Sagar Lonial, MD, FACP: So let’s go to the next segment which is, “Experimental Approaches and Emerging Treatments for Relapsed and Refractory Myeloma.” Let’s start off talking a little bit about Selinexor and what we know about these data. There were some data, there are some data that have been looked at during ASH [the American Society for Hematology Annual Meeting], certainly, and then there was a comparison with real-world analyses, which, by the way, is a phrase that just drives me crazy because it suggests that my patients don’t live in the real world. But anyway, go ahead Tom. Talk to us a little bit about Selinexor.
Thomas G. Martin, MD: So, Selinexor is the first oral selective inhibitor of nuclear export. It blocks transition of proteins from the nucleus to the cytoplasm, some important control proteins like P53 and other oncoproteins. And it has shown efficacy in preclinical models with myeloma. And then in combination with dexamethasone, we saw an early phase I study with come activity in relapsed refractory people, and then a much larger study of 122 patients, the STORM Study, where patient were treated with Selinexor and dexamethasone.
In patients who were refractory to IMiDs [immunomodulatory imide drugs], proteasome inhibitors [PIs], and the monoclonal antibody, they actually had quite a good response rate of 26%. That large phase II data were presented to the FDA, and the FDA’s Oncologic Drugs Advisory Committee decided not to approve the study based on a couple things. One is toxicity. There is toxicity from this molecule. There’s a lot of nausea, there’s a lot of anorexia, there’s hyponatremia, there’s some diarrhea associated with it, and fatigue. And there was a lot of supportive care that went into supporting patients that received this therapeutic.
The second concern is they were caught a little bit on the dexamethasone in that how much of that 26% of the response was truly from dexamethasone. And then the last part was, what is the control population? What is the triple class refractory control population, and what would be the expected PFS in that population? So actually at ASCO [the American Society of Clinical Oncology Annual Meeting], Paul Richardson, MD, did a retrospective review and tried to do a case control cohort of patients who were triple class refractory and got their first therapy as either Selinexor or the comparator arm, the control arm. And in fact in that one, the PFS [progression-free survival] was about a little over 5 months for patients hat received Selinexor and dexamethasone. And in the control arm it was less than 3 months, so it was a big difference. And survivals were actually less than 6months in that population. So where survivals were 10-plus months in patients getting Selinexor.
So really compared to the control arm, I actually think there’s some activity. The problem is, in my mind, the toxicity. Are we able to support these patients and can this really be taken to a broad clinical practice with all the support that’s needed?
Sagar Lonial, MD, FACP: Others have experience with Selinexor?
Saad Z. Usmani, MD, FACP: No, I don’t have any experience with the STORM patients outside of single patient IMiDs. But I agree. I think that the key issue is the safety profile and the fact that you are giving a lot of IV [intravenous] antiemetic support, IV fluids, for an oral therapy. So I think that’s the challenge. Even though those challenges get better, as therapy progresses, you’re going to have a selection by where patients who are going to do well with that compound are going to stay on and continue to tolerate treatment. The patients who either are going to fail therapy or not tolerate it are going to be out after a cycle or 2. But everyone requires more attention with supportive care during the first couple of months.
Thomas G. Martin, MD: So there is a phase III trial now, the BOSTON trial, which is Selinexor plus bortezomib and dexamethasone versus bortezomib and dexamethasone, and it’s in an earlier population. So maybe it’s in a less heavily pretreated population. Maybe that population is less frail or might be able to tolerate this therapy better, and we will actually get better data in terms of what the true toxicity is when you put it in a combination and whether you see as good an affect here, triplet versus doublet, that will lead to FDA approval. So, those data should be in by the end of the year.
Sagar Lonial, MD, FACP: I have to say, I’m actually fairly impressed with the PI combinations. First, in the ability to overcome resistance to a PI, both with bortezomib and carfilzomib. I think those data, the small trials, have been presented. The second, is that you actually give less Selinexor when you combine it with a PI, and that might mitigate some of the GI [gastrointestinal] toxicity that I think that you guys have talked a little bit about, at least that’s my experience. And then the data that was presented on dara [daratumumab] plus Selinexor also looked pretty interesting as well. So, I think we’ve got to work a little bit on dosing and scheduling to make it work a little bit.
Transcript Edited for Clarity