High-dose chemotherapy and autologous stem cell transplantation (ASCT) is an integral component of the overall management of patients with multiple myeloma who are 65 years of age or younger. Clinical studies have demonstrated that patients treated with high-dose chemotherapy live longer and experience a longer period before their cancer recurs compared to patients treated with only conventional dose chemotherapy.
The following is a general overview of the role of ASCT in the management of multiple myeloma. Treatment may consist of chemotherapy, biological therapy, stem cell transplant, or a combination of these treatment techniques. Multi-modality treatment, which utilizes two or more treatment techniques, is increasingly recognized as an important approach for improving a patient's chance of cure or prolonging survival . In some cases, participation in a clinical trial utilizing new, innovative therapies may provide the most promising treatment. Circumstances unique to each patient's situation may influence how these general treatment principles are applied. The potential benefits of multi-modality care, participation in a clinical trial, or standard treatment must be carefully balanced with the potential risks. The information on this website is intended to help educate patients about their treatment options and to facilitate a mutual or shared decision-making process with their treating cancer physician.
For a general overview of the process of autologous stem cell transplant, select Autologous Stem Cell Transplantation.
Despite the introduction of several new chemotherapy drugs over the past 20 years, conventional therapy has not extended survival time of patients with multiple myeloma. However, in the late 1980s, some cancer centers started reporting that the use of high-dose chemotherapy seemed to increase the duration of survival and delay the time before cancer recurred in selected patients with multiple myeloma.
French researchers have confirmed these observations; their clinical trial demonstrated that treatment of patients with stage II or III multiple myeloma with high-dose chemotherapy and ASCT improved responses compared to treatment with conventional-dose chemotherapy: They reported a four-fold increase in anti-cancer responses and survival for five years or more (see table 1). 1
Table 1 High-dose chemotherapy and ASCT improves anti-cancer response and survival compared to conventional-dose chemotherapy.
|High-dose chemotherapy and ASCT||Conventional-dose chemotherapy|
In addition, the patients treated with high-dose chemotherapy and ASCT were almost three times more likely to be free of disease at five years after treatment compared to patients treated with conventional-dose chemotherapy. High-dose chemotherapy and ASCT was equally safe; patients treated with ASCT had a 7% chance of dying from complications of their treatment compared to 5% for patients treated with the conventional chemotherapy. This clinical trial established high-dose chemotherapy and ASCT as a standard of care for patients under the age of 65 with newly diagnosed multiple myeloma.
Whole body irradiation may be administered as part of the aggressive treatment preceding stem cell transplantation. However, research has shown that high-dose chemotherapy was superior total body irradiation and chemotherapy as aggressive treatment before ASCT. 2 This is an important observation since the long-term side effects of irradiation are greater than for chemotherapy.
Stem cell transplantation may also be preceded by high-dose chemotherapy plus whole body irradiation.
Research also suggests that a second transplant can produce a remission in some patients who do not experience a remission after undergoing a single transplant.
ASCT is a treatment that is often reserved until multiple myeloma relapses, or progresses after treatment. Results of a clinical trial indicate that patients survived the same duration—nearly six years—regardless of whether they waited until cancer progression to undergo ASCT or underwent this treatment early in their treatment plan (directly after conventional treatment). However, there does appear to be some advantage to undergoing ASCT early. The patients who underwent high-dose treatment and stem cell transplantation early in their treatment plan experienced a longer interval (approximately 5.5 more months) without symptoms or treatment-related side effects and spent less time undergoing treatment (see table 2). 5
Table 2 Early versus delayed high-dose therapy with ASCT
|Early high-dose therapy plus ASCT||Delayed high-dose therapy plus ASCT|
|Overall survival (months)||64||64|
|Progression-free survival (months)||39||13|
|Interval without symptoms, treatment, or side effects (months)||27.8||22.3|
It is important to note that undergoing transplantation later in the treatment strategy will only work if stem cells are harvested prior to any other treatment because the bone marrow becomes damaged even with conventional-dose chemotherapy.
While an anti-cancer response to high-dose chemotherapy with stem cell transplantation can be dramatic and long-lasting, many patients still experience a relapse of their cancer. Relapse occurs because the high-dose therapy is either unable to kill all of the cancer cells in the patient and/or because cancer cells were present in the collected stem cells and are infused back into the patient. The goal of research is to improve treatment and reduce the chance of relapse.
The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Future progress in the treatment of multiple myeloma with stem cell transplantation will result from the continued evaluation of new treatments in clinical trials. Participation in a clinical trial may offer patients access to better treatments and advance the existing knowledge about treatment of this cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. Areas of active investigation aimed at improving stem cell transplantation for multiple myeloma include the following:
Improve treatment before high-dose chemotherapy: Current conventional chemotherapy treatments produce complete remissions in only 5 to10% of patients; most patients are not in complete remission at the time of high-dose chemotherapy and ASCT. Better treatments prior to high-dose chemotherapy and ASCT, which do not cause undue toxicities, could be of benefit and improve overall survival. Newer drugs that are effective treatments for multiple myeloma include Velcade® (bortezomib), Thalomid (thalidomide), and Revlimid® (lenalidomide). 6, 7, 8 Clinical trials are evaluating these drugs in combination with chemotherapy prior to ASCT.
Higher radiation dose-intensity: Since more treatment kills more cancer cells, increasing the intensity of treatment delivered to the myeloma cells can be accomplished by utilizing higher doses of anti-cancer therapies or by delivering more than one cycle of high-dose treatment supported by stem cells. While increasing the intensity of treatment may kill more myeloma cells, this approach may also damage normal cells and increase the number of side effects. Approaches for increasing the dose of drugs or radiation that can be delivered without increasing side effects include the following:
Minimal residual disease: Unfortunately, many patients whose cancer goes into remission following treatment still experience a relapse of their cancer. This is because not all of the cancer cells were destroyed with treatment, leaving some “minimal residual disease”. Many doctors believe that applying additional cancer treatments when only a few cancer cells remain represents the best opportunity to prevent the cancer from returning.
Intron®A (interferon) has long been used to prevent disease progression or relapses after autologous transplantation and is currently being analyzed in a large randomized trial. Researchers from the European Bone Marrow Transplant Group have found evidence indicating that administration of alfa interferon after an autologous stem cell transplant delayed recurrences and improved overall survival and was most effective in patients who did not achieve a complete remission to transplantation. 10
Maintenance chemotherapy: The administration of relatively low doses of chemotherapeutic drugs after an ASCT could delay time to cancer progression or prevent relapses. New drugs are constantly being evaluated in the conventional treatment of patients with multiple myeloma and could be used after high-dose chemotherapy with autologous stem cell support. Candidate drugs for maintenance therapy include Velcade, Thalomid, and Revlimid.
Vaccines: Vaccines are being actively investigated. One study from Italy has reported prolongation of time to relapse by the administration of an idiotype vaccine. 11 They also reported that immune response lasted up to 2 years. While research continues to evaluate the viability of vaccines, 12 this therapy is currently limited by the fact that a unique vaccine has to be developed for each specific patient.
Cell processing: When stem cells are collected from a patient for infusion after high-dose chemotherapy, cancer cells may also be present among the collected cells. Although the majority of cancer relapses after high-dose chemotherapy and ASCT occur because the high-dose chemotherapy did not kill all of the cancer cells in the patient, it is possible that some patients may also relapse from infusion of cancer cells with their stem cells. Many techniques are being evaluated that effectively remove cancer cells from the stem cell collection. It is currently unknown whether enough cancer cells can be removed to decrease relapse rates.
However, treatment of patients with multiple myeloma with only the “pure” stem cells—those that were selected and removed from the stored stem cell material–did not result in fewer cancer recurrences. In addition, this procedure was associated with increased infections because immune cells were also left behind in the selection process and not infused with the “pure” stem cells. 13
This study supports the theory that the major cause of relapse is cancer cells that remain in the patient after treatment, rather than cancer cells that are reinfused. Post-transplant treatments should be more effective than attempts to manipulate the graft.
To learn more about techniques for removing cancer cells from the stem cell product, select Autologous Stem Cell Collection and Processing.
Predicting which patients should undergo transplantation: There has been much progress in predicting which patients are likely to respond to current treatments and which are not. For example, researchers at the University of Arkansas have reported that they can use sophisticated tools that evaluate patients' genetics (cytogenetics and gene arrays) to predict which patients will respond to treatment. 14, 15 These tools may help doctors better predict which patients are likely to respond to conventional treatment and which might benefit more from alternative or more intensive therapies.
1 Attal M, Haroussseau JL, Stoppa AM, et al. A Prospective, Randomized Trial of Autologous Bone Marrow Transplantation and Chemotherapy in Multiple myeloma. Intergroupe Francais du Myelome. New England Journal of Medicine. 1996;335:91-97.
2 Moreau P, Facon T, Attal M, et al. Comparison of 200 mg/m2 Melphalan and 8 Gy Total Body Irradiation Plus 140 mg/m2 Melphalan as Conditioning Regimens for Peripheral Blood Stem Cell Transplantation in Patients with Newly Diagnosed Multiple myeloma: Final Analysis of the Intergroupe Francophone du Myelome 9502 Randomized Trial. Blood. 2002;99:731-735.
3 Weaver CH, Zhen B, Schwartzberg LS, et al. Phase I-II Evaluation of Rapid Sequence Tandem High-Dose Melphalan with Peripheral Blood Stem Cell Support in Patients with Multiple Myeloma. Bone Marrow Transplantation. 1998;22:245-251. Attal M, Haroussear J-L,
4 Facon t, et al. Single Versus Double Autologous Transplantation for Multiple Myeloma. The New England Journal of Medicine. 2003;349:2495-2502.
5 Fermand J-P, Ravaud P, Chevret S, et al. High-Dose Therapy and Autologous Peripheral Blood Stem Cell Transplantation: UP-Front or Rescue Treatments? Results of a Multicenter Sequential Randomized Trial. Blood. 1998;92:3131-3136.
6 Rajkumar, S, Hayman S, Gertz MA, et al. Combination Therapy with Thalidomide plus Dexamethasone for Newly Diagnosed Myeloma. Journal of Clinical Oncology. 2002;20:4319-4323.
7 Agrawal NR, Hussein MA, Elson P, et al. Pegalated Doxorubicin (D), Vincristine (V), and Reduced Frequency Dexamethasone (D) and Thalidomide (T) (Dv-T) in Newly Diagnosed (Nmm) and Relapsed/Refractory (Rmm) Multiple myeloma Patients. Proceedings of the 45th Annual Meeting of the American Society of Hematology. 2003;102:237a, Abstract #831.
8 Richardson P, Barlogie B, Berenson J, et al. A Phase II Multicenter Study of the Proteasome Inhibitor Bortezomib (Velcade™) Formerly PS-341 in Multiple myeloma Patients (Pts) with Relapsed/Refractory Disease. Proceedings of the 2002 Meeting of the American Society of Hematology. Blood. 2002;100:101a. Abstract 385.
9 Giralt S, Bensinger W, Goodman M, et al. 166Ho-DOTMP plus Melphalan Followed by Peripheral Blood Stem Cell Transplantation in Patients with Multiple Myeloma: Results of Two Phase ½ Trials. Blood. 2003;102:2684-2691.
10 Bjorkstrand B, Svensson H, Goldschmidt H, et al. Alfa-Interferon Maintenance Treatment is Associated with Improved Survival After High-Dose Treatment and Autologous Stem Cell Transplantation in Patients with Multiple myeloma: A Retrospective Registry Study from the European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplantation. 2001;27:511-515.
11 Long-Term Follow-Up of Idiotype Vaccination in Human Myeloma as a Maintenance Therapy after High-Dose Chemotherapy. Leukemia. 2004;18:139-145.
12 Curti A, Cellini C, Terragna C, et al. Phase I-II Trial of Anti-Cancer Vaccination for Multiple myeloma Patients Using Dendritic Cells Pulsed with Tumor Idiotype (Id) or Id (VDJ)-Derived Peptides. Proceedings of the 45th annual meeting of the American Society of Hematology. Blood. 2003;102:686a, abstract number 2539
13 Bourhis JS, Bouko Y, Koscielny S, et al. CD34+ Selection of Autologous Transplants in Patients with Newly Diagnosed Myeloma: Final Report of an EBMT Phase III Randomized Trial. Bone Marrow Transplantation. Blood. 2003;31, supl 1, abstract 0136:S8
14 Barlogie B, Shaughmessey JD. Early Results of Total Therapy II in Multiple myeloma: Implications of Cytogenetics and FISH. International Journal of Hematology. 2002;76 Supplement. 1:337-339.
15 Shaughnessy J, Rasmussen E, Zhan F, et al. Gene Expression Profiling Can Be Used to Predict EFS in Myeloma Patients Treated with High Dose Therapy and Tandem Stem Cell Transplant. Proceedings of the 45th annual meeting of the American Society of Hematology. Blood. 2003;102:190a, abstract number 662.