Tandem Autologous Hematopoietic Stem Cell Transplants (AuHCT) With or Without Maintenance Therapy (auto-auto) Versus Single AuHCT Followed by HLA Matched Sibling Non-Myeloablative Allogeneic HCT (auto-allo) for Patients With Standard Risk (SR) Multiple Myeloma (MM): Results From the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0102 Trial

Multiple myeloma is a form of blood cancer characterized by the overproduction of plasma cells in the bone marrow. Research has demonstrated that autologous stem cell transplantation, a procedure in which a patient is treated with high-dose chemotherapy followed by an infusion of his or her own stem cells, is associated with improved overall survival. However, relapse and progression of the disease still occur following this procedure.

Tandem autologous stem cell transplantation, a procedure in which a patient receives two sequential autologous stem cell transplants, may improve survival beyond that seen after a single transplant.

Additionally, donor (allogeneic) stem cell transplantation has potential for replacement of the malignant bone marrow with healthy donor cells as well as a potentially beneficial immune-mediated graft-versus-myeloma-effect. Past studies of allogeneic transplantation for multiple myeloma with full-intensity conditioning demonstrated long-term remission in a group of patients; however, side effects and mortality were high.

Non-myeloablative conditioning allogeneic stem cell transplantation (also known as a reduced-intensity transplant), in which a patient receives lower doses of chemotherapy or irradiation followed by an infusion of stem cells from a HLA-matched sibling, has been shown to reduce toxicity,while maintaining the beneficial immunologic effects of allogeneic transplantation.

The use of autologous followed by reduced-intensity allogeneic transplant has been shown to be feasible, and preliminary results suggest this approach may potentially be superior to tandem autologous transplant.

Researchers from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) sought to determine if a tandem autologous stem cell transplant (auto-auto) with or without maintenance therapy improves overall survival in patients with standard risk multiple myeloma as compared with a regimen of an autologous stem cell transplant followed by non-myeloablative allogeneic stem cell transplant (auto-allo). The BMT CTN is funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute of the National Institutes of Health and has the objective of conducting phase II and III clinical trials in transplantation in the United States. This large, multicenter phase III clinical trial (BMT CTM 0102) assigned 710 patients from 43 institutions to one of two treatment arms.

Patients without a matched sibling stem cell donor were enrolled in the auto-auto arm, in which a tandem autologous stem cell transplant was performed using a chemotherapy conditioning regimen of melphalan 200 mg/m2. Patients in this arm were further randomized to receive maintenance therapy of thalidomide and dexamethasone, which are active anti-myeloma drugs, or observation for one year.

Patients with a matched sibling stem cell donor were enrolled in the experimental arm, referred to as the auto-allo arm, in which patients underwent an autologous stem cell transplant using a chemotherapy conditioning regimen of melphalan 200 mg/m2 followed by an allogeneic stem cell transplant using a total body irradiation (2 Gy) conditioning regimen. All patients in the study received cyclosporine and mycophenolate mofetil for prevention of graft-versus-host disease. This is a common complication of bone marrow transplantation in which the transplanted donor cells attack the cells in the recipient's body. The primary endpoint of the study was three-year progression-free survival.

The study demonstrated that after three years of follow-up, progression-free survival was 46 percent for the standard auto-auto arm compared with 43 percent for the experimental auto-allo arm, demonstrating that the experimental auto-allo approach was not significantly better than the standard auto-auto approach. Overall survival was 80 percent and 77 percent for the auto-auto and auto-allo arms, respectively. The progression/relapse rates were 50 percent and 46 percent, and treatment-related mortality was 4 percent and 11 percent for the auto-auto arm and auto-allo arm, respectively. In those patients who received the assigned second transplant (82 percent in each arm), the three-year progression-free survival rate was 47 percent for the auto-auto arm and 44 percent for the auto-allo arm. Results of this study show that, in patients with standard risk multiple myeloma, an autologous stem cell transplant followed by reduced insensity allogeneic transplant did not differ from a tandem autologous stem cell transplant in terms of progression-free or overall survival.

The investigators reported that there was poor overall compliance with the maintenance therapy of thalidomide and dexamethasone in the auto-auto arm, with 84 percent of patients not completing the therapy due to overall poor tolerability of this regimen. Progression-free survival and overall survival between the maintenance and observation groups were not significantly different, perhaps due to the high rate of discontinuation of maintenance therapy.

"Research has shown that allogeneic stem cell transplantation can be a curative procedure for certain groups of patients with multiple myeloma; however, it can be associated with increased morbidity and mortality over autologous transplant. Therefore, it is still unknown if this procedure is better in some patients than in others or if it should be the standard of care for all myeloma patients," said lead study author Amrita Krishnan, MD, Director of the Multiple Myeloma Program at the City of Hope Cancer Center in Duarte, CA. "Our study addresses this unanswered question and shows that the toxicity of allogeneic transplantation outweighed the benefits of the reduced relapse risk in patients with standard-risk myeloma."


Source: ASH