AT-101 Enhances the Antitumor Activity of Lenalidomide in Patients with Multiple Myeloma.
Sikander AilawadhiRicardo D ParrondoNavnita DuttaBing HanGina CiccioYesesri CherukuriVictoria R AlegriaBetsy R LaPlantVivek RoyTaimur SherBrett EdwardsStephanie LanierAlak MannaKeisha HeslopThomas R CaulfieldEmir MaldosevicPeter StorzRami ManochakianYan AsmannAsher A Chanan-KhanAneel PaulusPublished in: Cancers (2023)
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.
Keyphrases
- multiple myeloma
- newly diagnosed
- end stage renal disease
- ejection fraction
- chronic kidney disease
- peritoneal dialysis
- prognostic factors
- induced apoptosis
- clinical trial
- small molecule
- risk factors
- signaling pathway
- drug delivery
- machine learning
- high dose
- diffuse large b cell lymphoma
- electronic health record
- cell death
- binding protein
- cell therapy