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Considering Selinexor in Penta-Refractory Myeloma

Panelists: A. Keith Stewart, MB, ChB, Mayo Clinic; Sagar Lonial, MD, FACP, Emory University School of Medicine; Thomas Martin, MD, UCSF Helen Diller Family; Edward A. Stadtmauer, MD, University of Pennsylvania; Ajai Chari, MD, Mount Sinai Hospital; Amrita Krishnan, MD, FACP, City of Hope Cancer Center
Published: Tuesday, Sep 04, 2018



Transcript: 

A. Keith Stewart, MB, ChB: In addition to the exciting immunotherapies we’ve been talking about, we’ve been talking about the antibodies and the T-cell enhancers. There’s also some small molecules emerging, one of which we heard about at ASH and I think we’re going to hear about at the EHA meeting in a few weeks, which is selinexor. And selinexor has a novel mechanism of action and has some pretty interesting data. So, Tom, maybe for the audience, summarize what we know about that.

Thomas Martin, MD: Selinexor is really a first-in-class selective inhibitor of a nuclear export. And it basically inhibits a nuclear pore protein and it keeps tumor suppressor proteins, the glucocorticoid receptor, and some mRNAs for oncoproteins in the nucleus. And it keeps the cells more regulated as normal function and makes them more applicable to apoptosis and other anti-cancer effects. So, this first-in-class inhibitor has been used now together with dexamethasone in patients that have relapsed/refractory myeloma. I think you just recently actually had a publication on this, looking at patients who were quad-refractory and even penta-refractory. And this drug together with dexamethasone has actually a very nice response rate of 20%. And these are in patients similar to the CAR T who don’t have many other options. I think the limitations with this drug at the current time are the toxicities associated with it, and mostly it’s GI toxicity and fatigue. I don’t know if you saw more toxicity, but as an agent, I think we just have to see what’s going to happen in the future. I’m a little nervous about the toxicity and how well this is going to be utilized going forward.

A. Keith Stewart, MB, ChB: Pretty good summary. I think the press release for the most recent update actually has about 25% response rate. Other thoughts on the other side of the table?

Edward A. Stadtmauer, MD: I think it was this study that defined the term penta-refractory, that just think of taking a group of patients who are so heavily pretreated and yet a quarter of those patients are responding to a single agent or an agent plus dexamethasone. So, I think we can’t discount this agent. I’m assuming that there will be adjustments to the drug potentially to make it have decreased toxicity, maybe next generation of these nuclear transplant, transport protein inhibitors. And then, of course, combining it with other agents holds a lot of promise.

A. Keith Stewart, MB, ChB: And we’ll talk about combinations in a minute. I must admit, we struggle to manage the toxicity in some patients, and I do have some worries that that’s going to be a limiting factor. But last night when I was telling some other physicians, they seem to have a much better experience, a learning curve, if you will, that once you get used to using the drug, it gets easier. Amrita, do you have much experience with this?

Amrita Krishnan, MD, FACP: We haven’t used the drugs.

Ajai Chari, MD: We’ve used it quite a bit, and I think the couple of issues are the patients. These are patients literally for whom many of them would have gone to hospice. So, I think the expectations need to be commensurate with that setting. And, in fact, some of these patients were progressing on DT-PACE, which is guaranteed to give you grade 3/4 heme toxicity. And so, that’s another toxicity part of it. With that patient population, you’re allowing patients with a neutrophil count of 1000, a platelet count of 50 if their marrow was ever replaced, and a clearance of only 20; these are really sick patients. And the fact that we’re seeing these responses, I think we have to distinguish. The purpose of this kind of single-arm study is really to see if there is single-agent activity, which I think we’ve seen there is. But we have to distinguish that from what actually will happen in the real world. It’s kind of like VMP. VMP was the registrational study, but no one ever even used it; but you needed to do that study to get that approval, and people used the bortezomib.

A. Keith Stewart, MB, ChB: What about combinations? I’ve heard that maybe they might allow us to lower the dose or even modify the toxicity a little bit.

Ajai Chari, MD: Right. So, the single agent is 80 mg twice weekly as the starting dose, but most of the combination studies with carfilzomib, with pomalidomide, with bortezomib are all being 100 mg weekly. So, I think we’ll have to see how this looks.

Transcript Edited for Clarity 

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Transcript: 

A. Keith Stewart, MB, ChB: In addition to the exciting immunotherapies we’ve been talking about, we’ve been talking about the antibodies and the T-cell enhancers. There’s also some small molecules emerging, one of which we heard about at ASH and I think we’re going to hear about at the EHA meeting in a few weeks, which is selinexor. And selinexor has a novel mechanism of action and has some pretty interesting data. So, Tom, maybe for the audience, summarize what we know about that.

Thomas Martin, MD: Selinexor is really a first-in-class selective inhibitor of a nuclear export. And it basically inhibits a nuclear pore protein and it keeps tumor suppressor proteins, the glucocorticoid receptor, and some mRNAs for oncoproteins in the nucleus. And it keeps the cells more regulated as normal function and makes them more applicable to apoptosis and other anti-cancer effects. So, this first-in-class inhibitor has been used now together with dexamethasone in patients that have relapsed/refractory myeloma. I think you just recently actually had a publication on this, looking at patients who were quad-refractory and even penta-refractory. And this drug together with dexamethasone has actually a very nice response rate of 20%. And these are in patients similar to the CAR T who don’t have many other options. I think the limitations with this drug at the current time are the toxicities associated with it, and mostly it’s GI toxicity and fatigue. I don’t know if you saw more toxicity, but as an agent, I think we just have to see what’s going to happen in the future. I’m a little nervous about the toxicity and how well this is going to be utilized going forward.

A. Keith Stewart, MB, ChB: Pretty good summary. I think the press release for the most recent update actually has about 25% response rate. Other thoughts on the other side of the table?

Edward A. Stadtmauer, MD: I think it was this study that defined the term penta-refractory, that just think of taking a group of patients who are so heavily pretreated and yet a quarter of those patients are responding to a single agent or an agent plus dexamethasone. So, I think we can’t discount this agent. I’m assuming that there will be adjustments to the drug potentially to make it have decreased toxicity, maybe next generation of these nuclear transplant, transport protein inhibitors. And then, of course, combining it with other agents holds a lot of promise.

A. Keith Stewart, MB, ChB: And we’ll talk about combinations in a minute. I must admit, we struggle to manage the toxicity in some patients, and I do have some worries that that’s going to be a limiting factor. But last night when I was telling some other physicians, they seem to have a much better experience, a learning curve, if you will, that once you get used to using the drug, it gets easier. Amrita, do you have much experience with this?

Amrita Krishnan, MD, FACP: We haven’t used the drugs.

Ajai Chari, MD: We’ve used it quite a bit, and I think the couple of issues are the patients. These are patients literally for whom many of them would have gone to hospice. So, I think the expectations need to be commensurate with that setting. And, in fact, some of these patients were progressing on DT-PACE, which is guaranteed to give you grade 3/4 heme toxicity. And so, that’s another toxicity part of it. With that patient population, you’re allowing patients with a neutrophil count of 1000, a platelet count of 50 if their marrow was ever replaced, and a clearance of only 20; these are really sick patients. And the fact that we’re seeing these responses, I think we have to distinguish. The purpose of this kind of single-arm study is really to see if there is single-agent activity, which I think we’ve seen there is. But we have to distinguish that from what actually will happen in the real world. It’s kind of like VMP. VMP was the registrational study, but no one ever even used it; but you needed to do that study to get that approval, and people used the bortezomib.

A. Keith Stewart, MB, ChB: What about combinations? I’ve heard that maybe they might allow us to lower the dose or even modify the toxicity a little bit.

Ajai Chari, MD: Right. So, the single agent is 80 mg twice weekly as the starting dose, but most of the combination studies with carfilzomib, with pomalidomide, with bortezomib are all being 100 mg weekly. So, I think we’ll have to see how this looks.

Transcript Edited for Clarity 
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