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Evaluation of ixazomib, with cyclophosphamide and dexamethasone, for newly diagnosed multiple myeloma

The proteasome inhibitor (PI) bortezomib (bor) is a very effective treatment option for multiple myeloma (MM) patients (pts), especially when used in combination with an immunomodulatory drug or an alkylating agent. A recently approved PI, ixazomib (ixa), is administered orally, providing an advantage to the cumbersome intravenous or subcutaneous administration of bor. An additional advantage of ixa is that peripheral neuropathy is observed less frequently, compared to treatment with bor. Currently, ixa is approved in combination with lenalidomide (len) and dex for the treatment of MM in pts who have received at least one prior line of treatment.

Shaji K. Kumar from the Division of Hematology, Mayo Clinic, Rochester, US, and colleagues, examined the combination of ixa (in the form of ixa citrate), cyclophosphamide (cyclo) and dexamethasone (dex) in a phase I/II clinical trial for newly diagnosed MM (NDMM) patients (pts). The primary objective of the phase I study was to establish the maximum tolerated dose (MTD) of cyclophosphamide (cyclo) that can be used in this combination. The primary objective of the phase II study was to establish the complete response (CR) and very good partial response (VGPR) or better (≥) rates of the ixa/cyclo/dex combination in NDMM pts. Secondary objectives included an assessment of progression-free survival (PFS) and overall survival (OS) and incidence of adverse events. The results of the study were published in Blood Cancer Journal in August 2018.

Study Design:
  • Number of pts = 48 (phase II, n = 45)
  • Number of males = 25
  • Median age = 64.5 (range, 41-88)
  • 28-day cycle
  • Induction treatment: ixa = 4 mg (orally on days 1, 8 and 15 of the cycle); cyclo = 300 or 400 mg/m2 (orally on days 1, 8, 15 and 22 of the cycle) and dex = 40 mg (orally on days 1, 8, 15 and 22 of the cycle)
  • Number of induction cycles = up to 12
  • Maintenance treatment: ixa, orally on days 1, 8 and 15 of the cycle
Key Data:
  • On May 2017 (time of data cut-off): n =11 pts (23%) had progressed; n = 46 pts (96%) were alive; n= 8 pts remained on therapy
  • Median follow-up = 25.6 months (range, 12.3-44.6)
  • Reasons for treatment discontinuation: alternative treatment (including autologous stem cell transplant [ASCT]) = 19 pts (48%); disease progression = 10 pts (25%); withdraw consent = 3 pts (8%); adverse events (AEs) = 3 pts (8%); lack of adequate response by pre-specified time-point = 5 pts (10%)
  • MTD = 400 mg/m2 cyclophosphamide weekly
  • ≥ Partial response = 77% (95% confidence interval [CI], 63-88); ≥ VGPR = 35% (95% CI, 22-50)
  • Median time to response = 1.9 months (range, 0.9-4.8)
  • Response rate (at the end of four cycles) = 71%
  • Median PFS = not reached (NR) (95% CI, 31.3-NR)
  • 18-month PFS = 81% (95% CI, 70-94)
  • Median OS = NR
  • 18-month OS rate = 96% (95% CI, 90-100)
  • 12-month OS rate = 100%
  • Median number of cycles = 7 (range, 3-46)
  • Grade 3 or 4 drug-related AEs = 42 pts (88%)
  • Common AEs = Cytopenias, fatigue, gastrointestinal intolerance
  • Most frequent grade 3 AEs: Neutropenia, leukopenia, lymphopenia
  • Grade 4 AEs: Neutropenia and lymphopenia
  • Peripheral neuropathy: grade 1 = 23 pts; grade 2 = 5 pts; grade 3 or higher = 0 pts
  • Stem cell collection = 28 pts; 19/28 had an ASCT after a median of 5 cycles (range, 3-20)
  • Ixa pharmacokinetic profile is similar to that previously observed as a monotherapy or in combination with other agents

This phase I/II trial explores the combination of ixa/cyclo/dex as a possible treatment for NDMM pts, presenting promising early data. This regimen shows similar efficacy to that of bor/cyclo/dex but with lower toxicity and easier administration. In addition, it is more affordable than the ixa/len/dex combination, making it an attractive alternative as a first line treatment, especially for NDMM pts who are not eligible for ASCT.


Kumar S.K. et al. Phase 1/2 trial of ixazomib, cyclophosphamide and dexamethasone in patients with previously untreated symptomatic multiple myeloma. Blood Cancer Journal. 2018 Jul 30;8(8):70. DOI: 10.1038/s41408-018-0106-3.

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