Allo: Multiple Myeloma

Overview
Multiple myeloma is, in general, a cancer of older individuals that affects specific blood cells and is considered incurable with many standard treatment options. However, survival of most patients has improved significantly over the past 20-30 years. In order to have the best chance of improved survival, it is important to understand the treatment options available and what is necessary to achieve the best results. Physicians have learned that one way to prolong survival in patients under the age of 65-70 is to administer high doses of chemotherapy followed by autologous stem cell support. Allogeneic stem cell transplantation is another way to deliver high doses of radiation and/or chemotherapy drugs over a short period of time.

A variety of factors ultimately influence a patient's decision to receive treatment of cancer. The purpose of receiving cancer treatment may be to improve symptoms of the cancer, increase a patient's chance of cure, or prolong a patient's survival. The potential benefits of receiving cancer treatment must be carefully balanced with the potential risks of receiving cancer treatment.

The following is a general overview of allogeneic stem cell transplantation for treatment of multiple myeloma. Circumstances unique to your situation and prognostic factors of your cancer may ultimately influence how these general treatment principles are applied. The information on this Web site is intended to help educate you about your treatment options and to facilitate a mutual or shared decision-making process with your treating cancer physician.

Most new treatments are developed in clinical trials. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Participation in a clinical trial may offer access to better treatments and advance the existing knowledge about treatment of this cancer. Clinical trials are available for most stages of cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. To ensure that you are receiving the optimal treatment of your cancer, it is important to stay informed and follow the cancer news in order to learn about new treatments and the results of clinical trials. For a general overview of the process of allogeneic stem cell transplantation, select Allogeneic Stem Cell Transplant.

In general, autologous transplants are performed much more frequently than allogeneic transplants for treatment of multiple myeloma. This is due in part to the fact that there are fewer patients with suitable stem cell donors and the side effects associated with an allogeneic transplant are greater. The risk of dying as a complication from an autologous transplant is approximately 1-5%, while deaths from allogeneic transplants are approximately 20-30%. The higher death rate is due to infections, side effects of the high-dose treatment, and graft-versus-host disease. These occur more frequently with increasing age.

Despite the increased toxicity, many doctors recommend allogeneic stem cell transplantation over autologous stem cell transplantation. This is because allogeneic stem cell transplantation may offer a greater chance of cure than autologous stem cell transplantation. Thus, for younger patients who are willing to accept treatment related risks for the chance of long-term survival, an allogeneic transplant is a serious consideration. The best results of allogeneic transplantation are achieved in younger patients who have responded to initial therapy.

Most transplant centers do not treat patients with multiple myeloma over the age of 55-60 years, although there has been recent interest in some centers in evaluating allogeneic transplantation following lower-dose chemotherapy in older individuals (mini transplants). Allogeneic or autologous stem cell transplantation should be considered as an integral component of the treatment plan for all patients under the age of 70 years. It is important that HLA testing is performed at diagnosis to determine the availability of a stem cell donor so that treatment can proceed in a timely manner.

Allogeneic Stem Transplantation as Initial Treatment
In clinical trials, treatment utilizing high-dose chemotherapy and autologous stem cell transplantation has been directly compared to treatment with conventional chemotherapy in patients with multiple myeloma. Results have demonstrated an increased chance of remission, decreased time to cancer recurrence, and improved survival with autologous stem cell transplantation compared to lower or conventional-dose chemotherapy. Clinical studies directly comparing allogeneic stem cell transplantation to autologous stem cell transplantation for the treatment of multiple myeloma have not been performed.

Patients under the age of 50 may want to consider treatment with an allogeneic transplant as initial therapy, as this form of treatment may produce the greatest chance of achieving a cure. In addition, cure rates tend to be higher and treatment-related mortality tends to be lower if patients receive an allogeneic transplant as initial therapy versus later in the course of their treatment. Data has indicated that 40% of patients with multiple myeloma under the age of 50 who are treated with an allogeneic transplant are alive and cancer-free five years following therapy. The risk of dying as a consequence of treatment in this group of patients is approximately 20%. Thus, patients must weigh the odds of treatment related mortality against the odds of improved cure rates when trying to choose a treatment strategy.

There are biological characteristics that a patient can be tested for that have been associated with suboptimal results following treatment with an autologous stem cell transplant. The inability to collect sufficient stem cells, a high beta 2 microglobulin, adverse chromosomal abnormalities, or failure to respond to induction chemotherapy treatment are all associated with a poor outcome and should be considered when evaluating treatment options. For patients who have these characteristics and are unlikely to have a good result following autologous stem cell transplantation, the decision to undergo an allogeneic transplant may be easier.

Allogeneic Transplantation for Treatment of Recurrent Multiple Myeloma

Patients who experience recurrence of myeloma following treatment with lower or moderate-dose chemotherapy make up the overwhelming majority of patients who have received allogeneic transplants to date. Mortality following allogeneic transplantation in patients with recurrent multiple myeloma is 40-50% and 20% of these patients survive without cancer recurrence 5 years from treatment. Data is limited for patients with multiple myeloma undergoing an allogeneic transplant who have had a cancer recurrence following an autologous transplant. There is the possibility of benefit from an allogeneic stem cell transplant in this group of patients, especially if there is more than a 2-year interval between the autologous and allogeneic transplants.

Strategies to Improve Treatment
The main reasons patients with multiple myeloma are not cured following an allogeneic transplant are treatment-related mortality and myeloma recurrence. Treatment-related mortality is significantly increased in the elderly and with previous exposure to cytotoxic agents resulting in regimen related toxicities, infections and graft-versus-host disease. Allogeneic stem cell transplants are also limited by donor availability since only one-third of patients will have an HLA-compatible family member donor. Doctors are performing clinical trials designed to improve the treatment of patients with multiple myeloma by the following approaches:

Use of Peripheral Blood Stem Cells: Stem cells may be collected from a number of sites in the body, including the bone marrow and the peripheral blood. Physicians at The Fred Hutchinson Cancer Center, City of Hope, and Stanford University performed a randomized clinical trial comparing allogeneic bone marrow transplantation (BMT) to peripheral blood stem cell (PBSC) transplantation in patients with leukemia and lymphoma. The results of this study were presented at the American Society of Hematology Annual Meeting in New Orleans.

Patients receiving PBSC experienced more rapid recovery from treatment than patients receiving BMT. White blood cell counts recovered 5 days earlier and platelets recovered 8 days earlier. There were more deaths in patients receiving bone marrow due to lung complications, infections and cancer recurrence. This occurred predominantly in patients with more advanced cancers. There was no difference in the incidence of acute graft-versus-host disease and there was an increase in the incidence of chronic graft-versus-host disease of approximately 10% in patients receiving PBSC. Although, the follow-up period for this study is too short to make definite conclusions about the incidence and severity of chronic graft versus host disease, the physicians concluded that allogeneic peripheral blood stem cells were superior to bone marrow stem cells.

"Mini-transplants": Traditionally, the high-dose radiation and chemotherapy regimens used in allogeneic stem cell transplants are very toxic and involve complete destruction of the bone marrow. Recently, several transplant centers have evaluated less toxic regimens, including lower doses of chemotherapy, radiation and/or biologic therapy prior to an allogeneic transplant. The concept of a mini-transplant is two-fold. The less toxic regimens utilizing lower doses of chemotherapy, radiation therapy and/or biologic therapy kill some cancer cells and suppress the patient’s immune system so that it won’t attack the donor cells. Once the donor cells are infused into the patient, they can recognize the patient’s cancer cells as foreign and mount an attack against the cancer.

Several small clinical trials have demonstrated that successful eradication of leukemia cells can be achieved with ("mini-transplants"). This represents a potential new approach for safer treatment of a large variety of cancers currently treated with allogeneic stem cell transplantation, including multiple myeloma. The technique of mini-transplants has now been expanded to include the use of unrelated HLA-matched donors and has the potential to make this therapy more widely applicable.

Radioactive Monoclonal Antibodies: Monoclonal antibodies are proteins that can be produced in the laboratory and are designed to recognize and bind to very specific sites on a cell. This binding action promotes anti-cancer benefits by eliminating the stimulating effects of growth factors and by stimulating the immune system to attack and kill the cancer cells to which the monoclonal antibody is bound. Monoclonal antibodies can also be used to deliver anti-cancer compounds, such as radioactive isotopes, directly to cancer cells.

Linking radioactive isotopes to monoclonal antibodies facilitates the delivery of increased dose intensity directly to the leukemia cells. In this manner, radiation is delivered primarily to the cancer cells and not in high doses to vital organs, such as the liver and lung. Early studies utilizing high doses of chemotherapy plus radioactive monoclonal antibodies have been highly successful in preventing relapses when given with allogeneic stem cell transplantation.

Researchers have tested a monoclonal antibody-isotope combination that targets bone marrow cells. Radiation from the isotope was selectively delivered to the bone marrow without toxic radiation to other normal tissues. They treated 44 patients with leukemia who had stopped responding to chemotherapy. All patients received the treatment regimen of chemotherapy, total body irradiation and the monoclonal antibody with radioactive isotope, followed by the infusion of autologous or allogeneic stem cells. This clinical trial was performed primarily to determine the optimal dose of isotope, although several patients appeared to benefit from this therapy. Seven of 25 patients with myeloid leukemia survived 7-89 months after treatment and 3 of 9 patients with lymphoid leukemia survived 23-70 months after treatment. This technique can now be applied to patients earlier in their disease when the number of cancer cells is small and resistance to treatment has not developed.

Enhancement of Immunity after Stem Cell Transplants: Allogeneic stem cell transplants are more effective in preventing relapses than autologous transplants because the donor cells recognize the cancer as foreign and kill cancer cells. Despite this graft-versus-leukemia reaction, many patients still relapse. Clinical trials are ongoing to evaluate strategies that may enhance this graft-versus-leukemia effect.

Biological Modifier Therapy: Biologic response modifiers are naturally occurring or synthesized substances that direct, facilitate or enhance the body's normal immune defenses. Biologic response modifiers include interferons, interleukins and monoclonal antibodies. In an attempt to improve survival rates, these and other agents are being evaluated following treatment with allogeneic stem cell transplantation.

Donor White Blood Cell Infusions: In patients who do not have graft-versus-host disease, infusions of white blood cells from the donor are being evaluated to prevent or treat relapses after allogeneic stem cell transplant. In some studies, these cells are combined with a biologic response modifier, such as Proleukin®, to further enhance the graft-versus-leukemia reaction.

Lymphocytes are white blood cells that are part of the body’s immune system. They are capable of destroying cancer cells. Doctors have been trying for several years to use lymphocytes reactive specifically against cancer cells as a form of treatment. For many reasons, this has been a difficult goal to achieve. First, billions of lymphocytes are needed in order to have a therapeutic effect because it takes several lymphocytes to kill a single cancer cell. Thus, in order for lymphocyte infusions to be practical therapy, extremely large numbers of specific immune lymphocytes need to be produced. Getting lymphocytes to grow and multiply in culture systems outside the body has been difficult. Second, the lymphocytes grown in culture have to be specifically reactive to the cancer cell that has to be killed. Lymphocytes normally attack and kill a variety of foreign invaders, but each lymphocyte is specific and only kills one target and no other. Third, the immune lymphocytes must survive and not be destroyed when infused into a patient with cancer.

Recently, doctors in Holland have been able to grow and expand lymphocytes outside the body that kill leukemia cells without damaging normal cells. They have now infused these lymphocytes into a patient with leukemia who had relapsed after an allogeneic bone marrow transplant. Following infusion of the lymphocytes, this patient achieved a complete disappearance of leukemia. This technique can potentially be used against a variety of cancers and offer a less toxic and more specific approach to cancer therapy.

Unfortunately, the use of donor lymphocytes can also be associated with the development of graft-versus-host disease. Several recent studies suggest that the risk for developing graft-versus-host disease may be decreased if a specific type of lymphocyte, the CD8 lymphocyte, is removed. Until now, there has not been an effective and efficient way to remove, or deplete, these CD8 cells from the other donor lymphocytes. Just recently, European researchers presenting at the European Group for Blood and Marrow Transplantation meeting in Austria reported the use of a new technique to deplete the CD8 lymphocytes from the donor cells that are to be infused into the patient.

Researchers treated 9 patients who experienced a recurrence of leukemia after undergoing high-dose therapy and an allogeneic stem cell transplantation. The researchers were able to deplete 98 to 100% of the CD8 lymphocytes from the donor lymphocyte samples, while still retaining 75% of the other lymphocytes needed to treat the recurrent leukemia. The donor CD8-depleted lymphocytes were then infused into the corresponding patients. Only 1 of the 9 patients developed graft-versus-host disease, a number much lower than would usually occur if CD8 lymphocytes were not depleted from the infusion.

These researchers concluded that the depletion of CD8 lymphocytes from the other donor lymphocytes by high-density microsphere separation appears to be effective. Furthermore, the CD8-depleted donor lymphocyte infusion appeared to decrease the incidence of graft-versus-host disease, while preserving the therapy’s anti-leukemia effect.

Neupogen® Versus Donor Leukocyte Infusion: The use of Neupogen® may help provoke an immune reaction against leukemia cells as effectively as would an infusion of donor white blood cells. The use of donor white blood cells can be associated with 2 complications: 1) graft-versus-host disease and 2) some of the tissue in the patient’s bone marrow can be damaged by the donor’s white blood cells. For these reasons, the availability of a biologic therapy that can help stimulate white blood cell production is a welcome advance in treatment. Neupogen® is a type of growth factor called a granulocyte colony-stimulating factor that, when injected under the skin, causes white blood cell counts (particularly granulocytes) to increase dramatically. Researchers in Nebraska conducted a clinical study to determine whether the use of Neupogen® would be as effective as infusions of donor white blood cells in treating recurrent leukemia.

Researchers used Neupogen® to help increase white blood cell counts in 14 patients who suffered a recurrence after undergoing high-dose therapy and an allogeneic stem cell transplant for CML or AML. The results showed that 43% of patients had a complete response to the therapy. However, 43% also developed chronic graft-versus-host disease. Fifteen months after treatment, 73% of the patients were alive and 43% had no signs or symptoms of disease.

While some of the positive effects observed in this study may have been due to discontinuation of the immunosuppressive therapy, it appears that the use of Neupogen® may be a good and safe initial approach to treating patients who have a recurrence of AML or CML after high-dose therapy and an allogeneic stem cell transplant. Should this strategy fail, patients could then receive an infusion of donor white blood cells.

Graft Manipulation: For many years, it has been known that the removal of lymphocytes from the donor-collected stem cells (graft) could prevent or ameliorate graft-versus-host disease. However, when T-cells are removed from the graft, there is an increase in graft rejection and relapse rates. Many clinical trials are currently being carried out to determine the optimal cellular composition of the graft to ensure engraftment, without graft-versus-host disease and without an increase in relapse. These studies have been made easier by the development of peripheral blood stem cell transplants, which allow for the collection and processing of large numbers of stem cells so that researchers may obtain adequate samples to perform studies without harm to the donor and/or patient.

Increase in the use of Donors other than HLA-Matched Siblings: Since only one-third of patients will have an HLA-matched family member donor, there is much ongoing research into increasing the number of available donors. There has been significant progress in the use of partially matched family member donors, especially in children. At the present time, an HLA-compatible unrelated donor can be found for approximately 70% of patient. However, the search must be initiated early enough in the disease course to be of benefit. There is also increasing definition of the degree of mismatching that can be tolerated in unrelated donors especially in children. The use of umbilical cord blood is expanding and since it is associated with a decreased incidence of graft-versus-host disease, it will increase the unrelated donor pool. Umbilical cord blood transplants have until recently been restricted to children due to the small amount of stem cells that can be collected. Recent clinical studies, however, suggest that umbilical cord blood cells can be increased in the laboratory and used successfully in adults.