Selina Chen-Kiang, MD, 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.
Selina Chen-Kiang, MD
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.1
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, MD, 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.Chen-Kiang: The so-called IMiDs are a class of drugs that include thalidomide (Thalomid), lenalidomide, and pomalidomide, and they have become almost essential drugs for treating myeloma. By themselves, they’re not quite as active; however, they always potentiate the second drug. Therefore, they have been combined with everything.
It is every important to understand how these act—their mechanism of action. Recently, it has been discovered, that lenalidomide works by binding to a class of E3 ligase called cereblon. Then, one of the reports indicates that cereblon is normally associated with another protein called MEIS2. Lenalidomide goes in and displays MEIS2, and then that cascades the action and leads to destruction of the protein that is needed for myeloma survival. That’s pretty much the working hypothesis.Now, we have discovered that lenalidomide not only displays MEIS2, it actually reduces the level of MEIS2. In other words, you reduce the competitor. This competitor self-inhibits lenalidomide’s action. If you knock it out, you enhance the lenalidomide action. Once we know that, we ask ourselves, “How can we prove this is actually meaningful?”
We used primary myeloma cells and we treated it with lenalidomide, but we also treated it with a CDK 4/6 inhibitor, palbociclib. What we found is that, when we have the CDK 4/6 treatment followed by lenalidomide or pomalidomide, you essentially enhance the destruction of the inhibitor and also increase the level of this E3 ligase.
The result is a profound reduction in the ratio of MEIS2 to cereblon that accelerates the loss of IKZF1, IKZF3, and IRF4, and enhances interferon. That is the principle of enhancing the cascade of destruction. It is very rapid; you can see the change within 1 hour with the addition of lenalidomide.
This is significant because the work is done in primarily myeloma cells, and for the tumor cell that responds to the action of the 2-drug compound, it actually subsequently responds to lenalidomide/pomalidomide therapy.We now have a clinical trial implementing this combination, and we will have to wait to publish that. However, we already know from the first 5 patients that this change in the ratio is associated with the response to this combination. Resistant patients do not have this change in ratio.
Therefore, it is not just a mechanist study in cell lines, it is truly from primary cells in 19 different patients, and it is associated with their responses. This is also important because IMiDs have been known to target tumor cells and target other immune cells. What the study says is a lot of the clinical response is, in fact, innate to the tumors.
There is a lot more to follow up, but these are very original findings. We hope that this will be helpful to explain how IMiDs work in combination with other drugs.Is this the mechanism that’s underlining this combination? If it is, then it brings up the importance of the endogenous inhibitor. We already know that, as patients are treated successfully, the cereblon levels are actually reduced. I think it’s a ratio of the cereblon and endogenous inhibitors that’s explaining this.
This is important because, in the genomic era, we can ask if there’s a mutation in any of the endogenous inhibitors. That is an immediate implication because we are all using sequencing, so we can interrogate the genome very quickly.
We do not know if a patient will or will not respond before treatment outright unless there is an obvious mutation. It would be very important to have a serial biopsy and longitudinal study to follow these patients. It doesn’t take long—maybe a week—and you would know the answer.One of the reasons why IMiDs are so important is because they are very well tolerated. At the low dose, they are used as maintenance therapy.
The CDK 4/6 inhibitor, palbociclib, has been approved for breast cancer and is very well tolerated. Neutropenia is a common adverse effect but, in hematologic malignancies, that is often overcome after a few cycles. Therefore, this combination is pretty well tolerated in our first few patients, but we need to have more patients in order to know.
Huang X, Jayabalan D, Di Liberto M, et al. Inhibition of CDK4/CDK6 sensitizes myeloma to IMiD by reducing the MEIS2 to cereblon ratio that accelerates IKZF1 and IKZF3 degradation. Presented at: 2015 ASH Annual Meeting. December 5-8, 2015; Orlando, FL. Abstract 500.