Editorial
Toward a Cure for Multiple Myeloma?
N Engl J Med 1991; 325:1304-1306October 31, 1991DOI: 10.1056/NEJM199110313251809
- Article
THERE has been little progress in the treatment of multiple myeloma since the introduction of the melphalan—prednisone regimen about 25 years ago (for review, see Barlogie et al.1). The lack of benefit from the addition of alkylating agents and anthracyclines has been well documented in multidrug trials and probably reflects the low level of activity of the individual drugs involved.2 Such regimens are designed to minimize myelosuppression, because of the immunodeficiency caused by the disease in what are typically elderly patients. Unfortunately, the marked efficacy of the VAD (vincristine—doxorubicin [Adriamycin] —dexamethasone) regimen in melphalan-resistant myeloma did not translate into extended survival when tested in previously untreated patients.3 , 4 In fact, recent data indicate that high doses of dexamethasone alone may be as effective as VAD,5 so that much of the palliation produced by standard treatments may result from the glucocorticoids that are usually a component of myeloma therapy.
The late Tim McElwain and his colleagues at the Royal Marsden Hospital first addressed the issue of the intensity of the dose of cytotoxic agents.6 Doses of intravenously administered melphalan at marrow-ablative levels, such as those used with total-body irradiation requiring hematopoietic stem-cell support, have consistently produced an incidence of complete remission in the range of 20 to 30 percent.7 8 9 The collective experience in more than 350 reported cases of autologous bone marrow transplantation, mainly with unpurged bone marrow, indicates that the greatest clinical benefit occurs when the disease is still responsive to standard doses of therapy, the tumor burden is low, and the patient's clinical performance is adequate.10 Under these conditions, treatment-related mortality is less than 5 percent and more than 30 percent of patients have complete remission, with four-year progression-free and overall survival of about 50 and 70 percent, respectively. There has thus been growing enthusiasm for autologous marrow transplantation because of its relative safety, even in elderly patients with myeloma. However, formal comparisons with standard-dose regimens have not been conducted.
Allogeneic bone marrow transplantation, pioneered by Nobel laureate E. Donnall Thomas in acute leukemia, has been investigated sporadically in younger patients with multiple myeloma.11 The report in this issue of the Journal by Gahrton and colleagues of a study involving 90 patients represents the first large-scale investigation of this approach in multiple myeloma, a currently incurable cancer in which the median survival does not exceed three years.12 The median age of the study patients (42 years) is more than 10 years less than that in most reported trials of autologous transplantation and 20 years less than the median age of typical patients who receive standard therapy. The other characteristics of the patients were more representative. More than half had advanced disease at the time of transplantation, almost two thirds had followed two or more previous regimens, and less than one half were in remission (usually partial) at the time of transplantation. The conditioning regimen before transplantation consisted of total-body irradiation in 90 percent of the patients, and prophylaxis against graft-versus-host disease (GVHD) varied. Almost 40 percent of the patients died of treatment-related complications within the first three to four months after transplantation. But 40 percent are projected to be alive after five years, and the median duration of relapse-free survival among those with a complete response was four years. As expected, a lower tumor burden and less previous therapy favored a higher incidence of complete remission, which was in turn associated with longer survival. The causes of death included the recurrence of disease in about one fifth of the patients, and severe GVHD (grade III or IV) was fatal in six of eight patients.
The authors conclude appropriately that allogeneic transplantation should be considered in patients up to the age of 55, especially since treatment-associated mortality was not significantly associated with the patients' ages. Given the relatively limited benefit of maintenance therapy with interferon after standard-dose chemotherapy,13 marrow transplantation should be considered in all patients with symptomatic myeloma. With both autologous and allogeneic transplantation, the rate of long-term success seems to be greater when they are used not as a last resort but for the consolidation of a remission or as early salvage therapy for refractory myeloma. Concerning the choice of allogeneic or autologous transplantation, longer follow-up will be required to determine whether the significantly higher rate of early mortality in allogeneic transplantation (40 percent vs. less than 5 percent during the first 6 to 12 months) is offset by more durable control of the disease and possibly by cures resulting from a graft-versus-myeloma effect. Gahrton et al. should examine whether a true complete remission (as assessed by sensitive immunofixation or molecular techniques) is a prerequisite for extended progression-free survival. Alternatively, a benign monoclonal gammopathy (MGUS, or "monoclonal gammopathy of undetermined significance") may persist without reducing longevity.1
The ages of patients and the availability of donors are important variables in recruitment for transplantation trials. For allogeneic transplants, an upper age limit of 55 years is imposed by concern over the steeply increasing mortality from acute GVHD, and this limit excludes 75 percent of the typical population with myeloma. Assuming in addition that an HLA-matched sibling donor can be identified only for every fourth patient, no more than 7 percent of those with myeloma can be offered allogeneic marrow transplants. In contrast, about 70 percent of all patients with myeloma are candidates for autologous marrow transplantation, since up to the age of 70, treatment-related mortality does not increase with age.9
Primary physicians should be aware of these new treatment approaches to myeloma, so that excessive damage to normal hematopoietic stem cells and secondary leukemia from long-term melphalan and nitrosourea therapy can be avoided in potential candidates for autologous transplantation. Because of the relative rarity of myeloma, formal clinical trials to compare standard approaches with marrow transplantation will be possible only in the framework of cooperative groups.
Bart Barlogie, M.D.
University of Arkansas Little Rock, AR 72205- References
References
1
Barlogie
Web of Science | Medline2
Boccadoro
Web of Science | Medline3
Barlogie
Full Text | Web of Science | Medline4
Alexanian
CrossRef | Web of Science | Medline5
Alexanian
Web of Science | Medline6
McElwain
CrossRef | Web of Science | Medline7
Barlogie
Web of Science | Medline8
Gore
CrossRef | Web of Science | Medline9
Jagannath
Web of Science | Medline10
Barlogie
Web of Science | Medline11
Buckner
Medline12
Gahrton
Free Full Text | Web of Science | Medline13
Mandelli
Free Full Text | Web of Science | Medline
- Citing Articles (7)
Citing Articles
1
Robert W. McKenna, Steven H. Kroft. Plasma Cell Neoplasms. In: Hematopathology. Elsevier, 2011:410-435.
2
Uwe Hahn, L. Bik To. Autologous Stem Cell Transplantation. In: Ex Vivo Cell Therapy. Elsevier, 1999:99-126.
3
Robert E. Nordon, Klaus Schindhelm. Summary and Future Directions. In: Ex Vivo Cell Therapy. Elsevier, 1999:323-349.
4
D. H. Vesole, S. Jagannath, G. Tricot, K. R. Desikan, D. Siegel, B. Barlogie. (1996) Autologous Bone Marrow and Peripheral Blood Stem Cell Transplantation in Multiple Myeloma. Cancer Investigation 14:4, 378-391
5
R. Niesvizky, D. Siegel, J. Michaeli. (1993) Biology and treatment of multiple myeloma. Blood Reviews 7:1, 24-33
6
Bart Barlogie, Thad Beck. (1993) Recombinant human erythropoietin and the anemia of multiple myeloma. Stem Cells 11:2, 88-94
7
(1992) Marrow Transplantation in Multiple Myeloma. New England Journal of Medicine 326:16, 1086-1088
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