Thalidomide in Multiple Myeloma

Introduction

Multiple myeloma accounts for 10% of malignant hematologic neoplasms.[1,2] In 2000, approximately 13,800 new cases of myeloma will be diagnosed in the United States and over 11,000 patients will die of the disease.[1] Recently, it has been found that thalidomide(Drug information on thalidomide) (Thalomid) can induce impressive responses in relapsed myeloma. The current status of thalidomide therapy in myeloma is summarized in this article.

Plasma-Cell Proliferative Disorders

Multiple myeloma is a clonal plasma-cell disorder characterized by the presence of a monoclonal (M) protein in the serum or urine, osteolytic bone lesions, increased plasma cells in the bone marrow, anemia, renal failure, and hypercalcemia.[2] Not all patients with evidence of a clonal plasma-cell proliferative disorder have multiple myeloma. Patients with a serum M protein < 3 g/dL, bone marrow plasma cells < 10%, and no evidence of anemia, hypercalcemia, renal failure, and bone lesions are considered to have monoclonal gammopathy of undetermined significance. These patients do not require any therapy. However, they need indefinite follow-up as approximately 20% to 25% will eventually transform to overt myeloma, amyloidosis, or a non-Hodgkin’s lymphoma at a rate of 1% per year.[3] The serum M protein is rechecked at 6 months, and if it remains stable, yearly thereafter.

Some patients have a serum M protein that is ³ 3 g/dL and/or ³ 10% plasma cells in the bone marrow without anemia, bone lesions, hypercalcemia, or renal insufficiency, and are considered to have smoldering multiple myeloma.[4] These patients have a higher risk of transformation to myeloma than those with monoclonal gammopathy of undetermined significance. However, many smoldering multiple myeloma patients can be observed without therapy for months to years. Close follow-up once every 4 months is recommended.

Patients who present with a single plasmacytoma, with no evidence of other bone or extramedullary lesions, are considered to have a solitary plasmacytoma. The usual treatment consists of radiation therapy to the involved area followed by close observation. These patients are also at risk for eventual progression to overt multiple myeloma, particularly if they have a residual monoclonal gammopathy of undetermined significance after radiation therapy.

Current Therapy for Multiple Myeloma

The standard therapy for multiple myeloma consists of melphalan(Drug information on melphalan) (Alkeran) and prednisone(Drug information on prednisone). With this regimen, the overall response rate is about 50% and the complete response rate is less than 10%.[5] The median survival is about 3 years and the 5-year survival rate is 24%.[5,6] Combination chemotherapy with regimens such as VBMCP (vincristine/carmustine [BiCNU]/melphalan/cyclophosphamide [Cytoxan, Neosar]/prednisone) leads to superior response rates (60% to 70%), but there does not appear to be a significant survival benefit.[5,7,8]

Stem-Cell Transplantation

High-dose therapy followed by autologous stem-cell transplantation has been shown to improve response rate and survival.[9-11] Response rates with stem-cell transplantation exceed 75% to 90%,[6,7] and complete response rates range from 20% to 40%.[10,12] Based on these results, autologous stem-cell transplantation has become the standard of care for patients less than 65 years of age with good performance status. However, transplantation is not curative and there is no plateau in the survival curves.[9]

Newly diagnosed patients considered candidates for stem-cell transplantation are typically treated with chemotherapy that is not toxic to stem cells, such as VAD (vincristine/doxorubicin [Adriamycin]/dexamethasone), for approximately 4 to 5 months to minimize tumor burden. Peripheral blood stem cells are then harvested, followed by high-dose melphalan conditioning and transplantation. There is no standard therapy after transplantation; patients are typically observed until evidence of disease progression.

Stem-cell transplantation can also be delayed until relapse without compromising survival, provided hematopoietic stem cells are harvested and cryopreserved early in the disease course. In this approach, newly diagnosed patients are first treated with chemotherapy such as VAD for 4 to 5 months. Peripheral blood stem cells are then mobilized and cryopreserved for future use. Patients then receive conventional chemotherapy, such as melphalan and prednisone, for approximately 1 year. Subsequently, patients are observed until relapse or progression, at which point stem-cell transplantation is considered. Data from randomized trials comparing early vs delayed transplantation approaches indicate that there is no significant difference in outcome between the two strategies.[13,14]

Interferon Alfa

The role of interferon alfa in the treatment of myeloma has been intensely studied.[15] Interferon alfa has been studied as part of induction treatment in myeloma, and has resulted in superior complete response rates and response duration with no effect on overall survival.[16] Several studies have shown that the use of interferon alfa as maintenance therapy prolongs the plateau phase in myeloma.[15,17-19] However, others have failed to show such an effect, and overall survival was not prolonged in any study.[20-22] A meta-analysis studying the role of interferon alfa is ongoing. A nationwide, large randomized trial in the United States evaluating the role of interferon alfa as maintenance therapy in myeloma is continuing to accrue patients. Interferon alfa has antiangiogenic properties; its effect on myeloma angiogenesis requires further study.

Therapy with bisphosphonates such as pamidronate(Drug information on pamidronate) (Aredia) can prevent fractures, hypercalcemia, and the need for radiation therapy. Bisphosphonates inhibit osteoclast activity and bone resorption. In a randomized trial of 392 patients, the incidence of skeletal events was significantly lower with pamidronate (24%) compared to placebo (41%), P < .001.[23] Bisphosphonates are now considered standard therapy in patients with myeloma who have lytic bony lesions or osteoporosis.[24-26]

Therapy for relapsed disease is disappointing. Typically patients who relapse are treated with chemotherapy regimens such as VAD, VBMCP, pulsed methylprednisolone(Drug information on methylprednisolone), or dexamethasone(Drug information on dexamethasone). Remissions with such therapy are usually short-lived. Recently, several studies have shown that thalidomide has significant activity in relapsed myeloma, making it the first drug to demonstrate clinically significant single-agent activity in relapsed myeloma in over 2 decades.

Thalidomide: Historical Background

Thalidomide was first introduced in clinical practice as a sedative. Beginning in the late 1950s, it was marketed in more than 40 countries. Due to US Food and Drug Administration (FDA) concerns about nerve damage, the drug was not approved for clinical use in the United States. In the countries in which it was available, thalidomide became popular because it provided good sleep quality and an unusually low risk of fatal overdose, unlike other sedatives marketed at the time.

Thalidomide was subsequently found to be effective in the treatment of morning sickness associated with pregnancy. Unfortunately, its severe teratogenic potential was not realized until 1961. Fetal malformations with thalidomide involve the extremities (phocomelia), ears, eyes, and the gastrointestinal tract.[27] Almost 10,000 children worldwide were affected with these birth defects as a result of thalidomide. The drug was withdrawn from the market in 1962.

Pregnant women are vulnerable to the teratogenic effects of thalidomide between days 27 and 40 of gestation. A single pill (50 mg) may be sufficient to cause these teratogenic effects. The mechanism of its teratogenicity is unclear, but may be related to its antiangiogenic properties or inhibition of tumor necrosis factor-alpha (TNF-alpha) production.[28] Free-radical-mediated oxidative damage to DNA has also been postulated as a mechanism for the teratogenic effects.[29]

Despite its tragic past, thalidomide has reentered clinical practice due to its immunomodulatory and antiangiogenic properties. It was found to be effective in the treatment of erythema nodosum leprae in the mid-1960s.[30] In the past 10 years, thalidomide has been studied and found to be useful in the treatment of AIDS-related cachexia and aphthous ulcers. It has also been effective in the treatment of aphthous ulcers in patients with Behcet’s disease and in the treatment of chronic graft-versus-host disease. In 1998, the FDA approved thalidomide for use in erythema nodosum leprae with substantial precautions.