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

作者：Sikander Ailawadhi, Ricardo Parrondo, Navnita Dutta, Bing Han, Gina Ciccio, Yesesri Cherukuri, Victoria R. Alegria, Betsy LaPlant, Vivek Roy, Taimur Sher, Brett Edwards, Stephanie Lanier, Alak Manna, Keisha Heslop, Thomas R. Caulfield, Emir Maldosevic, Peter Störz, Rami Manochakian, Yan W. Asmann, Asher Chanan‐Khan, Aneel Paulus · 发表于：Cancers · 年份：2023 · DOI：10.3390/cancers15020477 · 被引用次数：6 · 研究领域：Multiple Myeloma Research and Treatments、Protein Degradation and Inhibitors、Peptidase Inhibition and Analysis

Bcl-2 and Mcl-1 proteins play a role in multiple myeloma (MM) cell survival, for which targeted inhibitors are being developed. AT-101 is an oral drug, which disrupts Bcl-2 and Mcl-1 function, impedes mitochondrial bioenergetic processes and induces apoptosis in MM cells. When combined with lenalidomide and dexamethasone (Rd), AT-101 significantly reduced tumor burden in an in vivo xenograft model of MM. These data provided rationale for a phase I/II study to establish the effective dose of AT-101 in combination with Rd (ARd regimen) in relapsed/refractory MM. A total of 10 patients were enrolled, most with high-risk cytogenetics (80%) and prior stem cell transplant (70%). Three patients were lenalidomide-refractory, 2 were bortezomib-refractory and 3 were daratumumab-refractory. The ARd combination was well tolerated with most common grade 3/4 adverse events being cytopenia's. The overall response rate was 40% and clinical benefit rate was 90%. The median progression free survival was 14.9 months (95% CI 7.1-NE). Patients responsive to ARd showed a decrease in Bcl-2:Bim or Mcl-1:Noxa protein complexes, increased CD8+ T and NK cells and depletion of T and B-regulatory cells. The ARd regimen demonstrated an acceptable safety profile and promising efficacy in patients with relapsed/refractory MM prompting further investigation in additional patients.