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Using Pomalidomide in Multiple Myeloma

Panelists:Ajai Chari, MD, Mount Sinai Hospital; Sagar Lonial, MD, Emory University School of Medicine; Paul G. Richardson, MD, Harvard Medical School; Jatin J. Shah, MD, MD Anderson Cancer Center; Keith Stewart, MD, CHB, Mayo Clinic
Published: Wednesday, Mar 23, 2016


Transcript:

Keith Stewart, MB, CHB:
But I want to come to the fact that in the United States almost everybody has had a lot of lenalidomide when they progress, and they're often on lenalidomide when they progress. So how do we translate all these trials with lenalidomide at relapse into our practice? Jatin, you've explored pomalidomide at least in combination with carfilzomib and I think also with panobinostat, right?

Jatin J. Shah, MD: Not with panobinostat.

Keith Stewart, MB, CHB: With ixazomib.

Jatin J. Shah, MD: Yeah, well not with ixazomib, but we looked at it with carfilzomib. I think that's a very relevant clinical question that we see commonly and that's going to be what we all see in practice. What everybody sees globally is patients who are getting IMiD-based therapy with lenalidomide up-front and then progressing. So some of these trials don't necessarily apply to that. So I think pomalidomide is a very potent IMiD that is very active in that setting.

The challenge is it's about a 30% response rate in Revlimid-refractory patients. And so trying to find strategies to improve that response rate will be critically important. And so we did a trial with a number of colleagues with carfilzomib, pomalidomide, and dexamethasone, potentially combining the more potent proteome inhibitor and a very potent IMiD. And we saw (a), number one, that it's very well tolerated. So you can combine carfilzomib 27 mg/m2 in the standard schedule and pomalidomide 4 mg, and the response rates that were around 70% in that setting were in truly Revlimid-refractory as well as Velcade-refractory patients. So I think it's a very promising combination and a very active combination that we use frequently in the Revlimid-refractory patient.

Keith Stewart, MB, CHB: And, in fact, in my own practice, I know that it's become my first relapse regimen. Essentially you know people are coming in now, they've had VRD transplant, lenalidomide or lenalidomide and Velcade maintenance. And when they relapse, I’ve been using your regimen almost as my go-to treatment. But, Paul, you've had a lot of experience with pomalidomide, too, and some of the combinations coming along. Tell us about those.

Paul G. Richardson, MD: Yes. Well, I completely agree with Jatin. I think what we're very pleased with is pomalidomide; it's an excellent partner drug.

Keith Stewart, MB, CHB: Also the most potent of the IMiDs, is that correct?

Paul G. Richardson, MD: You're absolutely correct. And I think the other thing is that we find it partners beautifully with carfilzomib, it partners beautifully with bortezomib. We're able to recapture response even though they had multiple prior lines of therapy, etc. And the tolerability profile of pomalidomide I think is particularly encouraging. There have been no surprises and it's, I think, very well tolerated in renal disease as well, and it clearly I think it is an IMiD of choice in that setting now that we've got more information. But I think what's also very exciting, Keith, at this meeting is there are data now on pomalidomide and ixazomib.

Keith Stewart, MB, CHB: That's the one.

Paul G. Richardson, MD: Absolutely. That's our Alliance Study done by my colleague, Peter Voorhees, who has done a beautiful job with this early phase study. And it's moving now into a randomized phase II study. But the bottom line is Pete's showing beautiful tolerance and, at the same time, excellent activity in refractory patients, because the eligibility was the pomalidomide label (ie, refractory patients going into the trial). So that's one. And then I think it's perfect to have Ajai here because he can talk to us a little bit about pomalidomide and daratumumab.

Keith Stewart, MB, CHB: Let's hold that thought because we're going to finish our discussion this morning with daratumumab. We'll come back to that. So what I'm hearing is pomalidomide is a very potent drug—it works sometimes when you're refractory to lenalidomide—you can combine it with lots of different drugs, right?

Paul G. Richardson, MD: Yes, absolutely.

Keith Stewart, MB, CHB: And it hasn't been combined with elotuzumab yet, but there's no reason to think it wouldn't be combinable.

Ajai Chari, MD: It is, in trials.

Paul G. Richardson, MD: It is, and it's being studied. The trial's just opened.

Keith Stewart, MB, CHB: You know the main side effect, it seems to me, is neutropenia. What about dosing? We start at 4. Do you think 3 or 2 is the drop-down-to dose? Or what do you do in your own practice?

Paul G. Richardson, MD: Personally, I will start at 2 or 3 if I'm worried about a patient. But I'm very comfortable going in at 4 with most patients with adequate marrow reserve.

Keith Stewart, MB, CHB: Has there been an issue with combinations that neutropenia becomes more of a problem?

Jatin J. Shah, MD: In which combinations?

Keith Stewart, MB, CHB: With, well let's say carfilzomib and pomalidomide.

Jatin J. Shah, MD: So we've seen that it's actually been very well tolerated in that sense. We haven't seen much cytopenias in that setting. Even in that late-line setting where these are meeting the 5 or 6 lines of prior therapy, we haven't seen those degree of cytopenias or dose reductions necessary.

Keith Stewart, MB, CHB: And we talked about the fact that lenalidomide, you need to be a bit cautious with dosing and renal failures. Is that true for pomalidomide, too, or is that different?

Jatin J. Shah, MD: So you know there's a trial, M008, which will be looking at pomalidomide renal failure. And there's another study in Europe that's being presented here at ASH really showing that you can use pomalidomide very safely in renal failure similar to thalidomide, where it's not necessarily renally cleared.

Keith Stewart, MB, CHB: Including dialysis?

Jatin J. Shah, MD: Including dialysis and that you can continuously dose these patients, which is very distinctly different than lenalidomide, which you have to be careful with. So I think that's very important data for our patients with renal dysfunction.

Ajai Chari, MD: I think one thing to consider is given the difference in patient populations where pomalidomide is used relative to lenalidomide, for the community practice, you may need to check blood counts more, even though you typically see these IMiD patients once a month, given the risk of neutropenia and almost a third of patients in pomalidomide/dexamethasone do require growth-factor support. It may be prudent to check at least the cycle one. So mid-cycle checks of the blood counts to ensure that patients aren't getting too cytopenic.

Keith Stewart, MB, CHB: In your carfilzomib-pomalidomide trial, what was the toxicity profile like? There's been a little bit of noise around the kidney and the endothelial system in carfilzomib-treated patients.

Jatin J. Shah, MD: So we didn't see a signal in the carfilzomib and pomalidomide combination that was unexpected.

Keith Stewart, MB, CHB: Unexpected? Meaning you still saw some rare events or not?

Jatin J. Shah, MD: Saw some rare events. We treated over 100 patients in that trial, so I think there's a few cases but nothing that was unexpected.

Keith Stewart, MB, CHB: Anybody have any other comments to make about any of these issues before we move on?

Sagar Lonial, MD: I think the thoughts that pomalidomide is a great partner is right on, and its ability to enhance immune function probably much more potently than lenalidomide I think probably does bridge to where I suspect you're trying to go next, which is adding it to daratumumab.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Keith Stewart, MB, CHB:
But I want to come to the fact that in the United States almost everybody has had a lot of lenalidomide when they progress, and they're often on lenalidomide when they progress. So how do we translate all these trials with lenalidomide at relapse into our practice? Jatin, you've explored pomalidomide at least in combination with carfilzomib and I think also with panobinostat, right?

Jatin J. Shah, MD: Not with panobinostat.

Keith Stewart, MB, CHB: With ixazomib.

Jatin J. Shah, MD: Yeah, well not with ixazomib, but we looked at it with carfilzomib. I think that's a very relevant clinical question that we see commonly and that's going to be what we all see in practice. What everybody sees globally is patients who are getting IMiD-based therapy with lenalidomide up-front and then progressing. So some of these trials don't necessarily apply to that. So I think pomalidomide is a very potent IMiD that is very active in that setting.

The challenge is it's about a 30% response rate in Revlimid-refractory patients. And so trying to find strategies to improve that response rate will be critically important. And so we did a trial with a number of colleagues with carfilzomib, pomalidomide, and dexamethasone, potentially combining the more potent proteome inhibitor and a very potent IMiD. And we saw (a), number one, that it's very well tolerated. So you can combine carfilzomib 27 mg/m2 in the standard schedule and pomalidomide 4 mg, and the response rates that were around 70% in that setting were in truly Revlimid-refractory as well as Velcade-refractory patients. So I think it's a very promising combination and a very active combination that we use frequently in the Revlimid-refractory patient.

Keith Stewart, MB, CHB: And, in fact, in my own practice, I know that it's become my first relapse regimen. Essentially you know people are coming in now, they've had VRD transplant, lenalidomide or lenalidomide and Velcade maintenance. And when they relapse, I’ve been using your regimen almost as my go-to treatment. But, Paul, you've had a lot of experience with pomalidomide, too, and some of the combinations coming along. Tell us about those.

Paul G. Richardson, MD: Yes. Well, I completely agree with Jatin. I think what we're very pleased with is pomalidomide; it's an excellent partner drug.

Keith Stewart, MB, CHB: Also the most potent of the IMiDs, is that correct?

Paul G. Richardson, MD: You're absolutely correct. And I think the other thing is that we find it partners beautifully with carfilzomib, it partners beautifully with bortezomib. We're able to recapture response even though they had multiple prior lines of therapy, etc. And the tolerability profile of pomalidomide I think is particularly encouraging. There have been no surprises and it's, I think, very well tolerated in renal disease as well, and it clearly I think it is an IMiD of choice in that setting now that we've got more information. But I think what's also very exciting, Keith, at this meeting is there are data now on pomalidomide and ixazomib.

Keith Stewart, MB, CHB: That's the one.

Paul G. Richardson, MD: Absolutely. That's our Alliance Study done by my colleague, Peter Voorhees, who has done a beautiful job with this early phase study. And it's moving now into a randomized phase II study. But the bottom line is Pete's showing beautiful tolerance and, at the same time, excellent activity in refractory patients, because the eligibility was the pomalidomide label (ie, refractory patients going into the trial). So that's one. And then I think it's perfect to have Ajai here because he can talk to us a little bit about pomalidomide and daratumumab.

Keith Stewart, MB, CHB: Let's hold that thought because we're going to finish our discussion this morning with daratumumab. We'll come back to that. So what I'm hearing is pomalidomide is a very potent drug—it works sometimes when you're refractory to lenalidomide—you can combine it with lots of different drugs, right?

Paul G. Richardson, MD: Yes, absolutely.

Keith Stewart, MB, CHB: And it hasn't been combined with elotuzumab yet, but there's no reason to think it wouldn't be combinable.

Ajai Chari, MD: It is, in trials.

Paul G. Richardson, MD: It is, and it's being studied. The trial's just opened.

Keith Stewart, MB, CHB: You know the main side effect, it seems to me, is neutropenia. What about dosing? We start at 4. Do you think 3 or 2 is the drop-down-to dose? Or what do you do in your own practice?

Paul G. Richardson, MD: Personally, I will start at 2 or 3 if I'm worried about a patient. But I'm very comfortable going in at 4 with most patients with adequate marrow reserve.

Keith Stewart, MB, CHB: Has there been an issue with combinations that neutropenia becomes more of a problem?

Jatin J. Shah, MD: In which combinations?

Keith Stewart, MB, CHB: With, well let's say carfilzomib and pomalidomide.

Jatin J. Shah, MD: So we've seen that it's actually been very well tolerated in that sense. We haven't seen much cytopenias in that setting. Even in that late-line setting where these are meeting the 5 or 6 lines of prior therapy, we haven't seen those degree of cytopenias or dose reductions necessary.

Keith Stewart, MB, CHB: And we talked about the fact that lenalidomide, you need to be a bit cautious with dosing and renal failures. Is that true for pomalidomide, too, or is that different?

Jatin J. Shah, MD: So you know there's a trial, M008, which will be looking at pomalidomide renal failure. And there's another study in Europe that's being presented here at ASH really showing that you can use pomalidomide very safely in renal failure similar to thalidomide, where it's not necessarily renally cleared.

Keith Stewart, MB, CHB: Including dialysis?

Jatin J. Shah, MD: Including dialysis and that you can continuously dose these patients, which is very distinctly different than lenalidomide, which you have to be careful with. So I think that's very important data for our patients with renal dysfunction.

Ajai Chari, MD: I think one thing to consider is given the difference in patient populations where pomalidomide is used relative to lenalidomide, for the community practice, you may need to check blood counts more, even though you typically see these IMiD patients once a month, given the risk of neutropenia and almost a third of patients in pomalidomide/dexamethasone do require growth-factor support. It may be prudent to check at least the cycle one. So mid-cycle checks of the blood counts to ensure that patients aren't getting too cytopenic.

Keith Stewart, MB, CHB: In your carfilzomib-pomalidomide trial, what was the toxicity profile like? There's been a little bit of noise around the kidney and the endothelial system in carfilzomib-treated patients.

Jatin J. Shah, MD: So we didn't see a signal in the carfilzomib and pomalidomide combination that was unexpected.

Keith Stewart, MB, CHB: Unexpected? Meaning you still saw some rare events or not?

Jatin J. Shah, MD: Saw some rare events. We treated over 100 patients in that trial, so I think there's a few cases but nothing that was unexpected.

Keith Stewart, MB, CHB: Anybody have any other comments to make about any of these issues before we move on?

Sagar Lonial, MD: I think the thoughts that pomalidomide is a great partner is right on, and its ability to enhance immune function probably much more potently than lenalidomide I think probably does bridge to where I suspect you're trying to go next, which is adding it to daratumumab.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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