Multiple myeloma is an incurable plasma cell dyscrasia arising from clonal B cells. Approximately 14,600 new cases of the disease will be diagnosed in the United States in 2002. Median survival with conventional chemotherapy is about 36 months. Most patients with multiple myeloma have symptoms from their disease at presentation and require prompt therapy.
Conventional chemotherapy regimens in this setting have been stagnant for many years; the preferred initial regimen for potential transplant patients has long been infusional vincristine and doxorubicin(Drug information on doxorubicin) with oral dexamethasone(Drug information on dexamethasone) for 3 to 4 months. Alkylator-based chemotherapy regimens such as MP (melphalan [Alkeran], prednisone(Drug information on prednisone)) or VBMCP (vincristine, carmustine(Drug information on carmustine) [BiCNU], melphalan(Drug information on melphalan), cyclophosphamide(Drug information on cyclophosphamide) [Cytoxan, Neosar], prednisone) represent other commonly used standard regimens for initial treatment.[3,4]
In previously untreated patients, response rates with each of these regimens range from 50% to 60%, with comparable median survivals. The major toxicity of alkylator-based therapy is myelosuppression, which may result in prolonged cytopenias and/or myelodysplasia/acute leukemia.[6,7] In addition, alkylator-based chemotherapy damages the stem cell compartment, decreasing the ability to collect adequate peripheral blood stem cells. Hence, alkylator-based chemotherapy may be more suitable for patients who are not considered candidates for transplantation.
A recent report from the Mayo Clinic has demonstrated that the combination of thalidomide(Drug information on thalidomide) (Thalomid) and dexamethasone pulsing resulted in response rates exceeding 70%. The benefit of maintenance therapy is as yet uncertain. A number of poor prognostic factors associated with a short survival and/or inferior response to chemotherapy have been identified. These include elevated C-reactive protein and beta-2-microglobulin levels, abnormalities involving chromosome 13, increased soluble interleukin (IL)-6 receptor levels, high plasma cell labelling index, and high bone marrow microvessel density.
The use of high-dose therapy with autologous hematopoietic stem cell transplantation has improved outcomes in patients with newly diagnosed multiple myeloma. A randomized French trial of 200 newly diagnosed patients under 65 years old conclusively demonstrated that high-dose therapy with autologous hematopoietic stem cell transplant was superior to conventional therapy. Rates of overall response (81% vs 57%), complete remission (22% vs 5%), 5-year event-free survival (28% vs 10%), and overall survival (52% vs 12%) were all superior in the transplant group (all statistically significant, P < .05).
Investigators at the University of Arkansas reported the results of a pair-mate analysis comparing VAD chemotherapy (vincristine, doxorubicin [Adriamycin], dexamethasone) to tandem high-dose therapy with autologous hematopoietic stem cell transplant. They, too, showed superior results in the high-dose therapy group (event-free survival: 49 vs 22 months, overall survival: 62+ vs 48 months).
Thus, high-dose therapy with autologous hematopoietic stem cell transplant is now considered the standard of care for newly diagnosed multiple myeloma patients. For patients younger than 78 years (per Health Care Financing Administration guidelines), an autologous peripheral blood stem cell transplant should be considered as consolidation of induction therapy, if there are no significant comorbidities precluding this option. It is preferable that hematopoietic stem cells be collected before exposing the patient to alkylating agents and/or prolonged periods (> 12 months) of chemotherapy.
Tandem high-dose therapy with autologous stem cell transplant has shown improved event-free and overall survival in nonrandomized studies,[11-13] and three randomized trials comparing single to tandem transplants are awaiting final analyses. Even with tandem transplant, a plateau on survival curves has not been achieved. Although approximately 50% of patients who undergo high-dose therapy are alive at 5 years, the relapse rate continues to increase over time.
In contrast to these studies, a retrospective Spanish Registry study in 77 patients with mutliple myeloma (who were deemed transplant-eligible but who received conventional chemotherapy) demonstrated a 5-year median survival rate similar to that seen in the above trials. Thus, patient selection may play an important role in response and survival with different treatment options.
As suggested above, there does not appear to be a plateau in disease-free survival after high-dose therapy with autologous hematopoietic stem cell transplant, indicating that cures even with tandem autologous transplantation are unlikely. This may be due to either infusion of stem cell grafts contaminated with myeloma cells or the inability to eradicate minimal residual disease. In an attempt to avoid tumor cell contamination in autografts, three different groups have studied the use of highly purified CD34+ cells (positive selection) to support single or tandem high-dose therapy. However, these trials have failed to demonstrate a significant improvement in progression-free or overall survival.[15,16,16a]
Allogeneic transplantation offers two advantages: the absence of tumor-contaminating grafts and the benefit of a graft-vs-myeloma effect.[16,17] However, allogeneic transplant is an option for a small minority of patients (5%-10%) who have human leukocyte antigen (HLA)-compatible donors and are under age 60.
The largest experience in allogeneic transplant data was reported by the European Group for Blood and Marrow Transplantation (EBMT). They initially reported on 266 patients with a 51% complete response, an overall treatment mortality rate of approximately 40%, and actuarial survival rates of 30% at 4 years and 20% at 10 years. An update of the EBMT database in over 600 patients showed complete remission rates of 15% (by stringent criteria) with a transplant-related mortality of 20% (1994-1998 data). The relapse rate after the first 2 years was small, but late relapses continue to occur.
The largest single-institution studies have been reported by groups in Seattle (Bensinger et al) and Arkansas (Mehta et al). Bensinger et al reported the results of a trial in which 106 patients underwent allogeneic transplant. Approximately 70% of these patients had chemotherapy-resistant disease, and the majority were very heavily pretreated. The investigators observed a 50% treatment-related mortality within the first 100 days and a 57% overall treatment-related mortality at 1 year. At a median follow-up of 4 years, 23% were alive, but only 16% were progression-free.
These results are similar to findings reported by the Arkansas group in patients with similar characteristics. Table 1 shows results of single-institution trials with allogeneic transplants in mutliple myeloma.[18-23] Again, late relapses have been observed.
Alternative donor transplants have equally poor outcomes as those of HLA-identical sibling transplants. Ballen et al reported the National Marrow Donor Program experience in 71 myeloma patients undergoing unrelated donor transplant. They reported a 40% transplant-related mortality. The relapse rate was 35% at 3 years, and only 17% were alive at 5 years posttransplant. Similarly poor results have been reported utilizing alternative donors by the Seattle group.
One of the debates surrounding the outcome of allogeneic transplants concerns the fact that they have routinely been performed in heavily pretreated patients, often after autologous transplant. This argument is not supported by the North American Intergroup trial (S9321), which allowed allogeneic transplantation in patients under 55 who had HLA-identical sibling donors. Patients underwent allogeneic transplant following four cycles of VAD and high-dose cyclophosphamide (4.5 g/m²). This arm of the study was prematurely closed when the transplant-related mortality reached 41% in the first 36 patients (R. Kyle, personal communication).
Case-matched comparative studies between allogeneic and autologous transplantation have been reported: All have shown superior outcomes with autologous transplant, given a higher transplant-related mortality associated with allogeneic transplant.[24-27] Of interest, Gahrton et al compared the outcomes of syngeneic (n = 25), allogeneic (n = 125), and autologous (n = 125) transplantation in the EBMT database. The overall 4-year survival from transplant with syngeneic transplantation was 77%, with autotransplantation, 46%, and with allotransplantation, 31%.
Recommending Allogeneic Transplant
The selection of patients for allogeneic transplant entails a difficult clinical decision. Heavily treated patients and those with chemotherapy-resistant disease have a uniformly dismal outcome. Newly diagnosed patients with chemotherapy-sensitive disease may derive long-term remissions and potential cures. When the clinician is counseling his or her patient, it may be difficult to recommend the allogeneic approach, with its 20% to 50% early transplant-related mortality and less than 30% 5-year survival (compared with the superior data for autologous transplantless than 2% transplant-related mortality and projected 5-year median survival of over 50%). Perhaps patients with extremely poor prognostic features, chromosome 13 deletions, and elevated beta-2-microglobulin may be candidates for allogeneic transplant.