ArticlesAutologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial
Introduction
High-dose chemotherapy with autologous haemopoietic stem-cell transplantation (HSCT) improves survival compared with conventional chemotherapy in patients younger than 65 years with multiple myeloma.1, 2 However, despite high remission rates and improved survival, a continued risk of disease progression exists after one or two autologous HSCTs, even in patients with so-called standard-risk multiple myeloma (ie, absence of high-risk cytogenetic myeloma markers and β2-microglobulin <4·0 mg/L). Investigational strategies that might improve outcomes include tandem autologous HSCT, maintenance strategies after transplantation, and allogeneic HSCT.3, 4 Planned sequential autologous HSCT improves responses and survival outcomes compared with one-off autologous HSCT.5, 6, 7 Maintenance therapy with thalidomide and corticosteroids after autologous HSCT further prolongs progression-free survival (PFS) and overall survival.5, 8
Allogeneic HSCT, which provides a tumour-free graft, is an alternative treatment approach to autologous transplantation that could offer additional disease control through a graft-versus-myeloma effect. Early studies of allogeneic HSCT with myeloablative conditioning regimens reported an increased frequency of molecular remissions and lower rates of relapse compared with autologous HSCT, but overall benefits were offset by high treatment-related mortality.9, 10, 11, 12 Conversely, use of allogeneic HSCT with non-myeloablative conditioning regimens (which are designed more for immunosuppression than for cytoreduction) after autologous HSCT for cytoreduction might evoke a graft-versus-myeloma effect and reduce treatment-related mortality. A multicentre phase 2 clinical trial13 of this approach, which enrolled 54 patients, reported complete response (CR) in 57% of patients and a treatment-related mortality of 15%, which was much lower than that noted with allogeneic HSCT with myeloablative regimens. We aimed to assess a non-myeloablative allogeneic HSCT after autologous HSCT (auto-allo) approach for patients with multiple myeloma in a phase 3 trial with tandem autologous HSCT (auto-auto) as a control, which was chosen on the basis of data suggesting that such an approach had the best PFS of various transplant strategies and potentially offered an overall survival benefit.
Section snippets
Study design and patients
The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0102 trial was a phase 3 study undertaken at 37 transplant centres in the USA (see webappendix).14 Eligible patients were aged 70 years or younger, were without disease progression after start of initial therapy, and had serum bilirubin concentrations of less than two-times the upper limit of normal, liver aminotransferase concentrations of less than three-times the upper limit of normal, left ventricular ejection fractions of
Results
Between Dec 17, 2003, and March 30, 2007, we enrolled 710 patients with multiple myeloma who had completed initial antimyeloma therapy. The median follow-up was 40 months (IQR 38–43). No patient progressed or died before assignment to treatment groups. Figure 1 shows the trial profile, including treatment-group assignment and disease-risk classifications.
Table 1 shows demographic data for all patients. Patients in the auto-allo group were more likely to be white or younger than were those in
Discussion
In our trial of autologous HSCT followed by allogeneic HSCT with a non-myeloablative conditioning regimen in patients with standard-risk multiple myeloma, we did not show a benefit in 3 year PFS or overall survival compared with tandem autologous transplantation. We show indirect evidence of a graft-versus-myeloma effect with a 60% reduction in risk of relapse in patients diagnosed with chronic graft-versus-host disease. Treatment-related mortality was higher in the auto-allo group (11%) than
References (29)
- et al.
A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma
Blood
(2010) - et al.
Maintenance therapy with thalidomide improves survival in patients with multiple myeloma
Blood
(2006) - et al.
Allogeneic marrow transplantation for multiple myeloma: an analysis of risk factors on outcome
Blood
(1996) - et al.
Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma
Blood
(2003) - et al.
Blood and marrow transplant clinical trials network (BMT CTN): addressing unanswered questions
Biol Blood Marrow Transplant
(2007) - et al.
A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma
Blood
(2008) - et al.
Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma
Blood
(2006) - et al.
Low-dose thalidomide and donor lymphocyte infusion as adoptive immunotherapy after allogeneic stem cell transplantation in patients with multiple myeloma
Blood
(2004) - et al.
A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma
N Engl J Med
(1996) - et al.
High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma
N Engl J Med
(2003)
Single versus double autologous stem-cell transplantation for multiple myeloma
N Engl J Med
Long-term outcome results of the first tandem autotransplant trial for multiple myeloma
Br J Haematol
Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study
J Clin Oncol
Thalidomide and hematopoietic-cell transplantation for multiple myeloma
N Engl J Med
Cited by (249)
Long-Term Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Newly Diagnosed Multiple Myeloma
2023, Transplantation and Cellular TherapyCARTIFAN-1: Concerning fatal adverse events with global use of chimeric antigen receptor–T-cell therapy in multiple myeloma
2023, European Journal of CancerHematopoietic Cell Transplantation in Multiple Myeloma
2023, Manual of Hematopoietic Cell Transplantation and Cellular TherapiesChimeric Antigen Receptor T Cell Therapy versus Hematopoietic Stem Cell Transplantation: An Evolving Perspective
2022, Transplantation and Cellular TherapyLong-Term Follow-Up of Multiple Myeloma Patients Treated with Tandem Autologous Transplantation Following Melphalan and Upon Recovery, Total Marrow Irradiation
2022, Transplantation and Cellular TherapyCitation Excerpt :At a median follow-up of >10 years for live patients, 6-year PFS was 25% in the TASCT cohort versus 22% in the ASCT followed by allogeneic bone marrow transplantation cohort. OS was also similar in the 2 groups, at 60% versus 59% [31]. Toxicities were less severe with TMI than with melphalan.
- ‡
Authors contributed equally