By William I. Bensinger, M.D., Professor, University of Washington; Member, Fred Hutchinson Cancer Research Center
November 2005

Introduction

Currently, allogeneic stem cell transplantation is the only proven treatment for multiple myeloma that is potentially curative. This conclusion is based on observations of patients who have undergone allogeneic stem cell transplants and have been living disease-free for 5-15 years. The only possibly exception to this is the rare patient with an identical twin where syngeneic transplants have resulted in occasional disease-free survivals equal to that of allogeneic transplants.[1]

Patients who receive either allogeneic or autologous stem cell transplants for multiple myeloma have similar 3-5 year survivals, while only allograft recipients appear to enjoy long-term disease-free survival. Despite the fact that autologous transplants result in prolonged survival compared to conventional therapy, there is no evidence for a plateau on the survival curve. The prolonged survival in a fraction of patients receiving allogeneic transplants is most likely due to an allogeneic graft-versus-myeloma effect, demonstrated most dramatically by complete responses observed after the simple infusion of donor lymphocytes in patients who have relapsed after an allograft. Despite curative potential, the very high transplant-related mortality associated with standard allogeneic stem cell transplantation is currently the major limitation to wider use of this treatment modality. Complications are age-related, as they are for other diseases treated with allogeneic stem cell transplants, but in addition myeloma patients may be more prone to transplant complications due to underlying immunodeficiency. Thus, transplants are usually offered only to patients under age 55 who have failed conventional treatment. Thus, the majority of patients with multiple myeloma are not eligible for an allogeneic transplant in most centers.

Results of Conventional Allogeneic Stem Cell Transplants

The status of allogeneic stem cell transplants for multiple myeloma has been the subject of several reviews.[2],[3],[4]The largest series of patients comes from the European Bone Marrow Transplant (EBMT) Registry where data on 690 patients with multiple myeloma have been reported.4 Researchers evaluated results of 334 transplants performed from 1983-93 and 356 from 1994-98. The overall survival at 3 years from transplant improved from 35% during the 1983-93 period to 56% during the 1994-98 period. The most important observation was a reduction in transplant-related mortality from 46% to 30%. The reduction in mortality was a result of fewer deaths from opportunistic infections and interstitial pneumonias. This was due, in part, to better patient selection, improvements in supportive care and possibly, the fact that more patients received a transplant with peripheral blood stem cells rather than bone marrow.

At the Fred Hutchinson Cancer Research Center (FHCRC), 136 patients were treated between 1987-1999.[5],[6]The median age was 47 years, with only 21% of patients having chemotherapy sensitive disease. Mortality within the first year was 60% due to regimen-related toxicity, graft-versus-host disease, hemorrhage and infections, especially aspergillus. Patients whose serum albumin was less than 3.0 gm/dl had 1.7 times the risk of death within 100 days compared to patients with an albumin >3.0. The CR rate was 34% and for patients who achieved a CR (n=46), the survival and event-free survival at 5 years were 48% and 37%, respectively. The relapse-free survival for all patients was 22% at 3 years and 14% at 5 years. Twelve patients are surviving free of disease between 5-15 years from transplant. Only chemotherapy sensitivity or resistance influenced overall outcome, with resistant patients having 2.2 times the overall risk of death from any cause. Thus, one approach to improving outcomes is earlier transplant.< /SPAN>

Results of T-Cell Depleted Allogeneic Transplants

T-cell depleted grafts are, in theory, an attractive approach to preventing graft-versus-host disease and its associated morbidity. Unfortunately, most studies of T-cell depletion for patients with multiple myeloma have reported continuing problems with graft-versus-host-disease, high mortality from infections and attenuated graft-versus-myeloma effects.[7],[8]Currently, this approach has not improved outcomes.

Allogeneic Bone Marrow versus Peripheral Blood Stem Cells

Researchers from Italy have reported an apparent reduction in treatment-related mortality and improved survival in patients with multiple myeloma undergoing allogeneic peripheral blood stem cell transplants from HLA identical siblings following a myeloablative treatment regimen.[9]Thirty patients with multiple myeloma were treated with a myeloablative regimen consisting of busulfan and melphalan followed by allogeneic peripheral blood stem cells from HLA matched sibling donors. The median age was 48 years and the oldest patient was 55 years old. Half the patients in this study had responding disease and half did not. Overall treatment-related mortality was 30% with approximately half the deaths occurring in the first 3 months after transplant. The complete response (CR) rate was 71% and those in CR who survived were negative for minimal residual by a PCR test. There was only one relapse. Overall survival at 73 months was 60%. The authors speculate that the high CR rate and prolonged remissions was due to the graft-versus myeloma activity of chronic graft-versus host disease, which was present in over 70% of the surviving patients. This study demonstrates a modest decrease in treatment-related mortality and a relatively high disease-free survival. These results can be attributed to the use of peripheral blood stem cells rather than bone marrow and probably to earlier transplants in responding relatively young patients.

Results of Reduced Intensity Non-Ablative Allogeneic Stem Cell Transplants

Recently, reduced intensity conditioning regimens, designed more for immunosuppression than cytoreduction, have been evaluated. The goal of this approach is to establish consistent donor engraftment while minimizing toxicity and damage to normal host tissues. Furthermore, low intensity immunosuppression should minimize or eliminate the period of severe pancytopenia that always occurs after high intensity conditioning.

German researchers reported 2-year survivals of 25% following allogeneic transplansion using a reduced intensity regimen for patients with multiple myeloma who have failed conventional treatment.[10]In a subset of patients transplanted in chemosensitive relapse, the survival was over 60%. They treated 22 patients with multiple myeloma who had failed previous therapies with a non-marrow ablative regimen followed by stem cells from related (n=7) or unrelated (n=15) donors. The median age of this group of patients was 53 with the oldest being 66. Treatment-related mortality was 23%, which is approximately half of what one would anticipate from a transplant following a marrow ablative regimen. Follow-ups ranged from 8 to 36 months in this study. Two-year survival for the entire group was 25% but was better in patients with a chemosensitive relapse (62.5%). The two factors that were predictive of a poor outcome were chemorefractory disease and absence of chronic graft-versus host disease. This relatively small study confirms preliminary results from several centers suggesting that allogeneic transplants from related or unrelated donors can be carried out in patients with multiple myeloma who have failed other therapies including autologous transplants. This study and others suggest that this approach should be attempted before the development of refractory disease.< /SPAN>

Researchers from the University of Arkansas have treated 31 patients with multiple myeloma with a reduced intensity regimen followed by related or unrelated stem cells.  Thirty of these patients had already received one or more autologous transplant utilizing high-dose melphalan. At a median follow-up of 6 months, 61% of these patients were in a complete or near complete remission. At one year the event-free survival was 86% for those who had received one autograft and 31% for those who had received more than one autograft. There was a high incidence of acute and chronic graft-versus host disease in this study.[11]

One comparative study casts doubt on the advantages of reduced intensity regimens in patients with multiple myeloma. Researchers affiliated with the European Group for Blood and Marrow Transplantation (EBMT) Chronic Leukemia Working Party have concluded that there is no evidence that reduced intensity allogeneic stem cell transplants are better than conventional myeloablative transplants.[12]This analysis included 321 patients with multiple myeloma who had received reduced intensity transplants and 196 who had received conventional transplants between 1998 and 2002. These patients were matched by age and stage of disease. The median age was 49 years and patients had received a median of two prior regimens. Ten percent of patients had failed more than one autograft.

Table 1: Conventional Versus Reduced Intensity Transplants: EBMT Chronic Leukemia Working Party Study

These authors concluded that the reduced intensity transplants may decrease immediate mortality, but there was no evidence of long-term benefit in this patient population.

Tandem Autologous and Allogeneic Stem Cell Transplants

Sequential autologous and allogeneic stem cell transplants are being explored in an attempt to improve the outcomes of patients with multiple myeloma. Researchers from the Fred Hutchinson Cancer Research Center, City of Hope National Medical Center, Stanford University, University of Colorado, the University of Leipzig, and the University of Torino have reported that sequential autologous and allogeneic stem cell transplants produces complete remissions in 56% of patients with relapsed or refractory multiple myeloma.[13] In this study, 54 patients with multiple myeloma with a median age of 52 years and a range up to 71 years were treated with high-dose melphalan followed by autologous peripheral blood stem cell infusion. Two months later this was followed by the administration of 2 Gy of total body irradiation and an allogeneic peripheral blood stem cell transplant from an HLA compatible sibling. These authors reported that significant acute graft versus host disease occurred in approximately 40% of patients and chronic graft versus host disease in 46%. The ultimate complete response rate was 57% with relatively slow disease resolution reported. With a median follow-up of almost 2 years, 78% of patients were alive. The major causes of death in this study were related to acute or chronic graft versus host disease and the overall treatment-related mortality was 17%. Estimated progression-free survival for all patients at 2 years is 55%. One of the main advantages of this approach is that most of the treatment can be performed in an outpatient setting with admissions only for complications of therapy. This approach should next be evaluated in newly diagnosed patients with adverse risk factors for success following a single autologous transplant.

Future Directions

The use of peripheral blood stem cells rather than bone marrow may improve outcomes of allogeneic transplantation and has been widely adopted.[14] Earlier engraftment and immune reconstitution with peripheral blood stem cells should reduce infectious complications. The development of regimens that are less toxic but able to preserve anti-tumor effects such as external beam TBI with lung and liver shielding or radioisotopes linked to bone seeking chelates may be important.[15] Techniques using low intensity, non-ablative regimens appear to effectively reduce the early complications and mortality of allogeneic transplants, while retaining graft-versus myeloma effects sufficient to induce remissions. Such treatments could be combined with infusions of allogeneic donor lymphocytes or subsets of lymphocytes in the form of “engineered grafts,” for example CD4 lymphocytes, which may have a graft-versus myeloma effect without increasing graft-versus-host disease. The tandem autologous, reduced intensity allogeneic transplant regimen looks very promising in terms of low mortality and high response rates. It will require longer follow-up to determine if these remissions are durable. Randomized trials will likely be required to determine the relative benefits of these treatments compared to autologous transplantation.

References