New Questions About Transplantation in Multiple Myeloma: Review 1
Multiple myeloma is now the most common indication for autologous stem cell transplantation (ASCT) in North America, with over 5,000 transplants performed yearly (Center for International Blood and Marrow Transplant Research [CIBMTR] data). While the role of ASCT as initial therapy in multiple myeloma has been established by randomized studies, newer therapies are challenging the traditional paradigm. The availability of novel induction agents and newer risk stratification tools, and the increasing recognition of durability of remissions are changing the treatment paradigm. However, even with arduous therapy designed to produce more complete remissions—for example, tandem autologous transplants—we have seen no plateau in survival curves. A tandem autologous procedure followed by maintenance therapy may be performed in an attempt to sustain remission. Sequential autologous transplants followed by nonmyeloablative allotransplants are pursued with the hope of "curing" multiple myeloma. We examine how the key challenges of increasing the response rates and maintaining responses are being addressed using more effective induction and/or consolidation treatments and the need for maintenance therapies after ASCT. We argue that given the biologic heterogeneity of multiple myeloma, risk-adapted transplant approaches are warranted. While the role of curative-intent, dose-intense toxic therapy is still controversial, conventional myeloablative allogeneic transplants need to be reexamined as an option in high-risk aggressive myeloma, given improvements in supportive care and transplant-related mortality.
The paper "New Questions About Transplantation in Multiple Myeloma," by Drs. Hari, Pasquini, and Vesole, is a good review of the current literature about stem cell transplantion but leaves a number of questions unanswered since the literature is not clear in some areas.
Role of High-Dose Therapy
High-dose chemotherapy with autologous stem cell rescue is an accepted treatment strategy for the management of multiple myeloma in patients under age 70 years. With the use of peripheral blood progenitor cells and growth factors introduced in the early 1990s, dose-intensive therapy with single-agent melphalan (Alkeran) could be performed with minimal morbidity and mortality. This treatment option is consistently safe, generally applicable to a majority of patients under age 70, and as reviewed by Hari et al, it has been shown to be as effective as or better than conventional chemotherapy. Yet high-dose melphalan has improved median event-free and overall survival by a year or less. Therefore, as new agents and results of randomized trials become available, the role of high-dose therapy has to be constantly reviewed.
In randomized trials, incorporation of the novel agent thalidomide (Thalomid) to a regimen of melphalan and prednisone (MPT) has been shown to be superior to conventional as well as tandem intermediate-dose melphalan (100 mg/m2) and stem cell transplantation.[1] Due to the fact that MPT can be administered more readily, high-dose therapy need not be incorporated for the treatment of patients over age 70.
Achieving Complete Remissions
Achievement of durable complete remissions could be considered the first step toward a cure, provided such remissions are truly durable. The authors correctly point out that complete remission cannot be used as a surrogate for survival in myeloma. This may be partly attributable to the depth of remission. However, induction with novel agents followed by stem cell transplantation could provide a new paradigm for achieving complete remissions in more than one-half of the patient population and allowing us to understand whether the achievement of minimal residual disease status results in prolonged survival.
Increasing the intensity of the high-dose melphalan regimen by incorporating busulfan (Myleran) or total-body irradiation has not resulted in better survival but has increased morbidity.[2] Likewise, CD34 selection led to a significant decrease in myeloma cell contamination but no increase in event-free or overall survival.[3] However, it is possible that this may also be due to removal of the immune cell compartment, since syngeneic transplants do appear to yield high CR, event-free, and overall survival rates.[4] Therefore, it is somewhat surprising that the authors would recommend conventional myeloablative allogeneic transplants when they have been shown to be associated with unacceptable mortality. We would then come back full circle to the intensity of the regimen and not the role of the graft-vs-myeloma approach.
Primary Refractory Disease
While discussing the timing of transplantation in myeloma, the authors indicate that autologous transplant has been beneficial in primary refractory disease. However, a distinction should be made between patients who truly have primary refractory disease (ie, disease progression on therapy) vs those who show minimal response without clinical progression (stable disease or minor response), since the latter patients appear to do well even with conventional therapy.[5] In fact, in the referenced articles, "primary refractory" patients were defined as those without a 50% or 75% reduction in the M spike (depending upon the particular article). However, the authors clearly recommend a risk-based strategy.
Thus, transplant therapy in myeloma continues to pose a number of unanswered questions, as pointed out in the review article by Hari et al. In addition, some of the items mentioned above need to be considered in a critical appraisal of transplantation for patients with this disease.
-Sundar Jagannath, MD
-Amitabha Mazumder, MD
References:
1. Facon T, Mary J, Harousseau F, et al: Superiority of melphalan-prednisone (MP) + thalidomide (THAL) over MP and autologous stem cell transplantation in the treatment of elderly patients with multiple myeloma (abstract 1). J Clin Oncol 24(18S):1s, 2006.
2. Attal M, Harrousseau JL, Stoppa AM, et al: A prospective randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med 335:91-97, 1996.
3. Stewart AK, Vescio R, Schiller G, et al: Purging using CD34 selection does not improve high dose chemotherapy for myeloma. J Clin Oncol 19:3771-3779, 2001.
4. Gahrton G, Svensson H, Bjorkstrand B, et al: Syngeneic transplantation in myeloma. Bone Marrow Transplant 24:741-745, 1999.
5. Barbarano L, Corso A, Cantoni S, et al: Salvage therapy for refractory and relapsed myeloma. Haematologica 89:51-57, 2004.
