A phase I/II study of ixazomib, pomalidomide, and dexamethasone for lenalidomide and proteasome inhibitor refractory multiple myeloma (Alliance A061202)

Am J Hematol. 2021 Dec 1;96(12):1595-1603. doi: 10.1002/ajh.26361. Epub 2021 Oct 6.

Abstract

Preclinical studies have demonstrated activity of the oral proteasome inhibitor (PI) ixazomib (IXA) in bortezomib-resistant multiple myeloma (MM) and synergy with immunomodulatory drugs. We therefore conducted a phase I/II study to establish the safety and preliminary efficacy of IXA with pomalidomide (POM) and dexamethasone (DEX) in lenalidomide (LEN)/PI-refractory MM. Dose escalation established a 4 mg dose of POM and IXA and 20/40 mg dose of DEX as the maximum tolerated dose. The phase II portion of the trial was redesigned and started anew after six patients had been randomized to IXA-POM-DEX due to a rapidly changing treatment landscape. Among the 29 evaluable LEN/PI-refractory patients treated with IXA-POM-DEX in phase I/II, the overall response rate (partial response or better) was 51.7% with a median duration of response of 16.8 months (range 56 days to 4.1 years), median progression-free survival of 4.4 months (95% confidence interval [CI]: 3.0-18.4), and median overall survival of 34.3 months (95% CI: 19.2 to not reached). Hematologic, gastrointestinal, and constitutional adverse events were common and consistent with the side-effect profiles of the individual agents. Our results support further evaluation of this all-oral regimen in relapsed/refractory MM.

Trial registration: ClinicalTrials.gov NCT02004275.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Boron Compounds / administration & dosage
  • Boron Compounds / adverse effects
  • Boron Compounds / therapeutic use*
  • Dexamethasone / administration & dosage
  • Dexamethasone / adverse effects
  • Dexamethasone / therapeutic use*
  • Drug Resistance, Neoplasm / drug effects
  • Female
  • Glycine / administration & dosage
  • Glycine / adverse effects
  • Glycine / analogs & derivatives*
  • Glycine / therapeutic use
  • Humans
  • Lenalidomide / administration & dosage
  • Lenalidomide / adverse effects
  • Lenalidomide / therapeutic use*
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Multiple Myeloma / drug therapy*
  • Proteasome Inhibitors / administration & dosage
  • Proteasome Inhibitors / adverse effects
  • Proteasome Inhibitors / therapeutic use*
  • Thalidomide / administration & dosage
  • Thalidomide / adverse effects
  • Thalidomide / analogs & derivatives*
  • Thalidomide / therapeutic use

Substances

  • Boron Compounds
  • Proteasome Inhibitors
  • Thalidomide
  • ixazomib
  • Dexamethasone
  • pomalidomide
  • Lenalidomide
  • Glycine

Associated data

  • ClinicalTrials.gov/NCT02004275