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A triplet regimen that includes ixazomib twice a week for newly diagnosed multiple myeloma

Aug 9, 2018

Triplet regimens, especially the ones that include a proteasome inhibitor (PI) and an immunomodulatory agent are proven very effective for treating multiple myeloma (MM) patients (pts). Ixazomib (ixa) is an oral PI that has been approved by the US Food and Drug Administration(FDA) and the European Medicines Agency(EMA), in combination with lenalidomide (len) and dexamethasone (dex) for the treatment of MM pts who have received at least one prior treatment.

The same triplet combination (isa, len and dex) has also been used to treat newly diagnosed MM (NDMM) pts in the clinical trialsetting, using a single dose of ixa once a week for 12 cycles (28 days per cycle), followed by maintenance treatment with ixa until disease progression. Results from this study showed high overall response rate (ORR) at 92% and very good partial response (VGPR) at 58%.

Paul Richardsonfrom the Dana Farber Cancer Institute, Boston, US, and colleagues assessed the twice per week use of ixazomib (ixa) in combination with lenalidomide (len) and dexamethasone (dex), as front line treatment in NDMM pts in a phase I/II clinical trial. The phase I primary objectives were to determine the safety, tolerability, maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the regimen. The phase II primary objectives were to determine the combined rate of complete response (CR) plus VGPR, and to further evaluate tolerability and toxicity. The results of this study were published in the British Journal of Heamatologyin July 2018.

Study Design:

  • Number of pts = 64 (phase I, n = 14; phase II, n = 50)
  • Number of male/female = 40/24
  • Median age = 63.5 (range, 34-82)
  • 21-day cycle
  • Number of cycles = 16
  • Initial treatment: ixa = 3 or 3.7 mg (orally on days 1, 4, 8 and 11 of the cycle); len = 25 mg (orally on days 1-14 of the cycle); dex = 20 mg (10 mg in cycles 9-16) (orally on days 1, 2, 4, 5, 8, 9, 11 and 12 of the cycle)
  • Maintenance treatment = ixa, twice-weekly

Key Data:

  • On 18 October 2016 (time of data cut-off): 60 pts (94%) had discontinued treatment; n = 1 pt remained in phase I; n = 3 pts remained in phase II
  • RP2D = 3.0 mg
  • ORR = 94%; VGPR ≥ 68%; complete response (CR) = 24%
  • Median progression-free survival (PFS) = 24.9 months (95% confidence interval [CI], 17.4-40.5)
  • Median duration of response = 36.9 months
  • Median number of treatment cycles received = 9 (range, 1-75); 45 pts discontinued on or before cycle 16; 18 pts received maintenance therapy in cycle 17 and beyond
  • Reasons for treatment discontinuation: received autologous stem cell transplant (ASCT) = 31%; adverse events (AEs) = 20%; progressive disease = 20%; withdrawal of consent = 6%; unsatisfactory therapeutic response = 2%; other reasons = 14%
  • Grade 3 drug-related AEs = 64% of pts
  • Grade 3 AEs included: rash = 13%; peripheral neuropathy = 8%; hyperglycemia = 8%
  • Grade 4 drug-related AEs = none
  • New-onset drug-related AEs during ixa maintenance = 28% of pts (grade 3 AEs)
  • Number of deaths on study = one due to cardio-respiratory arrest


The use of ixa twice-weekly for treating NDMM pts, in combination with len and dex, showed promising outcomes, but also revealed higher toxicities than those observed when ixa was administered once per week. These regimen combinations may be appropriate for a subgroup of NDMM pts that have a better tolerance of higher concentrations of treatment agents.

  1. Richardson P.G. et al.Twice-weekly ixazomib in combination with lenalidomide-dexamethasone in patients with newly diagnosed multiple myeloma. British Journal of Haematology.2018 Jul;182(2):231-244. DOI: 10.1111/bjh.15394.