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Flavopiridol in patients with relapsed or refractory multiple myeloma: a phase 2 trial with clinical and

Angela Dispenzieri1, Morie A Gertz, Martha Q Lacy

  • 1Mayo Clinic Rochester, MN 55905, USA. angela@mayo.edu

Haematologica
|March 1, 2006
PubMed

Insights

Flavopiridol, a transcription inhibitor, showed limited efficacy in advanced myeloma patients. Despite laboratory cytotoxicity, in vivo treatment did not demonstrate significant anti-myeloma activity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Flavopiridol is a potent inhibitor of cyclin-dependent kinases and P-TEFb.
  • It exhibits anti-apoptotic and anti-angiogenic properties in preclinical models.
  • Malignant myeloma cells often rely on anti-apoptotic regulators for survival.

Purpose of the Study:

  • To evaluate the clinical activity of flavopiridol as a single agent in patients with advanced multiple myeloma.
  • To assess the in vivo effects of flavopiridol on myeloma cells, including modulation of key regulatory proteins.

Main Methods:

  • A phase I/II clinical trial involving 18 multiple myeloma patients treated with flavopiridol infusions.
  • Ex vivo treatment of patient myeloma cells to assess cytotoxicity.
  • Immunoblotting analysis to detect Mcl-1, Bcl-2, p53, cyclin D, phosphoRNA polymerase II, and phosphoSTAT 3.

Main Results:

  • Ex vivo flavopiridol induced cytotoxicity in myeloma cells, but required higher concentrations and longer exposure times than achievable in vivo.
  • In vivo administration of flavopiridol did not result in observable anti-myeloma activity.
  • No significant downregulation of Mcl-1 or upregulation of p53 was observed in vivo.

Conclusions:

  • Flavopiridol demonstrated disappointing clinical activity as a single agent in advanced multiple myeloma.
  • The pharmacokinetic and pharmacodynamic profile achieved in vivo limited its therapeutic potential.
  • Further investigation into combination therapies or alternative dosing strategies may be warranted.

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