Editorial
1.
Introduction
2.
Evidence in favor of ASCT
3.
Questions for the future
Autologous stem cell transplantation in multiple myeloma is not dead but alive and well Massimo Martino† & Fortunato Morabito †
Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by Nyu Medical Center on 06/10/15 For personal use only.
Hematology and Stem Cell Transplant Unit, Azienda Ospedaliera BMM, Reggio Calabria, Italy
In multiple myeloma (MM), the use of high-dose chemotherapy with autologous stem cell transplantation (ASCT) led to incremental advances in patient management in the 1990s. The clinical results for patients dramatically improved further in the 2000s with the introduction of immunomodulatory drugs and proteasome inhibitors. In the ‘modern’ era for MM treatment, transplant trials strongly support the use of upfront ASCT in the context of novel agents, and until proven otherwise, the old ASCT remains the standard of care for eligible patients. Nevertheless, some issues remain unresolved and this editorial aims to highlight the concerns to be addressed in the future. Keywords: autologous stem cell transplantation, high-dose melphalan, immunomodulatory drugs, multiple myeloma, new drugs, proteasome inhibitors Expert Opin. Biol. Ther. (2015) 15(2):149-154
1.
Introduction
From the history of multiple myeloma (MM), we have learned that among the multiple combinations of chemotherapy available until 1996, only melphalan and prednisone could improve the overall survival (OS) of patients. In that year, a French group [1] identified ‘something’ that could make a difference in the treatment and survival and that ‘something’ was high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT). In the 2000s, a dramatic increase in improvement rates was observed with the advent of immunomodulatory drugs (IMiDs) and proteasome inhibitors, and if this trend continues, the 5-year survival for a patient diagnosed in 2014 should be ~ 66% [2].The 2010s are characterized by studying the optimal combination, sequence and duration of therapies; however, the specific role and timing for ASCT has not been established with modern induction regimens. In the scientific community, there has been much debate on whether to withdraw the procedure, but we believe that ASCT in MM is not dead but alive and well. 2.
Evidence in favor of ASCT
Before the use of the new drugs in induction therapy, the complete remission (CR) rate did not exceed 10%. In this scenario, the rationale for proceeding to HDC with ASCT was to increase the depth of response. Over the past decade, this approach has been considered the standard of care for eligible patients with newly diagnosed MM, based on increased rate of CR, prolonged disease-free (DFS) [1,3-7] and OS [1,4],compared with conventional chemotherapy (CC). The major limitation to these studies is that all randomized trials of ASCT after induction therapy were designed and implemented before the availability of novel agents, but we believe that the role of transplantation is equally as strong in the ‘modern era’ (Table 1). 10.1517/14712598.2015.988611 © 2015 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted
149
Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by Nyu Medical Center on 06/10/15 For personal use only.
M. Martino & F. Morabito
The results of the Phase III PETHEMA trial [8] support the use of upfront ASCT in the context of novel drugs. In this study, the response rates were evaluated after induction therapy and after ASCT. The CR rates increased from 35% pretransplant to 57% post-transplant, in the group treated with bortezomib/thalidomide/dexamethasone (VTD) as induction therapy and from 14 to 40% in the group treated with thalidomide/dexamethasone (TD). Recently, Palumbo et al. [9]. published results of a randomized, Phase III study comparing melphalan 200 mg/mq (HDM) plus ASCT with melphalan--prednisone--lenalidomide (MPR). Both progression-free survival (PFS) and OS were significantly longer with HDM plus ASCT than with MPR (median PFS: 43.0 vs 22.4 months; hazard ratio [HR] for progression or death = 0.44; 95% CI: 0.32 -- 0.61; p
1.
Introduction
2.
Evidence in favor of ASCT
3.
Questions for the future
Autologous stem cell transplantation in multiple myeloma is not dead but alive and well Massimo Martino† & Fortunato Morabito †
Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by Nyu Medical Center on 06/10/15 For personal use only.
Hematology and Stem Cell Transplant Unit, Azienda Ospedaliera BMM, Reggio Calabria, Italy
In multiple myeloma (MM), the use of high-dose chemotherapy with autologous stem cell transplantation (ASCT) led to incremental advances in patient management in the 1990s. The clinical results for patients dramatically improved further in the 2000s with the introduction of immunomodulatory drugs and proteasome inhibitors. In the ‘modern’ era for MM treatment, transplant trials strongly support the use of upfront ASCT in the context of novel agents, and until proven otherwise, the old ASCT remains the standard of care for eligible patients. Nevertheless, some issues remain unresolved and this editorial aims to highlight the concerns to be addressed in the future. Keywords: autologous stem cell transplantation, high-dose melphalan, immunomodulatory drugs, multiple myeloma, new drugs, proteasome inhibitors Expert Opin. Biol. Ther. (2015) 15(2):149-154
1.
Introduction
From the history of multiple myeloma (MM), we have learned that among the multiple combinations of chemotherapy available until 1996, only melphalan and prednisone could improve the overall survival (OS) of patients. In that year, a French group [1] identified ‘something’ that could make a difference in the treatment and survival and that ‘something’ was high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT). In the 2000s, a dramatic increase in improvement rates was observed with the advent of immunomodulatory drugs (IMiDs) and proteasome inhibitors, and if this trend continues, the 5-year survival for a patient diagnosed in 2014 should be ~ 66% [2].The 2010s are characterized by studying the optimal combination, sequence and duration of therapies; however, the specific role and timing for ASCT has not been established with modern induction regimens. In the scientific community, there has been much debate on whether to withdraw the procedure, but we believe that ASCT in MM is not dead but alive and well. 2.
Evidence in favor of ASCT
Before the use of the new drugs in induction therapy, the complete remission (CR) rate did not exceed 10%. In this scenario, the rationale for proceeding to HDC with ASCT was to increase the depth of response. Over the past decade, this approach has been considered the standard of care for eligible patients with newly diagnosed MM, based on increased rate of CR, prolonged disease-free (DFS) [1,3-7] and OS [1,4],compared with conventional chemotherapy (CC). The major limitation to these studies is that all randomized trials of ASCT after induction therapy were designed and implemented before the availability of novel agents, but we believe that the role of transplantation is equally as strong in the ‘modern era’ (Table 1). 10.1517/14712598.2015.988611 © 2015 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted
149
Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by Nyu Medical Center on 06/10/15 For personal use only.
M. Martino & F. Morabito
The results of the Phase III PETHEMA trial [8] support the use of upfront ASCT in the context of novel drugs. In this study, the response rates were evaluated after induction therapy and after ASCT. The CR rates increased from 35% pretransplant to 57% post-transplant, in the group treated with bortezomib/thalidomide/dexamethasone (VTD) as induction therapy and from 14 to 40% in the group treated with thalidomide/dexamethasone (TD). Recently, Palumbo et al. [9]. published results of a randomized, Phase III study comparing melphalan 200 mg/mq (HDM) plus ASCT with melphalan--prednisone--lenalidomide (MPR). Both progression-free survival (PFS) and OS were significantly longer with HDM plus ASCT than with MPR (median PFS: 43.0 vs 22.4 months; hazard ratio [HR] for progression or death = 0.44; 95% CI: 0.32 -- 0.61; p
