Advances in the Treatment of Relapsed/Refractory Myeloma - Episode 9

Emerging Therapies: SINE inhibitor & the STORM trial

Transcript:Sagar Lonial, MD: The STORM trial really is an important study for a number of reasons. We know that patients have received lots of therapy, and in the context of the STORM trial, they were looking at quad- and penta-refractory patients—quad meaning resistant to bortezomib, lenalidomide, pomalidomide, and carfilzomib; penta being those 4 plus daratumumab. And the reason it’s so important is, despite all the advances we’ve made in the last decade, there are patients who become penta-refractory. And so having treatments that are available and can be effective in that situation is, I think, really important.

And what the STORM trial demonstrated was that you could get responses with selinexor and dexamethasone in patients who were penta-refractory. And then, in many patients, those responses could be quite durable, and so I think it gives new hope and options for patients where their treatment options are often quite limited.

Andrzej Jakubowiak, MD, PhD: New emerging therapies are badly needed. We are fortunate that only changing 1 drug into the other within the class—like proteasome inhibitor bortezomib; carfilzomib transition; or thalidomide, lenalidomide, pomalidomide transition—have given us so much that we’ve been, to some extent, spoiled by the availability of new emerging drugs within the class. But we have always thought and we continue to fight to bring new classes of drugs.

Selective inhibitors of nuclear export—selinexor—have emerged in the last few years. And 1 of those most promising drugs is now designated…as potentially awaiting approval based on FDA designation of the drug, which just tells you that this drug is not only appearing promising at a time when we were starting this drug development but also because of the objective data.

Why is this drug is different than prior classes of drugs that we use? And the prior class of drugs, in addition to proteasome inhibitors, even the modularity drugs, are also cytotoxics, to which, for example, cyclophosphamide belongs and melphalan for transplant—they…and steroids were those classes of drugs that we have used before.

Selinexor, from this new class of drugs that we are now evaluating, is targeting a nuclear export of some important proteins that are involved in malignancy, like, for example, proto-oncogenes. Not going into details of the mechanism of this action, it appears that malignant cells are actively expanding these proteins that otherwise would have potentially worked to eliminate a cell by self-kill, which is called apoptosis, and when you block this exit from the nucleus, the preclinical and then clinical work showed that we may potentially change the chemistry of the disease to again become self-destructive, as it’s supposed to do in any malignancy.

So that was the theoretical consideration we’ve learned, and studies to this date, available in what has been presented or published, show that indeed this drug is active on its own, particularly in combination with steroids, which has been used as a basis for submission to FDA for fast drug approval path, as well as in those other drugs, including proteasome inhibitors, which was predicted preclinically and then eventually validated, at least preliminarily, in the clinical trials.

Ajai Chari, MD: The STORM trial that was recently presented by my colleague Dr Jakubowlak at the SOHO [Society of Hematologic Oncology] meeting is different from this, the selinexor study that was published in JCO [Journal of Clinical Oncology], in that the JCO article does contain penta-refractory patients, but it was only about half of those 80 patients. Because of the signal that was seen, this study is specifically in patients who have been penta exposed. And that in itself is kind of interesting, because we recruited a lot of patients to the study, but basically, the eligibility required exposure to all 5 big myeloma drugs. So we’re talking about bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab or any other CD38 antibody. And then they have to be refractory to each of those classes of drugs.

And what’s interesting is that when we tried to accrue patients to the study, for those patients who were coming in from the community, we may not always be able to document progression per IMWG [International Myeloma Working Group]criteria to show refractoriness. So that in itself was an interesting learning point for enrollment in relapsed/refractory settings, and it’s for that reason the FDA allowed Karyopharm Therapeutics to modify the eligibility to not necessarily require refractory to all 5 drugs but to each class. So I think that’s important; and it’s really an unmet need, because what do you do with these patients?

And the second feature I would emphasize with the eligibility criteria here are that they were very permissive, so the creatinine clearance only needed to be 20. The neutrophil count only needed to be a thousand. Platelets, depending on their bone marrow involvement, if they were heavily replaced, could be as low as 30. So it’s important when we look at the toxicity profile that we think about who was getting on to these studies—penta-refractory, low blood counts, renal dysfunction—and these were rapid progressors, and that should be distinguished from the CAR [chimeric antigen receptor]—T process, which we’ll talk about. But unlike CAR-T, patients sign consent for selinexor and dose within 7 to 10 days, and so there’s not as much of a selection bias of who’s signing consent and actually getting to the infusion.

So those are some of the considerations we have to keep in mind when looking at the results of the STORM study that was presented.

Transcript edited for clarity.