Can JAK Inhibition Help Overcome Lenalidomide Resistance in Myeloma?

Phase I data presented at the 2023 American Society of Hematology (ASH) annual meeting showed the benefit of lenalidomide (Revlimid) rechallenge in relapsed/refractory multiple myeloma patients receiving treatment with the Janus kinase (JAK) inhibitor ruxolitinib (Jakafi) and methylprednisolone.

In this exclusive MedPage Today video, James R. Berenson, MD, founder and president of the Institute for Myeloma and Bone Cancer Research in West Hollywood, California, discusses the background to the study and touches on the potential role for JAK inhibitors in multiple myeloma.

Following is a transcript of his remarks:

So we’ve been working on this class of drugs [JAK inhibitors] now for about 5 or 6 years, both in our research laboratory and clinically. And we’ve uncovered a series of mechanisms that suggests that these drugs are going to be very active, probably not only in myeloma, which we’ve now shown, but in lots of other cancers as well. And what we’ve uncovered is that these drugs actually enhance the immune response to the cancer, also help overcome resistance by blunting down proteins that lead to resistance in other drugs in myeloma like Revlimid, or lenalidomide.

So we began work in the clinic early on, like 5 years ago, by using these drugs to treat highly, heavily previously treated patients with myeloma. And those patients were then given lenalidomide, ruxolitinib, and a steroid called methylprednisolone.

And what we learned is we had very high responses; about half the patients responded to some degree. And in that process we also learned those patients were resistant to the lenalidomide. So the rux [ruxolitinib] helped overcome that.

So then we decided to do the next step, we used a drug without lenalidomide. Let’s see if it works without it. And it did, and we published that work. But in that process, we decided: can we resurrect responses by adding the lenalidomide back to people who fail ruxolitinib and methylprednisolone? These are all pills. They’re well tolerated. And we did, and we got very long remissions with simply the use of these pills.

How does it actually work to stimulate the immune system? Well, believe it or not, it knocks out the checkpoint inhibitor proteins, just like those drugs that are on TV every night like pembro [pembrolizumab] (Keytruda), all those drugs. This does the same thing, but it’s just a pill. And by knocking out the checkpoint inhibitor proteins, the immune responses are enhanced. And we’ve shown that T-cell responses indeed are enhanced, in the test tube anyway. When you put ruxolitinib on the myeloma bone marrow, boy, the killing is markedly enhanced with T-cell effects from the enhancement from rux. It’s really good.

And so this is now leading us to use these drugs with all sorts of other drugs that have been used effectively to treat myeloma. We’re trying to start a series of new trials, and we’re about to start one in the next few weeks with a drug that’s been used for myeloma called selinexor [Xpovio]. And hopefully we’ll be able to start that soon.

We also have been able to identify a predictor for whether you’re going to respond or not. It’s serum B-cell maturation antigen, which is becoming more and more widely used to monitor myeloma, but it also could be used to predict whether you’re going to respond to treatments. And it looks like it does that in the face of ruxolitinib in myeloma. So we’re excited, the future looks bright for these drugs in myeloma.