Blood and Marrow Clinical Trials Network (BMT CTN) Multicenter Phase II, Double-blind Placebo Controlled Trial of Maintenance Ixazomib After Allogeneic Hematopoietic Stem Cell Transplantation for High Risk Multiple Myeloma (1302)
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August 2015 – October 2020
Dataset(s) Last Updated
August 31, 2023
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To evaluate the efficacy of ixazomib maintenance therapy after reduced-intensity conditioning allogeneic stem-cell transplantation from HLA-matched donors in patients with high-risk multiple myeloma.
Multiple myeloma (MM) is considered incurable using conventional agents. High-dose chemotherapy with autologous hematopoietic cell transplantation (HCT) is considered the standard of care in transplant eligible patients. However, progression-free survival (PFS) remains at 40 to 50 months, even with lenalidomide maintenance. Myeloma patients with high-risk disease, commonly defined as the presence of high-risk cytogenetics or fluorescence in situ hybridization (FISH) findings such as 13q deletion by conventional cytogenetics, t(4;14), t(14;16), or del(17p), have much shorter PFS with inferior survival. While there is clinical data on proteasome inhibitors and immunomodulatory agents, there remains a significant unmet need to mitigate disease relapse and improve survival in high-risk patients.
The BMT CTN 1302 study was initiated to determine if the addition of bortezomib to the conditioning regimen would optimize the anti-myeloma effect of fludarabine/melphalan and if post-HCT maintenance with the oral proteasome inhibitor, ixazomib, would further reduce the risk of disease relapse.
Eligible patients were age 18 to 70 years with a 6/6 sibling donor matched for HLA-A, -B, and HLA-DRB1; or an 8/8 related (other than a sibling) or unrelated donor matched for HLA-A, -B. -C, and -DRB1.
Eligible disease conditions were (1) high-risk MM in partial response (PR) or better with no prior progression and ≤24 months from auto-HCT (single or planned tandem), or ≤24 months from initiation of systemic antimyeloma therapy with no auto-HCT; (2) high-risk MM in very good partial response (VGPR) or better with 1 prior progression occurring ≤24 months after autoHCT (single or planned tandem), or ≤24 months after initiation of systemic antimyeloma therapy with no auto-HCT; (3) standard-risk MM in VGPR or better with 1 prior progression occurring ≤24 months from auto-HCT (single or planned tandem): and (4) Plasma cell leukemia (PCL) in VGPR or better with no prior progression and ≤18 months after auto-HCT, or ≤18 months after initiation of systemic anti-PCL therapy with no auto-HCT. High-risk MM was defined as one or more of the following detected at any time prior to enrollment: deletion of chromosome 13 by conventional karyotyping, hypodiploidy, chromosome 1q amplification, 1p deletion, t(4;14), t(14;16), t(14;20), or deletion of chromosome 17p by FISH or conventional karyotyping, or high-risk criteria based on gene expression profiling (GEP).
Of the 52 enrolled patients who underwent alloHCT, 43 proceeded to randomization. 21 patients were randomized to the ixazomib arm, and 22 patients were randomized to the placebo maintenance arm.
BMT CTN 1302 was a randomized phase 2, double-blinded, multicenter trial. The conditioning regimen consisted of fludarabine 30 mg/m2i.v. (reduced to 24 mg/m2 for creatinine clearance 40 to 70 mL/minute) from day -6 to day -3, melphalan 70 mg/m2i.v. on days -4 and -3, and bortezomib 1.3 mg/m2i.v. on day -3. The initial patients also received bortezomib on days +1, +4, and +7 after transplantation, but this was discontinued with a protocol amendment because of toxicity concerns. GVHD prophylaxis was provided with a combination of tacrolimus and methotrexate. Between day +60 and day +120 post-allo-HCT, eligible patients were randomized to either ixazomib maintenance therapy or placebo. The starting dose of ixazomib was 3 mg orally once daily on days 1, 8, and 15 of a 28-day cycle. After 3 cycles, the dose was escalated to 4 mg/day. A total of 12 cycles was planned. Ixazomib dosage adjustments were made for toxicities.
The primary endpoint was PFS as a time to event endpoint from randomization. Secondary endpoints included GVHD, overall survival, toxicity, infection, and quality of life.
BMT CTN 1302 demonstrated the feasibility of Flu/Mel/Bort reduced-intensity conditioning (RIC) regimen followed by HLA-matched related or unrelated donor HCT without post-HCT bortezomib for high-risk MM. The study was limited by early closure, which diminished the power to detect differences between the two randomized arms.
Bashir Q, Nishihori T, Pasquini MC, et al. A Multicenter Phase II, Double-Blind, Placebo-Controlled Trial of Maintenance Ixazomib After Allogeneic Transplantation for High-Risk Multiple Myeloma: Results of the Blood and Marrow Transplant Clinical Trials Network 1302 Trial. Transplant Cell Ther. 2023;29(6):358.e1-358.e7. doi:10.1016/j.jtct.2022.07.007
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