Is there still a role for allogeneic stem-cell transplantation in multiple myeloma?

Abstract

Despite significant improvements in survival for multiple myeloma patients through autologous stem-cell transplantation (SCT) and the introduction of novel drugs, the disease remains incurable for all but a small fraction of patients. Only allogeneic SCT is potentially curative, due in part to a graft-versus-myeloma effect. High transplant-related mortality with allogeneic SCT is currently the major limitation to wider use of this potentially curative modality. Mortality can be reduced through the use of lower-intensity conditioning regimens which allow engraftment of allogeneic stem cells, but this comes at a cost of higher rates of disease progression and relapse. Promising studies to improve outcomes of allogeneic transplants include the use of more intensive nonmyeloablative conditioning regimens, tandem transplants, peripheral blood cells, graft engineering to improve the graft-versus-myeloma activity while reducing graft-versus-host disease (GVHD), post-transplant maintenance, and targeted conditioning therapies such as bone-seeking radioisotopes. Keywords multiple myeloma; allogeneic stem-cell transplantationThe treatment of multiple myeloma has dramatically improved in the last 10 years. Highdose therapy followed by autologous stem-cell support has emerged as a promising means for increasing remission rates and improving survival. As such, autologous stem-cell transplantation has become the standard of care for many patients with multiple myeloma. In addition, insights into the biology and genetics of myeloma cells have resulted in the rapid introduction of new drugs with unique mechanisms of action. These drugs -which include thalidomide, lenalidomide and bortezomib -have shown significant activity in multiple myeloma, and when these new agents are combined with more traditional drugs, the response and complete remission rates are as high as responses achieved with autologous stem-cell transplantation. [1,2] Despite these advances, long-term survival after treatment with stem-cell transplantation or the newly developed drugs is rare, and disease recurs in virtually all patients.Stem-cell transplantation from allogeneic donors may be curative for 10-20% of patients with chemotherapy-resistant, refractory hematologic malignancies, and for up to 80% of . E-mail address: wbensing@fhcrc.org. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. patients who are transplanted in remission. Much of the high response and curative potential of allografts is attributed to a 'graft-versus-tumor' effect. In patients with multiple myeloma this effect has been well documented...

Favorable long-term outcome of patients with multiple myeloma using a frontline tandem approach with autologous and non-myeloablative allogeneic transplantation

“…13,20,[28][29][30][31][32][33][34][35] GvHD incidences vary widely in these cohorts due to heterogeneity in conditioning regimens and prophylaxis used, notably whether anti-thymocyte globulin was administered or not. From these publications, the incidence of grades II-IV acute GvHD ranged from 25 to 58%, chronic GvHD from 7 to 70% and NRM from 0 to 41%.…”

A Randomized Phase II Trial of Fludarabine/Melphalan 100 versus Fludarabine/Melphalan 140 Followed by Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Multiple Myeloma

“…The curative potential of allogeneic hematopoietic stem cell transplantation (allo-HCT) in myeloma is attributed to the graft-versus-myeloma (GVM) effect mediated by the donor derived T lymphocytes 1, 2 . Although allo-HCT after myeloablative conditioning (MAC) may result in durable remission and long-term survival, the transplant-related mortality (TRM) of 30–50% neutralizes any potential benefit in terms of overall survival (OS) 3, 4 .…”

Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Relapsed Multiple Myeloma

“…Allogeneic hematopoietic stem cell transplantation (allo HCT) offers a potentially curative option in 10–20% of patients with relapsed or refractory disease 10–13 . A tumor-free graft and graft-versus-myeloma (GVM) effect are two major reasons for this curative potential.…”

“…A tumor-free graft and graft-versus-myeloma (GVM) effect are two major reasons for this curative potential. The GVM effect has been well documented and is thought to be mediated by donor-derived T lymphocytes 10–12 . However, the high treatment related mortality (TRM) of up to 55% with myeloablative (MA) conditioning regimen neutralizes any potential benefit in terms of progression free survival (PFS) and overall survival (OS), and limits the use of allo HCT in patients with advanced multiple myeloma 12, 14, 15 .…”