Elsevier

The Lancet Oncology

Volume 12, Issue 13, December 2011, Pages 1195-1203
The Lancet Oncology

Articles
Autologous 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

https://doi.org/10.1016/S1470-2045(11)70243-1Get rights and content

Summary

Background

Autologous haemopoietic stem-cell transplantation (HSCT) improves survival in patients with multiple myeloma, but disease progression remains an issue. Allogeneic HSCT might reduce disease progression, but can be associated with high treatment-related mortality. Thus, we aimed to assess effectiveness of allogeneic HSCT with non-myeloablative conditioning after autologous HSCT compared with tandem autologous HSCT.

Methods

In our phase 3 biological assignment trial, we enrolled patients with multiple myeloma attending 37 transplant centres in the USA. Patients (<70 years old) with adequate organ function who had completed at least three cycles of systemic antimyeloma therapy within the past 10 months were eligible for inclusion. We assigned patients to receive an autologous HSCT followed by an allogeneic HSCT (auto-allo group) or tandem autologous HSCTs (auto-auto group) on the basis of the availability of an HLA-matched sibling donor. Patients in the auto-auto group subsequently underwent a random allocation (1:1) to maintenance therapy (thalidomide plus dexamethasone) or observation. To avoid enrolment bias, we classified patients as standard risk or high risk on the basis of cytogenetics and β2-microglobulin concentrations. We used the Kaplan-Meier method to estimate differences in 3-year progression-free survival (PFS; primary endpoint) between patients with standard-risk disease in the auto-allo group and the best results from the auto-auto group (maintenance, observation, or pooled). This study is registered with ClinicalTrials.gov, number NCT00075829.

Findings

Between Dec 17, 2003, and March 30, 2007, we enrolled 710 patients, of whom 625 had standard-risk disease and received an autologous HSCT. 156 (83%) of 189 patients with standard-risk disease in the auto-allo group and 366 (84%) of 436 in the auto-auto group received a second transplant. 219 patients in the auto-auto group were randomly assigned to observation and 217 to receive maintenance treatment, of whom 168 (77%) completed this treatment. PFS and overall survival did not differ between maintenance and observation groups and pooled data were used. Kaplan-Meier estimates of 3-year PFS were 43% (95% CI 36–51) in the auto-allo group and 46% (42–51) in the auto-auto group (p=0·671); overall survival also did not differ at 3 years (77% [95% CI 72–84] vs 80% [77–84]; p=0·191). Within 3 years, 87 (46%) of 189 patients in the auto-allo group had grade 3–5 adverse events as did 185 (42%) of 436 patients in the auto-auto group. The adverse events that differed most between groups were hyperbilirubinaemia (21 [11%] patients in the auto-allo group vs 14 [3%] in the auto-auto group) and peripheral neuropathy (11 [6%] in the auto-allo group vs 52 [12%] in the auto-auto group).

Interpretation

Non-myeloablative allogeneic HSCT after autologous HSCT is not more effective than tandem autologous HSCT for patients with standard-risk multiple myeloma. Further enhancement of the graft versus myeloma effect and reduction in transplant-related mortality are needed to improve the allogeneic HSCT approach.

Funding

US National Heart, Lung, and Blood Institute and the National Cancer Institute.

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

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