Relapsed/refractory patients

Significant PFS benefit with ixazomib in all-oral regimen for high-risk RRMM patients

The phase III TOURMALINE-MM1 clinical trial evaluated the efficacy and safety of the oral proteasome inhibitor ixazomib in combination with lenalidomide-dexamethasone (IRd), in patients with relapsed, refractory, or Relapsed and Refractory Multiple Myeloma (RRMM) who had previously received 1–3 prior lines of therapy. The results of this study were previously reported on the MM Hub and were pivotal in driving approval of ixazomib in the US and EU. In a sub-group analysis, published in Blood in October 2017, the outcomes were assessed according to cytogenetic risk status. This analysis was conducted by Hervé Avet-Loiseau from the Cancer Research Center of Toulouse.

Study Design:
  • Patients (pts) enrolled = 722 adults: IRd = 360 and Placebo-Rd = 362
  • Pts received ixazomib 4 mg orally or matching placebo on days 1, 8, and 15 of 28-day cycles, together with lenalidomide 25 mg orally on days 1–21 and dexamethasone 40 mg orally on days 1, 8, 15, and 2
  • Standard-risk (SR) group (n= 415): IRd = 199 and Placebo-Rd = 216
  • Pts with cytogenetic abnormalities (n = 552) (76%): IRd = 274, Placebo-Rd = 278
    • High-risk (HR) group (del(17p), t(4,14), t(14,16)) n = 137; IRd = 7, Placebo-Rd = 62
    • Pts with 1q21 amplification, n = 172; IRd = 80, Placebo-Rd = 92
    • Expanded high-risk group with any of the assessed cytogenetic abnormalities del(17p), t(4,14), t(14,16), 1q21, n = 309
    • IRd = 155; Placebo-Rd = 154
Key Highlights:

All data is given as IRd vs placebo

  • The PFS benefit was significant in the standard-risk group:
    • Median PFS = 20.6 vs 15.6 mon; HR = 0.640; P < 0.007, (95% CI, 0.462%-0.888%)
    • Overall response rate (ORR) = 160 vs 158
  • IRd increased progression free survival (PFS) in high-risk patients with del(17p) or t(4,14) alone:
    • Median PFS = 21.4 vs 9.7 months; HR = 0.543; P < 0.021, (95% CI, 0.321%-0.918%)
    • ORR: 59 vs 37
  • IRd increased PFS in pts with 1q21 amplification: HR = 0.781, (95% CI, 0.492%-1.240%)
  • In the expanded high-risk group:
    • Median PFS = 17.5 vs 11.1 months; HR = 0.664; P = 0.16; (95% CI, 0.474%-0.928%)
    • ORR = 116 vs 100
Safety:
  • Any grade ≥ 3 adverse event (AE): High Risk = 49 vs 45, Standard Risk = 149 vs 140
  • Serious AE: High Risk = 31 vs 32, Standard Risk = 90 vs 101
Conclusion 

This study reported a 35% improvement in PFS with IRd when compared with placebo-Rd, with limited additional toxicity for second-line treatment of RRMM patients. Importantly, this PFS benefit was consistent across all sub-groups for high-risk cytogenetics and overcomes the poor prognosis associated with this status. This analysis builds on a previous sub-group assessment, which indicated that there was a PFS benefit regardless of the type and number of prior treatment – see previous MM Hub article. This, therefore, represents an effective treatment option for patients with RRMM, regardless of cytogenetics and prior treatment, with the added benefit of being an oral medication. The key limitations of this study the lack of data from the main study on the effects of IRd on OS.

References
  1. Avet-Loiseau H. et al. Ixazomib significantly prolongs progression-free survival in high-risk relapsed/refractory myeloma patients. Blood. 2017 Oct 20. DOI: 10.1182/blood-2017-06-791228. [Epub ahead of print]
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