Objectives

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.

Background

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.

Participants

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.

Design

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.

Conclusions

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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