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Emerging Therapies in Myeloma: Selinexor

Insights From: Robert L. Ferris, MD, PhD, UPMC Hillman Cancer Center; Anna C. Pavlick, DO, NYU Langone Hospitals
Published: Thursday, Mar 07, 2019



Transcript:

A. Keith Stewart, MB, ChB:
What other new drugs are out there? Let’s stay away from CAR [chimeric antigen receptor] T for a minute.

Thomas Martin, MD: The other one is selinexor. Selinexor is a selective inhibitor, a nuclear exporter, a signed drug. And what it does is it turns off the chaperoning of proteins from the nucleus to the cytoplasm. And so, some of the tumor suppressor proteins are better if they’re in the nucleus. Cancer cells want to get them out of the nucleus. If you block that, the cells actually undergo apoptosis or are more normal. And so, this is a first-in-class drug. It actually may get FDA approved sometime in the next 2 or 3 months.

So they did this really interesting study, the STORM study, where they looked at quadruple refractory or even penta-refractory cases—so refractory to lenalidomide, bortezomib, carfilzomib, pomalidomide, and daratumumab—with selinexor plus dexamethasone. The selinexor was given twice weekly at 80 mg with dexamethasone. The response rate was reasonable, 20% to 21%. And when a secondary party looked at it they even got to 25% response rate. So that’s really good in this very refractory population.

The problem is there are adverse effects. You have to watch them fairly closely. And there’s GI [gastrointestinal] adverse effects—nausea, diarrhea. There’s low blood counts that you have to watch. There’s a little hyponatremia, and there’s some fatigue. And so, with this drug it’s going to be one of those where we’ve got to watch patients really closely, and you have to give them supportive care as needed. But I think it will find a little niche in these refractory patients to all of these drugs.

A. Keith Stewart, MB, ChB: Thoughts from this side of the table; Faith, selinexor?

Faith Davies, MD, MBBCh, MRCP, FRCPath: I agree. I think you need to take into account the types of patients that went into the study. They’re really hard patients to treat. But as you say, I think it’s managing those adverse effects in a very sick patient population. It’s going to be interesting.

A. Keith Stewart, MB, ChB: Rafael?

Rafael Fonseca, MD: You know there’s some interesting data that would suggest that if that mechanism of action works in myeloma, it can work on many other tumors. So from what I understand, without having direct experience in this, they’ve gone to the weekly schedule in lymphoma at the lower dose with reported, from what I hear from the lymphoma guys, better tolerability. I think that drug can be made tolerable. Then, again, just like we’re saying, venetoclax could be a sensitizer or an adjunct. You know you could imagine something again that increases MRD [minimal residual disease] upfront, which would be good.

Thomas Martin, MD: And it has been combined with pomalidomide, carfilzomib, daratumumab, all showing better response rates than as a single agent, with dexamethasone, or a doublet.

Adriana Rossi, MD: I am curious to see if for patients who haven’t been so far treated, if it may become more tolerable. Because part of it is these patients have been beat up quite a bit by the time they are penta-refractory.

Faith Davies, MD, MBBCh, MRCP, FRCPath: And if the DEX [dexamethasone] really helps with some of the adverse effects.

A. Keith Stewart, MB, ChB: I think for the audience if it does become more readily available, it is important to recognize that very aggressive supportive care is required to get patients through this with antiemetics, and we’ve seen all kinds of other solutions—salt tablets, and keeping them well hydrated. There are a lot of challenges, but it does perhaps have a role moving forward.

Transcript edited for clarity.

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Transcript:

A. Keith Stewart, MB, ChB:
What other new drugs are out there? Let’s stay away from CAR [chimeric antigen receptor] T for a minute.

Thomas Martin, MD: The other one is selinexor. Selinexor is a selective inhibitor, a nuclear exporter, a signed drug. And what it does is it turns off the chaperoning of proteins from the nucleus to the cytoplasm. And so, some of the tumor suppressor proteins are better if they’re in the nucleus. Cancer cells want to get them out of the nucleus. If you block that, the cells actually undergo apoptosis or are more normal. And so, this is a first-in-class drug. It actually may get FDA approved sometime in the next 2 or 3 months.

So they did this really interesting study, the STORM study, where they looked at quadruple refractory or even penta-refractory cases—so refractory to lenalidomide, bortezomib, carfilzomib, pomalidomide, and daratumumab—with selinexor plus dexamethasone. The selinexor was given twice weekly at 80 mg with dexamethasone. The response rate was reasonable, 20% to 21%. And when a secondary party looked at it they even got to 25% response rate. So that’s really good in this very refractory population.

The problem is there are adverse effects. You have to watch them fairly closely. And there’s GI [gastrointestinal] adverse effects—nausea, diarrhea. There’s low blood counts that you have to watch. There’s a little hyponatremia, and there’s some fatigue. And so, with this drug it’s going to be one of those where we’ve got to watch patients really closely, and you have to give them supportive care as needed. But I think it will find a little niche in these refractory patients to all of these drugs.

A. Keith Stewart, MB, ChB: Thoughts from this side of the table; Faith, selinexor?

Faith Davies, MD, MBBCh, MRCP, FRCPath: I agree. I think you need to take into account the types of patients that went into the study. They’re really hard patients to treat. But as you say, I think it’s managing those adverse effects in a very sick patient population. It’s going to be interesting.

A. Keith Stewart, MB, ChB: Rafael?

Rafael Fonseca, MD: You know there’s some interesting data that would suggest that if that mechanism of action works in myeloma, it can work on many other tumors. So from what I understand, without having direct experience in this, they’ve gone to the weekly schedule in lymphoma at the lower dose with reported, from what I hear from the lymphoma guys, better tolerability. I think that drug can be made tolerable. Then, again, just like we’re saying, venetoclax could be a sensitizer or an adjunct. You know you could imagine something again that increases MRD [minimal residual disease] upfront, which would be good.

Thomas Martin, MD: And it has been combined with pomalidomide, carfilzomib, daratumumab, all showing better response rates than as a single agent, with dexamethasone, or a doublet.

Adriana Rossi, MD: I am curious to see if for patients who haven’t been so far treated, if it may become more tolerable. Because part of it is these patients have been beat up quite a bit by the time they are penta-refractory.

Faith Davies, MD, MBBCh, MRCP, FRCPath: And if the DEX [dexamethasone] really helps with some of the adverse effects.

A. Keith Stewart, MB, ChB: I think for the audience if it does become more readily available, it is important to recognize that very aggressive supportive care is required to get patients through this with antiemetics, and we’ve seen all kinds of other solutions—salt tablets, and keeping them well hydrated. There are a lot of challenges, but it does perhaps have a role moving forward.

Transcript edited for clarity.
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