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Study Finds Ixazomib Beneficial in MM Patients With High-Risk Cytogenic Traits


A recent study found that ixazomib was associated with better progression-free survival versus a placebo in multiple myeloma regardless of cytogenetic risk status.

For patients with multiple myeloma (MM), certain cytogenic abnormalities (CAs) are associated with worse prognosis, but treatment with proteasome inhibitors (PIs) such as ixazomib (Ninlaro, Takeda) seems to benefit patients even when high-risk CAs are present. A study published in Blood Cancer Journal found that regardless of cytogenetic status, ixazomib was associated with better progression-free survival (PFS) versus a placebo in MM patients.

In recent decades, treatments such as immunomodulatory imide drugs, anti-CD38 antibodies, and PIs have improved outcomes for patients with MM, but various prognostic factors impact survival. Cytogenetic risk is one factor with prognostic indications, with certain CAs noted in the International Myeloma Working Group (IMWG) 2016 definition of high-risk cytogenetics. Deletion of chromosome 17p (del[17p]); translocation between chromosomes 4 and 14 (t[4;14]); translocation between chromosomes 14 and 16 (t[14;16]); and amplification of 1q21 (amp1q21) and aside from amp1q21 are all CAs associated with poor prognosis.

Prior phase 3 studies of ixazomib within a combination regimen or alone versus a placebo in MM, have found ixazomib, an oral PI, to benefit patients with high-risk CAs. The new study aimed to assess the PFS benefit of ixazomib versus a placebo in patients with CAs that are considered high-risk.

A total of 2247 patients were included in the study. Data from the TOURMALINE-MM1 and TOURMALINE-MM2 studies included results of ixazomib plus lenalidomide-dexamethasone (Rd) versus placebo-Rd. The TOURMALINE-MM3 and TOURMALINE-MM4 studies examined ixazomib versus a placebo. Patients in the pooled analysis were stratified by the presence of CAs.

The pooled median follow-up was 25.6 months, and the hazard ratio (HR) for PFS with ixazomib versus the placebo regimens in high-risk patients was 0.74 (median PFS [mPFS] of 17.8 versus 13.2 months), and 0.70 (mPFS of 26.3 versus 17.6 months) in patients without high-risk CAs. High-risk was defined as having del(17p) and/or t(4;14) and/or t(14;16).

Individuals who had 1 or more high-risk CA and/or amp1q21 were considered “expanded high-risk” patients. In expanded-risk patients, the HR was 0.75 (mPFS of 18.1 versus 14.1 months), and the HR was 0.71 (mPFS of 36.1 versus 21.4 months) in standard-risk patients.

In patients with t(4;14), the hazard ratio on ixazomib versus placebo was 0.68 (mPFS of 22.4 vs 13.2 months). The HR for patients with amp1q21 was 0.77 (mPFS of 18.8 vs 14.5 months). The results suggest that ixazomib may provide greater PFS benefits for patients with these cytogenetic traits.

Overall, ixazomib was beneficial regardless of CA status in the pooled analysis, and the PFS benefits were similar regardless of cytogenetic risk factors in this cohort. These data are in line with previous findings.

Still, the study authors suggest prioritizing individual patient characteristics and responses to therapy during treatment for MM.

“Although identification of certain cytogenetic abnormalities has guided stratification of high-risk patients and helped to characterize prognosis, not all patients with high-risk cytogenetic abnormalities exhibit the same response to therapy, and the efficacy of available treatment options varies according to the presence of particular cytogenetic abnormalities,” the authors wrote. “Accordingly, treatment decisions should be based on individual cytogenetic data.”


Chng WJ, Lonial S, Morgan GJ, et al. A pooled analysis of outcomes according to cytogenetic abnormalities in patients receiving ixazomib- vs placebo-based therapy for multiple myeloma. Blood Cancer J. Published online January 12, 2023. doi:10.1038/s41408-022-00768-5

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