Multicenter phase II, double-blind placebo-controlled trial of maintenance ixazomib after allogeneic transplantation for high-risk multiple myeloma: Results of the BMT CTN 1302 Trial

Background: The role of allogeneic hematopoietic cell transplantation (allo-HCT) followed by maintenance therapy in high-risk multiple myeloma remains controversial. We evaluated the efficacy of ixazomib maintenance therapy after a reduced-intensity allo-HCT from HLA-matched donors in patients with high-risk multiple myeloma.

Objectives: The primary endpoint for this study was progression-free survival (PFS) post-randomization, treated as a time to event. Secondary endpoints were grades 2-4 and 3-4 acute graft-versus-host-disease (GVHD), chronic GVHD, best response, disease progression, non-relapse mortality (NRM), overall survival (OS), toxicity, infection, and health-related quality of life (HRQOL).

Study design: In this phase 2, double-blinded, prospective multicenter trial, we randomized patients with high-risk multiple myeloma (poor-risk cytogenetics, plasma cell leukemia, or relapsing within 24 months after autologous transplant) to ixazomib (3 mg, days 1, 8, 15) or a placebo after allo-HCT. The conditioning regimen included fludarabine/melphalan/bortezomib with tacrolimus plus methotrexate for GVHD.

Results: Fifty-seven patients were enrolled. 52 (91.2%) received allo-HCT, and 43 (82.7%) were randomized to ixazomib vs. placebo. At 21-month post-randomization, ixazomib vs. placebo groups had similar PFS (55.3% vs. 59.1%, p=1.00) and OS (94.7% vs. 86.4%, p=0.17). Cumulative incidences of grade III-IV acute GVHD at 100 days (9.5% vs. 0%) and chronic GVHD at 12 months (68.6% vs. 63.6%) were similar. The secondary analysis showed that at 24 months post-allo-HCT, PFS and OS were 52% and 82%, respectively, with corresponding non-relapse mortality of 11.7%.

Conclusions: These results show the safety and durable disease control with allo-HCT in high-risk myeloma patients. We could not adequately assess the efficacy of ixazomib maintenance as the trial terminated early because of enrollment delays, but there was no signal of an impact on outcomes.

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