Objectives

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol # 0102 trial compared progression-free survival of patients with multiple myeloma biologically assigned to receive autologous hematopoietic cell transplantation (autoHCT) followed either a second auto HCT or by allogeneic transplantation (alloHCT). Patients within the tandem autologous transplantation (auto-auto) arm were randomized to receive one years of maintenance therapy with thalidomide plus dexamethasone (Thal-Dex) or observation (Obs).

Background

High-dose chemotherapy with autologous hematopoietic cell transplantation (autoHCT) improves survival in multiple myeloma patients younger than 65 years compared to conventional chemotherapy. However, despite high remission rates and improved survival, there is continued risk of disease progression after a single or tandem autoHCT even in patients with “standard risk” myeloma. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0102 trial investigated several options to improve upon these results, including tandem autoHCT (auto-auto), post-transplant maintenance strategies, and allogeneic HCT (alloHCT). Preliminary studies suggested that planned sequential autoHCT improves responses and survival outcomes compared to single autoHCT. Furthermore, it was thought that maintenance therapy with thalidomide and corticosteroids after autoHCT further prolongs progression-free and overall survival.

AlloHCT, which provides a tumor-free graft, is an attractive alternative treatment approach as it offers potential additional disease control through a graft-versus-myeloma effect (GVM). Early studies of alloHCT with myeloablative conditioning regimens demonstrated a higher frequency of molecular remissions and lower rates of relapse compared to autoHCT, but overall benefits were offset by high treatment-related mortality (TRM). Nonmyeloablative conditioning regimens on the other hand, are designed more for immunosuppression than cytoreduction. Furthermore, when used after an autoHCT for cytoreduction, AlloHCT with nonmyeloablative conditioning adds a potential for GVM with lower TRM.

Participants

Patients were eligible for the trial if they were 70 years old or less, had Karnofsky scores of at least 70%, met Durie and Salmon criteria for diagnosis of multiple myeloma, had symptomatic multiple myeloma with no disease progression after the start of initial therapy, had received at least three cycles of systemic therapy, and were within 2-10 months of the start of the initial therapy. Patients must have had adequate organ function as measured by serum bilirubin less than two times the upper limits of normal, liver transaminases less than three upper limits of normal, left ventricular ejection fraction greater than 40%, and creatinine clearance greater than 40ml/min. Patients must have had an autograft of at least 4.0 x 106 CD34+ cells/kg patient weight unless it was known prior to enrollment that they would receive an allogeneic transplant after their initial autologous transplant. Patients with a consenting, eligible HLA-matched sibling must have had an autograft of at least 2.0 x 106 CD34+ cells/kg patient weight. A total of 710 patients were enrolled after completion of initial therapy.

Design

Eligible patients were assigned to the auto-allo treatment arm if an HLA-matched sibling donor was identified. Treatment assignment occurred when donor availability status was confirmed. Those without a suitable sibling donor were assigned to the auto-auto arm and randomized to receive one year of maintenance therapy with thalidomide plus dexamethasone (Thal-Dex) or observation. Randomization to Thal-Dex or observation was performed using a permuted block in a 1:1 fashion at the time of biological assignment. Patients were classified as having standard risk disease after enrollment if their serum β-2 microglobulin was less than 4.0 mg/L and no deletion of chromosome 13 was detected by metaphase karyotyping. Comparison of auto-allo and auto-auto in standard risk patients was the primary objective of the study.

Enrolled patients received melphalan 200mg/m2 (Mel200) followed by autologous peripheral blood stem cell (PBSC) infusion 48 hours later. The day of first autoHCT was designated as day 0. Filgrastim was started at day 5 and continued until neutrophil recovery. Recovery from autografting was defined as hematopoietic recovery, no active infections, resolution of mucositis and gastrointestinal symptoms, and being off hyperalimentation and intravenous hydration. Once recovered, and at least 60 days after the first autoHCT, patients received a second HCT, according to treatment arm.

Those assigned to auto-allo received 200 cGy of total body irradiation in a single fraction followed by allogeneic PBSC infusion. The target cell dose for allografts was 2.0 × 106 CD34+ cells/kg. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mycophenolate mofetil (MMF). MMF was discontinued on day 28 after alloHCT. In patients without active GVHD, cyclosporine was tapered starting at day 84. Chimerism and engraftment analyses were performed.

Patients without an HLA-matched sibling donor received a second autoHCT with Mel200 conditioning. Stem cell infusion was the same as with the first autoHCT. For patients randomized to Thal-Dex, thalidomide (200 mg/day) and dexamethasone (40 mg/day for 4 consecutive days, once a month) orally was started at least 60 days after the second HCT, with a goal of one year of therapy.

The primary endpoint was three-year progression-free survival in patients with standard risk disease, defined as time from the first auto-HCT to disease relapse or progression, initiation of non-protocol anti-myeloma therapy, or death, with patients censored at time of last contact. Secondary endpoints were overall survival, incidence of disease relapse or progression, treatment-related mortality, disease response, and incidence of grade 3–5 adverse events.

Conclusions

Thal-Dex maintenance was associated with poor compliance and did not improve progression-free or overall survival. At three years there was no improvement in progression-free or overall survival with auto-allo compared to auto-auto transplantation in patients with standard risk myeloma.

Lancet Oncol. 2011 Dec; 12(13): 1195–1203.

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