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Antibodies for Relapsed/ Refractory Multiple Myeloma

Panelists: Keith Stewart, MB, CHB, Mayo Clinic; Gareth Morgan, MD, PhD, University of Arkansas for Medical Science; Saad Z. Usmani, MD, Levine Cancer Institute/Carolinas Healthcare System; Ivan M. Borrello, MD, Johns Hopkins Kimmel Cancer Center; Thomas G. Martin, MD, University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center; Sagar Lonial, MD, Winship Cancer Institute of Emory University
Published Online: Tuesday, Jul 11, 2017



Transcript:

Keith Stewart, MB, ChB:
Let’s move on and discuss relapsed disease. We’re all getting pretty comfortable, now, with daratumumab in this setting. But just to bring the audience up to speed, tell us about the studies that have been presented, recently, in daratumumab in relapsed myeloma. Ivan?

Ivan M. Borrello, MD: The 2 studies that were recently published in the New England Journal of Medicine were the CASTOR and POLLUX trials—CASTOR being daratumumab, bortezomib, and dexamethasone (DVd), and POLLUX with lenalidomide, daratumumab, and dexamethasone (DRd). These studies were rather impressive. They showed a significant improvement in progression-free survival in patients getting the monoclonal antibody, as well as achievement in a significant number of these patients of MRD (minimal residual disease)-negativity.

Keith Stewart, MB, ChB: No overall survival yet, right? Just PFS so far?

Ivan M. Borrello, MD: If I remember correctly, yes. I think the thing that, in my opinion, is still somewhat of an issue that hasn’t been resolved is how to integrate in monoclonal antibodies that may also have an immune-mediated mechanism with regimens that may be slightly immunosuppressive. And specifically, I’m referring to a combination of a monoclonal with a proteasome inhibitor.

I think if you look at the difference between the control arm and the DVd versus Revlimid(lenalidomide) and dexamethasone versus the DRd, I think that augmentation really speaks to the fact that there may, in fact, be some immune modulation that’s occurring with daratumumab that is weakened when you come in with a proteasome inhibitor.

Keith Stewart, MB, ChB: Did the results of the daratumumab with lenalidomide look a bit better than the proteasome inhibitor combination?

Ivan M. Borrello, MD: Yes. Our practice, at least, has been more to go in the direction of an IMiD as opposed to a proteasome inhibitor in combination with daratumumab.

Keith Stewart, MB, ChB: What about your practical experience of using daratumumab? Side effects, infusion, how are you getting on with that, Saad?

Saad Z. Usmani, MD: I think less than half of the patients get some degree of infusion reaction the first time around. For the most part, it’s grade 1 and 2, and it doesn’t occur again with subsequent infusions. Infusion time is usually around 6 or 7 hours the first time around, but it can be cut down to between 3 to 3.5 hours.

Keith Stewart, MB, ChB: Correct me if I’m wrong. You’re exploring new routes of delivery, is that correct?

Saad Z. Usmani, MD: That’s correct. We, along with other colleagues, are looking at a subcutaneous formulation of daratumumab. We presented the data at the ASH Annual Meeting. The overall response rates, in a cohort of roughly 40-odd patients, was fairly comparable to the intravenous formulation. There is a newer formulation, a premix formulation, that we are examining right now.

Keith Stewart, MB, ChB: But only in clinical trials, right?

Saad Z. Usmani, MD: Only in clinical trials. It is not ready for prime time, yet.

Keith Stewart, MB, ChB: Any other comments on daratumumab? Tom, is this your go-to first relapsed drug, now, or are you still using carfilzomib, or both together? What are you up to?

Thomas G. Martin, MD: We have a panacea of options, especially in the first relapse. It ends up being a very long discussion with the patients, and convenience probably plays a big role here. I tell them I would like to do a triple therapy for most of the patients. We have all oral triplets—ixazomib-lenalidomide-dexamethasone. We have pomalidomide-Cytoxan-dexamethasone as orals. We have some intravenous options—elotuzumab-lenalidomide-dexamethasone—where the infusion rate is a little bit faster and it’s less time in the clinic. And then, we have daratumumab, which seems to give you the biggest bang for the buck.

I would like to see what everybody else feels is appropriate. In terms of the daratumumab, with the infusion reactions, I give patients steroids for the first 2 infusions. After that, my patients don’t take day 2 or 3 dexamethasone at all, and I quickly taper off their pre-dexamethasone pre-medication.

Keith Stewart, MB, ChB: I think we’ve basically just used the same regimen each time. That might be laziness more than anything.

Saad Z. Usmani, MD: Except for maybe adding more montelukast, as well, for the first couple of doses—days 1 and 8. For patients who have a reaction, we continue it in cycle 1, and then we don’t need premedications from cycle 2 onwards.

Keith Stewart, MB, ChB: Do you do the same thing?

Sagar Lonial, MD: Yes.

Keith Stewart, MB, ChB: There was an abstract here on cytogenetic risk in the studies. Is anybody familiar with that?

Sagar Lonial, MD: There are both CASTOR and POLLUX data looking at subsets of patients. It appears, certainly with the lenalidomide arm, that the high-risk patients treated with daratumumab did better than either the standard-risk or the high-risk patients without daratumumab. The difference between the curves was less in the bortezomib arm than it was with the lenalidomide arm, and I would disagree a little bit about what Ivan says about the immunosuppressive effects of proteasome inhibitors. I think that what you’re seeing, the reason why the PFS is so good with lenalidomide, is that it’s continuous therapy as opposed to the bortezomib arm.

Keith Stewart, MB, ChB: And they stopped the bortezomib after 9 months, right?

Sagar Lonial, MD: Right. I think it’s a continuous therapy versus noncontinuous therapy arm, and I think that’s what the difference is between why the curves are more disparate in the lenalidomide arm than they are with the bortezomib arm.

Keith Stewart, MB, ChB: I thought the results of the control arm in the CASTOR study were not particularly good for bortezomib-dexamethasone alone. I must say, in my own practice, I’m not re-treating with bortezomib that much. I am switching to carfilzomib. How often do you re-treat with bortezomib, Sagar—again, because you use a lot of it in induction and maintenance?

Sagar Lonial, MD: For us, when somebody is progressing on lenalidomide-maintenance, our first salvage is to probably go to pomalidomide plus daratumumab, because the POLLUX trial was hard to extrapolate. The other choice is bortezomib plus daratumumab. I think that’s sort of the decision point for us.

Keith Stewart, MB, ChB: Very good. Elotuzumab. Are you using much elotuzumab, Tom?

Thomas G. Martin, MD: I use it in patients, honestly, who are more frail—in patients who do not want to spend 6 hours in the infusion chair. In that patient population, it actually works really well. When you get a nice response (and I’m curious to what Sagar says), and say they have some lenalidomide-based toxicity, I continue them on elotuzumab, alone. I’ve had people continue to respond for quite some time on just elotuzumab, alone.

Keith Stewart, MB, ChB: Ivan, are you using elotuzumab?

Ivan M. Borrello, MD: No, I haven’t really used it much in either maintenance or the relapsed setting.

Keith Stewart, MB, ChB: And you’re using a lot of daratumumab at relapse?

Ivan M. Borrello, MD: We’re using more daratumumab, yes.

Keith Stewart, MB, ChB: Saad, how about you?

Saad Z. Usmani, MD: I think the only place that I can find for elotuzumab, because it is an option, is that slow biochemical relapse in an elderly or frail patient where you have the luxury of time to see if this combination will help them or not before you move on to that next line of treatment. That’s where I would probably use it.

Gareth Morgan, MD, PhD: There’s a challenge with the sequencing, so I wonder about the use of elotuzumab if you’ve already been exposed to daratumumab, because of the cellular populations that get taken out.

Transcript Edited for Clarity

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Transcript:

Keith Stewart, MB, ChB:
Let’s move on and discuss relapsed disease. We’re all getting pretty comfortable, now, with daratumumab in this setting. But just to bring the audience up to speed, tell us about the studies that have been presented, recently, in daratumumab in relapsed myeloma. Ivan?

Ivan M. Borrello, MD: The 2 studies that were recently published in the New England Journal of Medicine were the CASTOR and POLLUX trials—CASTOR being daratumumab, bortezomib, and dexamethasone (DVd), and POLLUX with lenalidomide, daratumumab, and dexamethasone (DRd). These studies were rather impressive. They showed a significant improvement in progression-free survival in patients getting the monoclonal antibody, as well as achievement in a significant number of these patients of MRD (minimal residual disease)-negativity.

Keith Stewart, MB, ChB: No overall survival yet, right? Just PFS so far?

Ivan M. Borrello, MD: If I remember correctly, yes. I think the thing that, in my opinion, is still somewhat of an issue that hasn’t been resolved is how to integrate in monoclonal antibodies that may also have an immune-mediated mechanism with regimens that may be slightly immunosuppressive. And specifically, I’m referring to a combination of a monoclonal with a proteasome inhibitor.

I think if you look at the difference between the control arm and the DVd versus Revlimid(lenalidomide) and dexamethasone versus the DRd, I think that augmentation really speaks to the fact that there may, in fact, be some immune modulation that’s occurring with daratumumab that is weakened when you come in with a proteasome inhibitor.

Keith Stewart, MB, ChB: Did the results of the daratumumab with lenalidomide look a bit better than the proteasome inhibitor combination?

Ivan M. Borrello, MD: Yes. Our practice, at least, has been more to go in the direction of an IMiD as opposed to a proteasome inhibitor in combination with daratumumab.

Keith Stewart, MB, ChB: What about your practical experience of using daratumumab? Side effects, infusion, how are you getting on with that, Saad?

Saad Z. Usmani, MD: I think less than half of the patients get some degree of infusion reaction the first time around. For the most part, it’s grade 1 and 2, and it doesn’t occur again with subsequent infusions. Infusion time is usually around 6 or 7 hours the first time around, but it can be cut down to between 3 to 3.5 hours.

Keith Stewart, MB, ChB: Correct me if I’m wrong. You’re exploring new routes of delivery, is that correct?

Saad Z. Usmani, MD: That’s correct. We, along with other colleagues, are looking at a subcutaneous formulation of daratumumab. We presented the data at the ASH Annual Meeting. The overall response rates, in a cohort of roughly 40-odd patients, was fairly comparable to the intravenous formulation. There is a newer formulation, a premix formulation, that we are examining right now.

Keith Stewart, MB, ChB: But only in clinical trials, right?

Saad Z. Usmani, MD: Only in clinical trials. It is not ready for prime time, yet.

Keith Stewart, MB, ChB: Any other comments on daratumumab? Tom, is this your go-to first relapsed drug, now, or are you still using carfilzomib, or both together? What are you up to?

Thomas G. Martin, MD: We have a panacea of options, especially in the first relapse. It ends up being a very long discussion with the patients, and convenience probably plays a big role here. I tell them I would like to do a triple therapy for most of the patients. We have all oral triplets—ixazomib-lenalidomide-dexamethasone. We have pomalidomide-Cytoxan-dexamethasone as orals. We have some intravenous options—elotuzumab-lenalidomide-dexamethasone—where the infusion rate is a little bit faster and it’s less time in the clinic. And then, we have daratumumab, which seems to give you the biggest bang for the buck.

I would like to see what everybody else feels is appropriate. In terms of the daratumumab, with the infusion reactions, I give patients steroids for the first 2 infusions. After that, my patients don’t take day 2 or 3 dexamethasone at all, and I quickly taper off their pre-dexamethasone pre-medication.

Keith Stewart, MB, ChB: I think we’ve basically just used the same regimen each time. That might be laziness more than anything.

Saad Z. Usmani, MD: Except for maybe adding more montelukast, as well, for the first couple of doses—days 1 and 8. For patients who have a reaction, we continue it in cycle 1, and then we don’t need premedications from cycle 2 onwards.

Keith Stewart, MB, ChB: Do you do the same thing?

Sagar Lonial, MD: Yes.

Keith Stewart, MB, ChB: There was an abstract here on cytogenetic risk in the studies. Is anybody familiar with that?

Sagar Lonial, MD: There are both CASTOR and POLLUX data looking at subsets of patients. It appears, certainly with the lenalidomide arm, that the high-risk patients treated with daratumumab did better than either the standard-risk or the high-risk patients without daratumumab. The difference between the curves was less in the bortezomib arm than it was with the lenalidomide arm, and I would disagree a little bit about what Ivan says about the immunosuppressive effects of proteasome inhibitors. I think that what you’re seeing, the reason why the PFS is so good with lenalidomide, is that it’s continuous therapy as opposed to the bortezomib arm.

Keith Stewart, MB, ChB: And they stopped the bortezomib after 9 months, right?

Sagar Lonial, MD: Right. I think it’s a continuous therapy versus noncontinuous therapy arm, and I think that’s what the difference is between why the curves are more disparate in the lenalidomide arm than they are with the bortezomib arm.

Keith Stewart, MB, ChB: I thought the results of the control arm in the CASTOR study were not particularly good for bortezomib-dexamethasone alone. I must say, in my own practice, I’m not re-treating with bortezomib that much. I am switching to carfilzomib. How often do you re-treat with bortezomib, Sagar—again, because you use a lot of it in induction and maintenance?

Sagar Lonial, MD: For us, when somebody is progressing on lenalidomide-maintenance, our first salvage is to probably go to pomalidomide plus daratumumab, because the POLLUX trial was hard to extrapolate. The other choice is bortezomib plus daratumumab. I think that’s sort of the decision point for us.

Keith Stewart, MB, ChB: Very good. Elotuzumab. Are you using much elotuzumab, Tom?

Thomas G. Martin, MD: I use it in patients, honestly, who are more frail—in patients who do not want to spend 6 hours in the infusion chair. In that patient population, it actually works really well. When you get a nice response (and I’m curious to what Sagar says), and say they have some lenalidomide-based toxicity, I continue them on elotuzumab, alone. I’ve had people continue to respond for quite some time on just elotuzumab, alone.

Keith Stewart, MB, ChB: Ivan, are you using elotuzumab?

Ivan M. Borrello, MD: No, I haven’t really used it much in either maintenance or the relapsed setting.

Keith Stewart, MB, ChB: And you’re using a lot of daratumumab at relapse?

Ivan M. Borrello, MD: We’re using more daratumumab, yes.

Keith Stewart, MB, ChB: Saad, how about you?

Saad Z. Usmani, MD: I think the only place that I can find for elotuzumab, because it is an option, is that slow biochemical relapse in an elderly or frail patient where you have the luxury of time to see if this combination will help them or not before you move on to that next line of treatment. That’s where I would probably use it.

Gareth Morgan, MD, PhD: There’s a challenge with the sequencing, so I wonder about the use of elotuzumab if you’ve already been exposed to daratumumab, because of the cellular populations that get taken out.

Transcript Edited for Clarity
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