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NEJM
Edward A. Stadtmauer, M.D. Contrary to a widely held belief, multiple myeloma is not a rare, rapidly fatal disorder that affects only elderly patients. Instead, it is the second most common hematologic cancer after non-Hodgkin's lymphoma � more than 50,000 patients in the United States alone have the disease. About half of these patients received the diagnosis when they were younger than 60 years of age, and increasingly, the disease is detected in persons under the age of 40. The detection of myeloma in patients who are relatively young and otherwise healthy has allowed the use of increasingly aggressive and potentially more efficacious therapies. For 50 years, the orally administered alkylating agent melphalan (L-phenylalanine mustard [Alkeran]), ionizing radiation, and corticosteroids were the cornerstones of treatment for myeloma. Their use can relieve symptoms and cause regression of the disease but has not produced improved survival beyond the median of three years. Furthermore, melphalan and radiation are toxic to bone marrow and increase the risk of leukemia because they can trigger genetic damage in stem cells. Recent technical advances have allowed substantial escalations in the dose of melphalan and the use of total-body irradiation, followed by rescue of bone marrow with autologous hematopoietic stem cells. In patients who have undergone such treatment, rates of a complete response of up to 50 percent are possible, with a mortality rate of less than 3 percent, even among those who have not had a response to other therapies. Given such results, the use of hematopoietic stem-cell rescue after intensive chemotherapy or chemoradiotherapy has become part of the initial treatment plan for patients who have myeloma. Two randomized trials that incorporated autologous stem-cell transplantation into the early treatment of myeloma showed considerable long-term advantages in overall and event-free survival in patients 65 years of age or younger who received a single course of high-dose melphalan, with or without total-body irradiation, and afterward underwent autologous hematopoietic stem-cell rescue, as compared with patients who received conventional chemotherapy.1,2 All the patients in both trials first received four to six months of conventional chemotherapy; if organ function and stem-cell collection were adequate, they then underwent transplantation. Similar gains were also shown in three nonrandomized comparisons.3,4,5 These remarkable results have radically altered the management of myeloma in patients under 65 years of age. Today, myeloma is the most common indication for hematopoietic stem-cell transplantation in the world, and more data support the benefit of this procedure in myeloma than in any other disease. In this issue of the Journal, Attal et al.6 take the next step: if the combination of a single cycle of high-dose therapy and hematopoietic stem-cell rescue improves survival, will a second cycle be even better? They assigned 399 patients with untreated myeloma who were under 60 years of age to receive three or four courses of vincristine, doxorubicin, and oral dexamethasone (the VAD regimen) and afterward randomly assigned these patients to single or double transplantation. Patients in the group that received a single transplant received a preparative regimen of high-dose melphalan (140 mg per square meter of body-surface area) and total-body irradiation. Those in the group that received a double transplant underwent the first transplantation after receiving a preparative regimen of melphalan alone (140 mg per square meter) and underwent the second transplantation after receiving the same combination of melphalan and total-body irradiation received by the single-transplant group. After a median follow-up period of approximately six years, response rates in the two groups were not significantly different, but the probabilities of event-free survival and overall survival were doubled with a double transplant � benefits that had not been evident in the authors' earlier analyses. The benefits were greatest among patients who had not had a very good partial response to the first transplant. This report establishes double transplantation as one of the options for treating patients who have myeloma, particularly those younger than 60 years of age who have a suboptimal response to a single transplant. The InterGroupe Francophone du My�lome, which conducted the study, should be commended for the successful completion of this investigation. However, a number of questions remain unanswered. Other trials have shown that melphalan at a dose of 200 mg per square meter is at least as effective as and is less toxic than preparative regimens that include total-body irradiation and melphalan at a dose of 140 mg per square meter or less.7 Perhaps the beneficial response in the double-transplant group in the study by Attal et al. reflects the higher total dose of melphalan that these patients received (280 mg per square meter), as compared with the single-transplant group (140 mg per square meter). A single transplant with the use of maximally tolerated doses of melphalan may be as good as a double transplant. Also, double transplantation without the use of total-body irradiation, as reported by Barlogie et al.,3 has shown promising results. In the study by Attal et al., mortality rates were similar in the two groups. Nonfatal adverse events are not well described in this report; however, longer hospitalization and an increased risk of toxic effects such as mucositis would be expected in the double-transplant group. The survival benefit of double transplantation comes at a cost. Double autologous transplantation regimens have been used to treat myeloma for the past decade, but their advantage over single transplantation has been unclear until now, with the findings reported by Attal et al. Preliminary accounts of other comparisons of single and double transplantation have failed to show a difference in outcome, but the follow-up periods may have been too short to show the survival benefit found in this trial, or the studies may have been too small to provide a basis for definitive conclusions. Despite the favorable results reported by Attal et al., however, it remains the case that progressive myeloma will develop in almost 80 percent of patients within seven years after they have undergone double transplantation. In the light of these results, what should physicians recommend to patients who have received a diagnosis of myeloma? No therapy is indicated for asymptomatic patients without imminent clinical problems or for those with smoldering myeloma. Symptomatic patients younger than 70 years of age should be treated initially with dexamethasone alone or in combination with chemotherapy or thalidomide, in the expectation that autologous stem-cell transplantation will be included in the treatment. Melphalan or extensive radiation should be used only in patients who are not candidates for transplantation. Parenteral bisphosphonates can improve bone disease and survival in cases of advanced disease and should be given to most patients with bone lesions.8 Candidates for transplantation should expect a high probability of a response, rapid recovery, and low mortality after the procedure. A second transplant should be considered, with particular attention to the patient's tolerance of the treatment and the response to the first transplant. The benefits of reserving transplantation until the disease progresses have not been established. Allogeneic hematopoietic stem-cell transplantation has the potential to eradicate residual disease, because the donor's T lymphocytes can respond to antigens on the recipient's myeloma cells. However, this procedure, when performed after high-dose, myeloablative chemotherapy, is associated with extremely high mortality. Recently, Maloney et al. found that patients who underwent autologous stem-cell transplantation followed by a nonmyeloablative immunosuppressive regimen and an allogeneic stem-cell infusion had a high response rate with acceptable toxic effects.9 A consortium sponsored by the National Institutes of Health has just initiated a study in which autologous transplantation followed by nonmyeloablative allogeneic stem-cell transplantation is being compared with double autologous transplantation in patients 70 years of age or younger who do not have a matched sibling donor. This and other studies should further clarify the benefits and toxic effects of these two approaches. During the past decade, the pace of advances in the treatment of myeloma has been fast and furious. The treatment of myeloma has become a fertile testing ground for a number of new antineoplastic agents. Thalidomide, once infamous, has redeemed itself as a potent immunomodulatory agent that induces responses even in patients with relapsed or therapy-resistant myeloma.10 Thalidomide therapy is a viable initial alternative to chemotherapy when combined with dexamethasone. Bortezomib, a proteosome inhibitor, has substantial single-agent activity against myeloma.11 Studies are under way that incorporate treatment with this drug early in the course of the disease, as are trials of bortezomib in combination with other agents. How such developments will alter therapy for myeloma remains to be seen, but these new chapters in the story have greatly expanded the options for the treatment of patients with this disease. The year 2004 will be an encouraging time for patients with myeloma, but the best is yet to come. Stay tuned.
From the Bone Marrow and Stem Cell Transplant Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia. References
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