Oral ixazomib, lenalidomide, and dexamethasone for MM

In April 2016, Philippe Moreau from the University Hospital Hôtel Dieu in Nantes, France, and colleagues, published their findings of the TOURMALINE MM-1 trial in the New England Journal of Medicine. This double-blind, phase III trial recruited 722 patients (from 147 sites in 26 countries, between August 2012 and May 2014) who had relapsed, refractory, or Relapsed and Refractory Multiple Myeloma (RRMM). Patients were randomly assigned into one of two treatment groups: ixazomib or placebo, on a background of a lenalidomide plus dexamethasone treatment regime. The primary endpoint was progression-free survival (PFS).

Key Findings:

• Treatment:
  • Patients were given oral ixazomib (4 mg) or placebo on days 1, 8 and 15 of a 28-day cycle
  • All patients received 25 mg of oral lenalidomide on days 1 to 21, and 40 mg of oral dexamethasone on days 1, 8, 15 and 22
  • Treatment was continued until disease progression or the development of unacceptable adverse effects (AE’s)
• Median follow-up (first analysis): ixazomib = 14.8 months, placebo = 14.7 months
• Events of disease progression or death: ixazomib = 129, placebo = 157
• Median PFS: ixazomib =20.6 months; placebo = 14.7 months; HR = 0.74 (95% CI, 0.59-0.94; P=0.01)
• This represents a 40% longer PFS with ixazomib vs placebo
• Median PFS by patient subgroup:
  • High-risk cytogenetic abnormalities: ixazomib (75 pts) = 21.4 months; placebo (62 pts) = 9.7 months (HR = 0.54; 95% CI, 0.32-0.92; P=0.02)
  • Patients with del(17p): ixazomib (36 pts) = 21.4 months; placebo (33 pts) = 9.7 months (HR = 0.60; 95% CI, 0.29-1.24)
  • Patients with t(4;14) without del(17p) or t(14:16): ixazomib (36 pts) = 18.5 months; placebo (25 pts) = 12 months (HR = 0.65; 95% CI, 0.25-1.66)
• ORR: ixazomib = 78.3%; placebo = 71.5% (P=0.04)
• CR = 48% and PR = 39%
• Median time to response: ixazomib = 1.1 months; placebo = 1.9 months
• Median duration of response: ixazomib = 20.5 months; placebo = 15.0 months
• Median follow-up = 23 months (at which point median OS had not been reached)
• Rate of death during study period: ixazomib = 4%; placebo = 6%
• Overall rate of serious adverse events (AEs): ixazomib = 47%; placebo = 49%
• Comparison of AEs:
  • AEs ≥ grade 3: ixazomib = 74%; placebo = 69%
  • Thrombocytopenia grade 3 or 4: ixazomib = 12% and 7%; placebo = 5% and 4%
  • Rash: ixazomib = 36%; placebo = 23%
  • Peripheral neuropathy: ixazomib = 27%; placebo = 22%
  • Most AEs were experienced within the first three months

In conclusion, treatment of patients with ixazomib on a background of a lenalidomide and low-dose dexamethasone regime, enabled a significantly longer PFS. In addition, there was a favourable safety profile and the added convenience of a completely oral regime, which allowed patient self-administration at home. The results of this study were used to drive approval of ixazomib by the EMA in 2016, and the results of the interim analysis were assessed as the key data leading to US FDA approval in 2015.