Relapsed/refractory patients

Panobinostat as a maintenance treatment for MM: results from the MUK six trial

Panobinostat (pan) is an oral deacetylase inhibitor which is used, in combination with bortezomib (bor) and dexamethasone (dexa), for treating relapsed or relapsed/refractory multiple myeloma (RRMM) after 1–4 lines of treatment.

The Myeloma UK (MUK) six clinical trial, a phase I/II trial, examined the efficacy of pan therapy, in combination with bor, thalidomide (thal) and dex, for relapsed or RRMM patients (pts), followed by maintenance treatment with pan. The primary end points of the study were the number and types of dose limiting toxicities and the proportion of participants achieving at least a partial response. Secondary endpoints included safety and toxicity of the trial. These results have been published previously1.

Rakesh Popat, from the NIHR/UCLH Clinical Research Facility, University College London Hospitals, London, UK, and collaborators, followed-up on the progression-free survival (PFS), overall survival (OS), and benefits of maintenance treatment with pan. These results were published in the British Journal of Heamatology in August 20182.

Study Design:
  • 21-day cycle
  • Number of cycles = 16
  • Bor = 1.3 mg/m2 (on days 1 and 8 of the cycle)
  • Thal = 100 mg/day or 50 mg/day, in case of peripheral neuropathy
  • Dex = 20 mg (on days 1, 2, 8 and 9 of the cycle)
  • Pan = 10 mg, 15 mg or 20 mg (on days 1, 3, 5, 8, 10 and 12 of the cycle)
  • Number of pts treated with 20 mg pan = 46
  • Pan maintenance = 1 year duration for pts completing 16 cycles of treatment
Key Data:
  • Median overall PFS = 16.1 months (95% confidence interval [CI], 13.40–21.55)
  • 24/46 pts came off study to receive an autologous stem cell transplant (ASCT); median PFS = 29.4 months (95% CI, 18.73–37.65)
  • 22/46 pts continued therapy; median PFS = 15.11 months (95% CI, 7–20.47)
  • Median OS = not reached
  • Estimated 2-year OS = 71.4% (95% CI, 47.2%–86%) (for pts who continued therapy, n= 22)
  • Number of pts completing 16 cycles of treatment = 20
  • Number of pts receiving pan maintenance = 15/20
  • 5/20 pts did not receive pan maintenance: 3 received an ASCT; 2 had prior toxicity to pan
  • Dose of pan maintenance = 12/15 pts received 20 mg; 3/15 received 15 mg due to reductions in the initial therapy
  • Median time pts remained in pan maintenance = 7.5 cycles (range, 3–18)
    • 5 pts completed the full year of maintenance treatment: 3/5 maintained their response; 2/5 showed disease progression at the end of the year
    • 9 pts stopped early due to disease progression
    • 1 pt withdrew due to toxicity
  • No pts deepened their response on treatment
  • Median PFS for pts that received maintenance = 17.9 months (95% CI, 13.4–21.5)
  • Serious adverse events (AEs) during maintenance = none
  • AEs during maintenance = diarrhea (grade 1, 3/15; grade 3, 2/15); anorexia (grade 1, 4/15); infection (grade 1, 3/15; grade 2, 1/15)
Conclusions

The follow-up of the MUK six clinical trial showed that 11/15 pts developed myeloma while on pan maintenance treatment. Although the results are limited to a small number of pts, they do not support the clinical benefit of pan as maintenance treatment.

 References
  1. Popat R. et al. Bortezomib, thalidomide, dexamethasone, and panobinostat for patients with relapsed multiple myeloma (MUK-six): a multicentre, open-label, phase 1/2 trial. Lancet Heamatology. 2016 Dec 3(12):e572-e580. DOI: 10.1016/S2352-3026(16)30165-X.
  2. Popat R. et al. Extended follow-up and the feasibility of Panobinostat maintenance for patients with Relapsed Multiple Myeloma treated with Bortezomib, Thalidomide, Dexamethasone plus Panobinostat (MUK six open label, multi-centre phase I/II Clinical Trial). British Journal of Haematology. 2018 Aug 20. DOI: 10.1111/bjh.15551. [Epub ahead of print].
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