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Venetoclax: Potential Use in Multiple 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: Thursday, Sep 06, 2018



Transcript: 

A. Keith Stewart, MB, ChB: Let’s talk about venetoclax. Venetoclax—your group, Sagar—has been at the forefront of describing this drug. Tell us a bit about what this is all about.

Sagar Lonial, MD, FACP: Venetoclax is a drug that the lymphoma and CLL groups are pretty familiar with, targeting BCL2. And what we know about myeloma is that about 15% to 20% of myelomas are BCL2-dependent. Most myelomas are MCL1-dependent. But there is a subset and they tend to be enriched in the 11;14 subset of patients. So, there have been a series of trials looking at venetoclax/dexamethasone across the board, looking at venetoclax alone in 11;14 and venetoclax/dexamethasone in 11;14. And what really struck me is even in penta-refractory patients, venetoclax/dexamethasone does have a response rate somewhere around 65% to 70%, and some of those responses can be quite durable.

Thomas Martin, MD: That’s in the 11;14 translocation patients.

Sagar Lonial, MD, FACP: Correct.

Thomas Martin, MD: Do you ever use it in the non-11;14 translocation patients?

Sagar Lonial, MD, FACP: So, at our center, Larry Boise will do sensitivity testing on anybody we want to give it to. And there are a few patients who are not 11;14 but are B–cell like, and they actually do respond.

Edward A. Stadtmauer, MD: I think venetoclax is really sort of a game-changer for the patients who have the 11;14 translocation. We’re not as sophisticated with the other BCL1 overexpression tests to really know, to differentiate the other patients. But that is still about 15%, 20% of patients, and I think it might even be enriched as patients have more and more relapses. It is remarkable sometimes that just giving the single agent will lead to responses in patients, like you said, who are penta-refractory. And we did participate in the presentation that was given yesterday by Dr. Costa.

A. Keith Stewart, MB, ChB: Let’s talk about that, but that’s with carfilzomib.

Edward A. Stadtmauer, MD: Carfilzomib and dexamethasone. And this was an early group of patients who had not received carfilzomib in the past, but they were all relapsed patients. And there’s a remarkable response rate in a relatively small study, a phase I trial, using different doses and schedule of the carfilzomib. But there were responses even in patients who were 11;14 nontranslocated. And for the patients who were translocated, the vast majority of those patients responded beautifully.

A. Keith Stewart, MB, ChB: Amrita, your takeaways from the presentation yesterday of carfilzomib and venetoclax?

Amrita Krishnan, MD, FACP: I think that it shows that using a proteasome inhibitor with venetoclax is very important because of the effects of the proteasome inhibitor in MCL1. And we had said that. I think the future is going to be combinations with venetoclax. There are MCL1 inhibitors specifically in clinical trials.

A. Keith Stewart, MB, ChB: Yes, there are.

Amrita Krishnan, MD, FACP: So, I’m very interested to see that in the future, but I just echo the enthusiasm. In fact, for Tom’s point, since we don’t have access to some of the other testing that Larry Boise does, I certainly have used it in other people. By the time you get to fifth line, I’m willing to try anything. I’ll do venetoclax/carfilzomib/bortezomib, and I’ve been surprised with some of the responses.

Edward A. Stadtmauer, MD: I think also that’s sort of an impressive difference from CLL and lymphoma, that there doesn’t seem to be the tumor lysis syndrome. And even patients taking 800 mg daily of the venetoclax…

Amrita Krishnan, MD, FACP: Wasn’t there a death on your study from tumor lysis syndrome?

Thomas Martin, MD: There was one, yes.

Edward A. Stadtmauer, MD: There was.

A. Keith Stewart, MB, ChB: It was tumor lysis, correct?

Edward A. Stadtmauer, MD: But this was not something that was common.

Thomas Martin, MD: For us in San Francisco, it is a sequencing thing. And so, for the patients, I do think we have a biomarker. We have the 11;14 translocation. I think it’s a nice biomarker specifically for this drug. So, I typically in the sequence do daratumumab-based therapy in first relapse. But once they have second relapse or third relapse, and they’re the 11;14, I think this is a perfect place to fit venetoclax, including together with dexamethasone.

A. Keith Stewart, MB, ChB: What dose do you use, Tom?

Thomas Martin, MD: Typically for people over the age 70, I start them off at 300 mg daily and then I’ll go to 600 mg. If they’re younger, I start them off at 400 mg and inch my way up to 700 mg or 800 mg.

A. Keith Stewart, MB, ChB: What’s your target, 800 mg or…?

Thomas Martin, MD: I think somewhere between 600 mg and 800 mg is the target dose. That said, I have an 85-year-old that’s on 100 mg. He has been on it for the last year and he’s in remission and doing fine. So, I do think there’s a variability in terms of a dose that you need for this drug.

A. Keith Stewart, MB, ChB: Even up to 1200 mg in a clinical trial, and I’ve used that. I do think it’s a bit of a dose effect, too.

Amrita Krishnan, MD, FACP: Any of you guys using single agents or are you using combinations?

A. Keith Stewart, MB, ChB: Both, but mostly single agents in 11;14. Again, this is off. Their clinical trial is underway. It’s not FDA approved. You can obtain it on compassionate grounds. Ajai?

Ajai Chari, MD: I would like to see a larger study because I’m not really clear. I’ve had patients with limited activity so far, but I think I would like to see, ideally, a biomarker-based study where you’re stratified and you get randomized to plus/minus and show what really happens. Because all the studies so far have been relatively small numbers, I think the question that was asked yesterday of Dr. Costa was what is the venetoclax adding to Kd in this setting, which I think it’s not a fair comparison because these are small numbers. But that’s why I’m holding my judgment until I see the randomized phase III.

Transcript Edited for Clarity 

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Transcript: 

A. Keith Stewart, MB, ChB: Let’s talk about venetoclax. Venetoclax—your group, Sagar—has been at the forefront of describing this drug. Tell us a bit about what this is all about.

Sagar Lonial, MD, FACP: Venetoclax is a drug that the lymphoma and CLL groups are pretty familiar with, targeting BCL2. And what we know about myeloma is that about 15% to 20% of myelomas are BCL2-dependent. Most myelomas are MCL1-dependent. But there is a subset and they tend to be enriched in the 11;14 subset of patients. So, there have been a series of trials looking at venetoclax/dexamethasone across the board, looking at venetoclax alone in 11;14 and venetoclax/dexamethasone in 11;14. And what really struck me is even in penta-refractory patients, venetoclax/dexamethasone does have a response rate somewhere around 65% to 70%, and some of those responses can be quite durable.

Thomas Martin, MD: That’s in the 11;14 translocation patients.

Sagar Lonial, MD, FACP: Correct.

Thomas Martin, MD: Do you ever use it in the non-11;14 translocation patients?

Sagar Lonial, MD, FACP: So, at our center, Larry Boise will do sensitivity testing on anybody we want to give it to. And there are a few patients who are not 11;14 but are B–cell like, and they actually do respond.

Edward A. Stadtmauer, MD: I think venetoclax is really sort of a game-changer for the patients who have the 11;14 translocation. We’re not as sophisticated with the other BCL1 overexpression tests to really know, to differentiate the other patients. But that is still about 15%, 20% of patients, and I think it might even be enriched as patients have more and more relapses. It is remarkable sometimes that just giving the single agent will lead to responses in patients, like you said, who are penta-refractory. And we did participate in the presentation that was given yesterday by Dr. Costa.

A. Keith Stewart, MB, ChB: Let’s talk about that, but that’s with carfilzomib.

Edward A. Stadtmauer, MD: Carfilzomib and dexamethasone. And this was an early group of patients who had not received carfilzomib in the past, but they were all relapsed patients. And there’s a remarkable response rate in a relatively small study, a phase I trial, using different doses and schedule of the carfilzomib. But there were responses even in patients who were 11;14 nontranslocated. And for the patients who were translocated, the vast majority of those patients responded beautifully.

A. Keith Stewart, MB, ChB: Amrita, your takeaways from the presentation yesterday of carfilzomib and venetoclax?

Amrita Krishnan, MD, FACP: I think that it shows that using a proteasome inhibitor with venetoclax is very important because of the effects of the proteasome inhibitor in MCL1. And we had said that. I think the future is going to be combinations with venetoclax. There are MCL1 inhibitors specifically in clinical trials.

A. Keith Stewart, MB, ChB: Yes, there are.

Amrita Krishnan, MD, FACP: So, I’m very interested to see that in the future, but I just echo the enthusiasm. In fact, for Tom’s point, since we don’t have access to some of the other testing that Larry Boise does, I certainly have used it in other people. By the time you get to fifth line, I’m willing to try anything. I’ll do venetoclax/carfilzomib/bortezomib, and I’ve been surprised with some of the responses.

Edward A. Stadtmauer, MD: I think also that’s sort of an impressive difference from CLL and lymphoma, that there doesn’t seem to be the tumor lysis syndrome. And even patients taking 800 mg daily of the venetoclax…

Amrita Krishnan, MD, FACP: Wasn’t there a death on your study from tumor lysis syndrome?

Thomas Martin, MD: There was one, yes.

Edward A. Stadtmauer, MD: There was.

A. Keith Stewart, MB, ChB: It was tumor lysis, correct?

Edward A. Stadtmauer, MD: But this was not something that was common.

Thomas Martin, MD: For us in San Francisco, it is a sequencing thing. And so, for the patients, I do think we have a biomarker. We have the 11;14 translocation. I think it’s a nice biomarker specifically for this drug. So, I typically in the sequence do daratumumab-based therapy in first relapse. But once they have second relapse or third relapse, and they’re the 11;14, I think this is a perfect place to fit venetoclax, including together with dexamethasone.

A. Keith Stewart, MB, ChB: What dose do you use, Tom?

Thomas Martin, MD: Typically for people over the age 70, I start them off at 300 mg daily and then I’ll go to 600 mg. If they’re younger, I start them off at 400 mg and inch my way up to 700 mg or 800 mg.

A. Keith Stewart, MB, ChB: What’s your target, 800 mg or…?

Thomas Martin, MD: I think somewhere between 600 mg and 800 mg is the target dose. That said, I have an 85-year-old that’s on 100 mg. He has been on it for the last year and he’s in remission and doing fine. So, I do think there’s a variability in terms of a dose that you need for this drug.

A. Keith Stewart, MB, ChB: Even up to 1200 mg in a clinical trial, and I’ve used that. I do think it’s a bit of a dose effect, too.

Amrita Krishnan, MD, FACP: Any of you guys using single agents or are you using combinations?

A. Keith Stewart, MB, ChB: Both, but mostly single agents in 11;14. Again, this is off. Their clinical trial is underway. It’s not FDA approved. You can obtain it on compassionate grounds. Ajai?

Ajai Chari, MD: I would like to see a larger study because I’m not really clear. I’ve had patients with limited activity so far, but I think I would like to see, ideally, a biomarker-based study where you’re stratified and you get randomized to plus/minus and show what really happens. Because all the studies so far have been relatively small numbers, I think the question that was asked yesterday of Dr. Costa was what is the venetoclax adding to Kd in this setting, which I think it’s not a fair comparison because these are small numbers. But that’s why I’m holding my judgment until I see the randomized phase III.

Transcript Edited for Clarity 
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