Bone marrow or peripheral blood stem cells supplied from normal donors are used to perform allogeneic transplants. Standard allogeneic transplants generally utilize very high amounts of chemotheraputic drugs with or without radiation usually given to the entire body at once (total body irradiation). These high dose treatments accomplish two main goals: 1) cytoreduction which means effective killing of the myeloma cells and 2) immunosuppression which means sufficient reduction in the patients immune system to allow the donor graft to become established and prevent rejection.
The problem with very high dose regimens is that they have a fairly high amount of side effects due to the dose intensity that is used. As a result, complications and even death result from these types of transplants. Patients that are older or have pre-existing organ damage such as kidney problems (which frequently occurs in myeloma) are at an even greater risk of complications and death. It has been observed that much of the benefit from allogeneic transplants is derived from the anti-myeloma effects of the graft; that is, the donor graft is capable of seeking out and destroying myeloma cells in the patient (graft-versus-myeloma). Thus, several years ago a numbers of transplant groups began to explore the use of allogeneic transplants using reduced intensity treatments. The idea here was to cut down on the amount of chemotherapy and/or radiation given to patients prior to transplant with the aim of reducing the complications and mortality from transplants. The primary aim of these treatments is immunosuppression sufficient to allow the donor graft to become established. If successful, such transplants could allow more patients to survive the early treatment and potentially benefit from the graft-versus-myeloma effects.
Treatments commonly used to accomplish this immunosuppression include low dose radiation (200 cGy), fludarabine, cyclophosphamide and or melphalan. The drugs cyclosporine, methotrexate, anti-thymocyte globulin and mycophenolic acid are usually added to provide additional immunosuppression and prevent graft-versus-host disease. Since these drugs do not often provide enough tumor cell killing, other chemotherapy agents may be added. At present there is no established drug combination for the reduced intensity regimens but most transplant experts agree that the doses of drugs and chemotherapy are not enough to destroy the patient's bone marrow function alone. These transplants have come to be known as "non-ablative" or "mini-transplants". Since these transplants rely mainly on the graft-versus-myeloma effects, they appear to work best when a person's cancer grows slowly so the newly engrafted stem cells have sufficient time to grow and mount an immune attack.
A regimen that we have utilized at the Fred Hutchinson Cancer Research Center is shown as an example in the accompanying figure. The preliminary results for patients with myeloma suggest that donor engraftment can be established safely with a relatively low mortality of about 10%. For patients with advanced multiple myeloma or who have relapsed after an autologous transplant, patients do not regularly achieve significant responses unless they are responding to salvage chemotherapy prior to the "mini-transplant". This observation has been confirmed by several other transplant centers; mainly that patients who are responding to their initial therapy or responding to salvage therapy are most likely to achieve partial or complete responses after mini-allografting and that these responses are more likely to be durable than patients with resistant disease. This suggests that the "graft-versus-myeloma" effect works best in the setting of minimal disease.
This observation has led to the development of a "tandem" autologous/mini-allogeneic transplant approach shown in the second figure. In this approach patients first have their stem cells harvested using chemotherapy and G-CSF. They next undergo an autologous transplant using a standard, well tolerated regimen of high dose melphalan. This provides the myeloma cell kill. Patients are then allowed to recover from the autologous transplant for 2-3 months. The final step is to perform the mini-transplant. We have omitted the fludarabine from the mini-transplant regimen when used in the tandem approach because there is sufficient immunosuppression provided by the autologous transplant. Preliminary results suggest that this strategy is well tolerated with a 15 % risk of death, reliable engraftment and a 50-60% of obtaining a complete remission in which all evidence of myeloma is gone. Further follow-up is needed, however, to see how durable these remissions will be or that patients can truly be cured with a mini-allograft.
At present, it is not yet possible to definitely say that mini-allografts are safer than standard allografts or that patients are more likely to be cured. Most of studies have utilized matched family members as donors. Fewer trials have explored the use of matched unrelated donors ("MUDs") which appear to be associated with a higher risk of graft rejection and graft-versus-host disease. Patients should only consider this form of therapy at a well-established, experienced transplant center and then only within the context of a clinical trial.