Lenalidomide in the Treatment of Multiple Myeloma
Lenalidomide in the Treatment of Multiple Myeloma
Purpose: The pharmacology, clinical use, adverse effects, dosage and administration, and cost of lenalidomide in the treatment of multiple myeloma (MM) are reviewed.
Summary: Lenalidomide is an analogue of thalidomide and has been shown to be more potent than thalidomide in the stimulation of T-cell, interleukin-2, and interferon-γ production. Both drugs have direct cytotoxic effects on myeloma cells and are capable of inducing apoptosis. They are also capable of reducing angiogenesis through the inhibition of the secretion of vascular endothelial growth factor (VEGF). Inhibition of VEGF leads to alterations in the microvasculature of the bone marrow environment and inhibits myeloma cell growth and proliferation. Unlike thalidomide, lenalidomide has almost no sedative or constipative properties and induces only minimal neurotoxicity; however, there is concern about lenalidomide's teratogenic potential. Phase I, II, and III trials have been carried out with lenalidomide in patients with relapsed or refractory MM, and the drug has shown impressive response rates in relapsed disease. The combination of lenalidomide and dexamethasone has shown superior patient survival. Lenalidomide's efficacy in newly diagnosed MM is currently being studied. Neutropenia and thrombocytopenia were found to be the most common grade 3 or higher toxicities. Rates of these toxicities varied among trials and may have been affected by the setting in which lenalidomide was used (i.e., relapsed or refractory disease versus newly diagnosed MM).
Conclusion: Lenalidomide, a thalidomide analogue, has produced good results when used with dexamethasone in patients with relapsed or refractory MM. Lenalidomide is associated with hematologic toxicities, and participation in a restricted-distribution program is required of prescribers, pharmacies, and patients because of the drug's teratogenic potential.
Multiple myeloma (MM) is the second most commonly diagnosed hematologic malignancy. In 2007, there will be an estimated 19,900 new cases of MM and 10,790 deaths due to MM in the United States. The average age at diagnosis is 65 years. The disease is characterized by the accumulation of malignant plasma cells in the bone marrow. This accumulation leads to the overproduction of an immunoglobulin, most commonly a monoclonal immunoglobulin G or A. These immunoglobulins, also known as paraproteins, are detectable in the urine and blood of patients with MM. Consequences of MM include anemia, the development of destructive bony lesions, and renal insufficiency.
Historically, standard first-line therapy for MM consisted of combination therapy with an alkylating agent, such as melphalan, and prednisone. Response rates with such combination therapy are approximately 50%, but five-year survival rates remain low at 33%. For younger patients, debulking chemotherapy followed by autologous stem-cell transplantation with melphalan is the current treatment of choice to increase the potential for a sustained durable remission. A large percentage of patients diagnosed with MM, however, are not suitable candidates for stem-cell transplantation because of age or comorbidities. Also, despite the improved survival offered by standard therapies, MM remains an incurable disease. These factors point to the need for the development of new, more effective agents for treatment.
Fortunately, the approach to the treatment of MM has undergone a radical transformation over the past decade, including the introduction of the proteasome inhibitor bortezomib and the immunomodulatory agents thalidomide, lenalidomide, and CC-4047. This review will focus on the development of the role of immunomodulatory drugs (IMiDs) in the treatment of MM, concentrating on the role of lenalidomide.
Abstract and Introduction
Abstract
Purpose: The pharmacology, clinical use, adverse effects, dosage and administration, and cost of lenalidomide in the treatment of multiple myeloma (MM) are reviewed.
Summary: Lenalidomide is an analogue of thalidomide and has been shown to be more potent than thalidomide in the stimulation of T-cell, interleukin-2, and interferon-γ production. Both drugs have direct cytotoxic effects on myeloma cells and are capable of inducing apoptosis. They are also capable of reducing angiogenesis through the inhibition of the secretion of vascular endothelial growth factor (VEGF). Inhibition of VEGF leads to alterations in the microvasculature of the bone marrow environment and inhibits myeloma cell growth and proliferation. Unlike thalidomide, lenalidomide has almost no sedative or constipative properties and induces only minimal neurotoxicity; however, there is concern about lenalidomide's teratogenic potential. Phase I, II, and III trials have been carried out with lenalidomide in patients with relapsed or refractory MM, and the drug has shown impressive response rates in relapsed disease. The combination of lenalidomide and dexamethasone has shown superior patient survival. Lenalidomide's efficacy in newly diagnosed MM is currently being studied. Neutropenia and thrombocytopenia were found to be the most common grade 3 or higher toxicities. Rates of these toxicities varied among trials and may have been affected by the setting in which lenalidomide was used (i.e., relapsed or refractory disease versus newly diagnosed MM).
Conclusion: Lenalidomide, a thalidomide analogue, has produced good results when used with dexamethasone in patients with relapsed or refractory MM. Lenalidomide is associated with hematologic toxicities, and participation in a restricted-distribution program is required of prescribers, pharmacies, and patients because of the drug's teratogenic potential.
Introduction
Multiple myeloma (MM) is the second most commonly diagnosed hematologic malignancy. In 2007, there will be an estimated 19,900 new cases of MM and 10,790 deaths due to MM in the United States. The average age at diagnosis is 65 years. The disease is characterized by the accumulation of malignant plasma cells in the bone marrow. This accumulation leads to the overproduction of an immunoglobulin, most commonly a monoclonal immunoglobulin G or A. These immunoglobulins, also known as paraproteins, are detectable in the urine and blood of patients with MM. Consequences of MM include anemia, the development of destructive bony lesions, and renal insufficiency.
Historically, standard first-line therapy for MM consisted of combination therapy with an alkylating agent, such as melphalan, and prednisone. Response rates with such combination therapy are approximately 50%, but five-year survival rates remain low at 33%. For younger patients, debulking chemotherapy followed by autologous stem-cell transplantation with melphalan is the current treatment of choice to increase the potential for a sustained durable remission. A large percentage of patients diagnosed with MM, however, are not suitable candidates for stem-cell transplantation because of age or comorbidities. Also, despite the improved survival offered by standard therapies, MM remains an incurable disease. These factors point to the need for the development of new, more effective agents for treatment.
Fortunately, the approach to the treatment of MM has undergone a radical transformation over the past decade, including the introduction of the proteasome inhibitor bortezomib and the immunomodulatory agents thalidomide, lenalidomide, and CC-4047. This review will focus on the development of the role of immunomodulatory drugs (IMiDs) in the treatment of MM, concentrating on the role of lenalidomide.