Adding a CDK 4/6 inhibitor, such as palbociclib (Ibrance), to immunomodulatory drugs (IMiDs), including lenalidomide (Revlimid) and pomalidomide (Pomalyst), sensitizes multiple myeloma cells to those treatments, according to results of an early clinical trial.
Researchers of the study, which was presented during the 2015 ASH Annual Meeting, investigated the mechanism of action of IMiDs and the functional consequences in myeloma cells regarding response to lenalidomide or pomalidomide before or after biopsy.
Through the use of transcriptome sequencing, protein analysis, and functional assays, it was reported that myeloma cells are addicted to transcription factors IKZF3-IRF4 for survival, lenalidomide-mediated IRF4 loss leads to de-repression of IRF7, induction of interferon response genes and TRAIL-mediated apoptosis, and the magnitude of interferon induction is tightly associated with killing myeloma from treatment with lenalidomide.
Importantly, the IMiDs’ sensitivity in myeloma cells ex vivo correlated with the prior or subsequent clinical response to such therapies in individual patients with myeloma, suggesting that the clinical response to IMiDs is largely intrinsic to myeloma cells.v IMiDs are known to create cell cycle arrest, specifically G1 arrest. These data provide the first evidence that induction of prolonged early G1 arrest occurs by adding CDK 4/6 inhibitors, including palbociclib. This leads to a reduction in the ratio of endogenous substrate MEIS2 to cereblon that accelerates the loss of IKZF1, IKZF3 and IRF4, and enhances interferon and TRAIL induction.
In an interview with OncLive, Selina Chen-Kiang, Ph.D., professor of Pathology and Laboratory Medicine, Microbiology and Immunology at Weill Cornell Medicine and NewYorkPresbyterian Hospital, discusses how CDK 4/6 inhibition sensitizes myeloma cells to IMiDs and the impact this can have on the treatment of patients with multiple myeloma.