The New England Journal of Medicine --
Thalidomide -- A Revival Story
One of the most devastating tragedies of modern medicine was set into motion by the over-the-counter marketing of thalidomide in Europe during the late 1950s for the treatment of morning sickness. The drug was withdrawn in the 1960s after the appearance of reports of teratogenicity and phocomelia associated with its use. The recent return of thalidomide stems from the broad spectrum of its pharmacologic and immunologic effects. (1) Thalidomide has been approved by the Food and Drug Administration for the treatment of erythema nodosum leprosum, an inflammatory manifestation of leprosy, (2) and potential therapeutic applications span a wide spectrum of other diseases.
In 2000, multiple myeloma will be diagnosed in about 13,700 patients in the United States. This incurable bone marrow cancer accounts for 2 percent of cancer-related deaths. (3) Treatment of this disease has been notoriously difficult. In this issue of the Journal, Singhal et al. report on the use of thalidomide as a single agent in the treatment of refractory myeloma. (4) In their study, 76 of the 84 patients in the trial (90 percent) had received at least one cycle of high-dose chemotherapy, and 42 percent had high-risk cytogenetic abnormalities. The overall rate of response was 32 percent, as evidenced by a reduction of at least 25 percent in the level of the myeloma protein in serum or Bence Jones protein in urine. This response was associated with a decrease in the percentage of plasma cells in bone marrow, indicating a reduction in the tumor burden. Since the median time to disease progression among patients who had a response had not been reached after a median follow-up of14.5 months, the responses appear in some cases to be durable. Given that the patients in the study had relapsed after chemotherapy, which was usually given in massive doses, this effect of thalidomide is indeed remarkable.
Although the results of Singhal et al. indicate that a new drug can be added to the armamentarium of agents against myeloma, important questions remain. The study design called for a gradual increase in the dose, but only 55 percent of the patients received the intended maximal daily dose of 800 mg; it is unclear whether this was due to dose-limiting toxicity. Most patients received 400 mg of thalidomide daily, but whether there is a dose-response relation in the antimyeloma activity of thalidomide was not established. Both factors are critical, since somnolence, neuropathy, and other side effects were common with the higher dose of thalidomide. The optimal dose of thalidomide and schedule of administration therefore remain to be determined.
A low plasma-cell-labeling index, indicating a slow rate of tumor-cell replication, was associated with a response to thalidomide, but it is unclear whether other factors that are useful for predicting the outcome of conventional or high-dose chemotherapy will also apply to thalidomide. The absence of clinically significant treatment-related myelosuppression suggests that thalidomide can readily be tested in earlier stages of myeloma, both alone and with other types of chemotherapy.
New therapies for myeloma are urgently needed. The five-year survival rate for patients treated with chemotherapy has remained at 29 percent for more than four decades. In an overview of 6633 patients from 27 randomized trials in which combination chemotherapy was compared with melphalan plus prednisone, the response rates were higher with combination chemotherapy, but there was no difference in survival. (5) A randomized, controlled trial conducted by the Intergroupe Francais du Myelome showed that high-dose chemotherapy followed by autologous bone marrow transplantation resulted in better response rates, overall survival, and event-free survival than conventional chemotherapy, but few, if any, patients were cured. (6) Moreover, the high mortality rate among patients with myeloma who undergo allogeneic bone marrow transplantation has limited the use of this procedure. More needs to be done to improve the outcome of high-dose chemotherapy and autologous hematopoietic stem-cell rescue and to make treatment of residual disease after transplantation more effective -- for example, through the use of vaccination against the patient's own myeloma protein or other forms of immunotherapy. (7)
The mechanism of action of thalidomide in myeloma is unknown. Recent reports of increased blood-vessel formation (angiogenesis) in the bone marrow of patients with myeloma (8,9) and the antiangiogenic properties of thalidomide (10) provided the rationale for the study by Singhal et al. of thalidomide in myeloma. Factors produced by myeloma cells stimulate angiogenesis in the marrow, and it is likely that progression of myeloma follows an increase in bone marrow neovascularization. (9) Nevertheless, Singhal et al. found no correlation between signs of angiogenesis in the marrow and the response to thalidomide, suggesting that inhibition of angiogenesis may not be the primary mechanism of this drug in myeloma. (3)
Possible mechanisms of action of thalidomide, its in vivo metabolites, or both, in myeloma are shown in Figure 1. Thalidomide may directly inhibit the growth and survival of myeloma cells, bone marrow stromal cells, or both. Oxidative damage to DNA mediated by free radicals, which probably has a role in the teratogenicity of thalidomide, (11) may be important here. A second mechanism relates to the finding that adhesion of myeloma cells to bone marrow stromal cells triggers the secretion of cytokines that augment the growth and survival of myeloma cells (12) and induces drug resistance in them. (13) Thalidomide, by modulating the profile of adhesion molecules, (14) may influence the growth and survival of tumor cells. Cytokines that are secreted into the microenvironment of the marrow, such as interleukin-6, 1(beta), and 10 and tumor necrosis factor (alpha), modulate the growth and survival of myeloma cells (12); thalidomide may alter the secretion and biologic activity of such cytokines. (15) Thalidomide may inhibit vascular endothelial growth factor and basic fibroblast growth factor 2, which stimulate angiogenesis. (16) Finally, thalidomide may act against myeloma by inducing the secretion of interferon-(gamma) and interleukin-2 by CD8+ T cells. (17) Determining which of these mechanisms mediate the activity of thalidomide against myeloma will be critical in defining its clinical utility and deriving more potent analogues with fewer side effects. Two new classes of thalidomide analogues have already been identified: phosphodiesterase 4 inhibitors, which inhibit the production of tumor necro-sis factor (alpha) but have little effect on the activation of T cells, and another class, which does not inhibit phosphodiesterase, but instead markedly stimulates T cells and the secretion of interferon-(gamma) and interleukin-2. (15)
The efficacy of thalidomide treatment in patients with refractory, relapsed myeloma suggests that this drug can be used to overcome resistance to conventional chemotherapy. Its demonstrated efficacy in late-stage disease and its low toxicity provide the rationale for evaluating its effect in patients with early disease, either as a single agent or in combination with chemotherapy. Ongoing studies of the way in which thalidomide affects myeloma cells and of resistance to thalidomide in myeloma will guide the synthesis of analogues with enhanced activity and even less toxicity. Current clinical studies of thalidomide open possibilities for novel treatments that target the tumor cell and its microenvironment.
Noopur Raje, M.D.