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AT-101 Enhances the Antitumor Activity of Lenalidomide in Patients with Multiple Myeloma

Sikander Ailawadhi1,2, Ricardo D Parrondo1, Navnita Dutta2

  • 1Deparment of Hematology-Oncology, Mayo Clinic Florida, 4500 San Pablo Road S, Jacksonville, FL 32224, USA.

Cancers
|January 21, 2023
PubMed

Insights

The novel ARd regimen, combining AT-101 with lenalidomide and dexamethasone, shows promise for multiple myeloma (MM). This combination therapy demonstrated significant efficacy and an acceptable safety profile in relapsed/refractory MM patients.

Area of Science:

  • Hematology
  • Oncology
  • Pharmacology

Background:

  • Bcl-2 and Mcl-1 proteins are crucial for multiple myeloma (MM) cell survival.
  • Targeted inhibitors disrupting these proteins are under development for MM treatment.
  • AT-101 is an oral drug designed to inhibit Bcl-2 and Mcl-1, impacting mitochondrial function and inducing apoptosis in MM cells.

Purpose of the Study:

  • To establish the effective dose of AT-101 in combination with lenalidomide and dexamethasone (ARd regimen).
  • To evaluate the safety and efficacy of the ARd regimen in patients with relapsed/refractory multiple myeloma.

Main Methods:

  • A Phase I/II clinical study was conducted enrolling 10 patients with relapsed/refractory MM.
  • Patients received the ARd combination regimen.
  • Tumor burden, response rates, progression-free survival, and safety profiles were assessed.

Main Results:

  • The ARd combination was well tolerated, with cytopenias as the most common grade 3/4 adverse events.
  • An overall response rate of 40% and a clinical benefit rate of 90% were observed.
  • Median progression-free survival was 14.9 months, with promising biomarker changes in responsive patients.

Conclusions:

  • The ARd regimen exhibits an acceptable safety profile and promising efficacy in relapsed/refractory multiple myeloma.
  • Biomarker analysis indicated a decrease in Bcl-2:Bim and Mcl-1:Noxa complexes and modulation of immune cells in responsive patients.
  • Further investigation of the ARd regimen in a larger patient cohort is warranted.
Keywords:
Bcl-2 inhibitionapoptosismultiple myeloma

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