and Celgene. Ravi Vij, MD, has been on the speakers bureau for Celgene and Millennium, served on advisory boards for Celgene and Onyx, and received research support from Onyx and Celgene. Ruben Niesvizky, MD, has had research supported by Celgene, Millennium, and Onyx, been on the speakers bureau for Celgene and Millennium, and served as consultant for Celgene, Millennium, and Onyx. Acknowledgments: The authors would like to thank all of the patients who contributed to these studies and their families. Critical review of the manuscript for scientific accuracy was undertaken by Thomas Renau, PhD (Onyx Pharmaceuticals). Medical writing and editing services were provided by Brian E Szente, PhD (Fishawack Communications, North Wales, PA) and supported by funding from Onyx Pharmaceuticals, Inc. Received: June 29, 2012 Accepted: August 17, 2012 Citation: Oncology & Hematology Review, 2012;8(2):106–10 Correspondence: Ravi Vij, MD, Associate Professor of Medicine, Washington University School of Medicine, Section of Stem Cell Transplant and Leukemia, Division of Medical Oncology, 660 S. Euclid Avenue, Campus Box 8007, St Louis, MO 63110, US. E: rvij@DOM.wustl.edu Support: The studies described in this article were supported by Onyx Pharmaceuticals, Inc. Multiple myeloma (MM) is a plasma cell malignancy characterized by the overproduction of monoclonal immunoglobulins and the presence of hypercalcemia, renal injury, anemia, osteolytic lesions, and frequent infections. 1,2 Other complications include hyperviscosity and amyloidosis. 1,2 It is the second most common hematologic malignancy after non-Hodgkin’s lymphoma and will represent nearly 15 % of new hematologic malignancies diagnosed in 2012 in the US. 3 MM is generally a disease of older individuals; 4 the median age at diagnosis is approximately 69 years. 5 With the approvals of the newer agents bortezomib, thalidomide, and lenalidomide, the median overall survival (OS) has improved from approximately two years in the late 1970s to 4.4–7.1 years in the decade since 2000. 6 However, in patients with relapsed disease that is refractory to the aforementioned agents, the median event-free survival and OS times are five and nine months, respectively. 7 106 A number of factors may influence the course of disease in an individual patient with MM. Advanced age, poor performance status, the presence of specific cytogenetic markers (e.g., deletion 17p, t(4;14)), the presence of immunoglobulin (Ig)A isotype, serum creatinine ≥2 mg/dl, extramedullary disease, and renal insufficiency each independently predict worse outcomes. 1,8 Additional items of concern relate to the patient’s treatment history and include prior therapy-associated toxicity and prior stem cell transplant. The newer agents (i.e., bortezomib, thalidomide, and lenalidomide) have distinct toxicity profiles (including myelosuppression, peripheral neuropathy, and venous thromboembolic events [VTEs]), 9 and the effective management of adverse events (AEs) associated with these agents is crucial to ensure that patients are able to receive the most effective treatment with minimal need for interruption. While the median survival in patients with MM has increased due to the use of the newer agents, the duration of response (DOR) to post-relapse © TOUCH BRIEFINGS 2012