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Impact of Elotuzumab in R/R Myeloma Therapies

Panelists: A. Keith Stewart, MB, ChB, Mayo Clinic; Cristina Gasparetto, MD, Duke University Medical Center; Parameswaran Hari, MD, MRCP, MS, Medical College of Wisconsin; Robert Orlowski, MD, PhD, MD Anderson Cancer Center; Noopur Suresh Raje, MD, Massachusetts General Hospital
Published: Monday, Feb 19, 2018



Transcript: 

A. Keith Stewart, MB, ChB: What about elotuzumab, Hari, where do you use that?

Parameswaran Hari, MD, MRCP, MS: I tend to use elotuzumab in just 1 setting: where a person is on lenalidomide maintenance, either posttransplant or nontransplant eligible, and thereby chemically their numbers are going up, but they feel exceptionally well. And I just don’t want to wait on that disease. I try to get more mileage for the lenalidomide by adding in elotuzumab and going up on the lenalidomide. And it works in some cases, and it might prolong the next big regimen that we have to use.

A. Keith Stewart, MB, ChB: Noopur, you’re using elotuzumab?

Noopur Suresh Raje, MD: I’m using elotuzumab less and less. I think it’s hard to find a place for elotuzumab. I do think elotuzumab is a drug that should be used early on in the disease and probably as a maintenance strategy, the way Bob is using it in his trial. We just don’t have the data to speak to that just yet, but my patient, who is somebody I’m treating with lenalidomide, with a low-risk relapse would be where I would add elotuzumab.

A. Keith Stewart, MB, ChB: Is everybody in agreement with that? That’s the general use of elotuzumab?

Robert Orlowski, MD, PhD: There were up-front studies with elotuzumab-based combos. Through SWOG, we did a combination with elotuzumab/lenalidomide/bortezomib/dexamethasone versus RVd for high-risk patients, and we don’t have the data yet because they haven’t really read out yet.

A. Keith Stewart, MB, ChB: In relapse or in newly diagnosed?

Robert Orlowski, MD, PhD: This was frontline, and there was actually an abstract from Jacob Laubach at this meeting looking at elotuzumab/RVd frontline, which was actually a little concerning because there were quite a few infections, probably because of the lymphocytopenia. So, it’s definitely a regimen that one has to be careful about, and I’m not sure about its role in the up-front setting at this point.

A. Keith Stewart, MB, ChB: People who are getting daratumumab in the frontline setting, do you think elotuzumab will be an antibody we use at relapse or do you think we’d re-treat with daratumumab?

Cristina Gasparetto, MD: I think re-treatment with daratumumab. I was actually waiting for the results of their study in the maintenance. I was very interested to see how the high-risk patients behaved with the addition of elotuzumab after transplant. That will be interesting. Rather than combine with a proteasome inhibitor, going with elotuzumab. But I think in relapse, I will go ahead and re-treat with daratumumab.

A. Keith Stewart, MB, ChB: In patients who are on daratumumab and they’re beginning to progress, is anybody changing the schedule? I’ve heard this bandied around as one strategy. Noopur, what?

Noopur Suresh Raje, MD: I think all of us have done that.

A. Keith Stewart, MB, ChB: And describe what you do for the audience.

Noopur Suresh Raje, MD: So, typically what happens with a daratumumab-based regimen is you give weekly daratumumab for the first 8 weeks, then you go every other week for the next 4 months, and then you go to monthly. So, if somebody is progressing on monthly, I have gone back to a more intensive daratumumab regimen, which is either start off weekly or sometimes every other week. And we do recapture responses in that. Again, those may not be long-lived responses but we’ve done that.

A. Keith Stewart, MB, ChB: Hari?

Parameswaran Hari, MD, MRCP, MS: I do exactly the same thing. There are probably data that are coming soon about drugs that can increase antigen expression, including things like cyclophosphamide at low doses and metronomic doses of cyclophosphamide/ATRA (all-trans retinoic acid)
 
A. Keith Stewart, MB, ChB: When you treat your patients with, let’s say, daratumumab/pomalidomide/dexamethasone at relapse, is your plan in a younger patient to use a second transplant or are you using that as a risk-adapted, depending on the response, strategy? Christina, do you retransplant people?

Cristina Gasparetto, MD: It depends on the duration of the first remission. And I think our cutoff was 18 months, 24 months. However, now with the maintenance, I think we need to revisit that cutoff because we see even the high-risk patient going longer. And so, if they’re going to benefit from a second autologous transplant, it isn’t clear to me yet. So, we need to revisit that in the transplant world. But yes, if I have a patient in remission for 4 to 5 years, I rechallenge with another transplant, reset the clock in that way. What is confusing right now is what we do in the maintenance in that situation, right? Are we going to go with the pomalidomide? Are we going to go back with pomalidomide/daratumumab? Is the transplant allowing us to achieve the depth and then continuation? So, a little bit of confusion in that setting.

A. Keith Stewart, MB, ChB: Bob, what do you think about second transplants?

Robert Orlowski, MD, PhD: I agree. I think it’s reasonable in people who have had a good benefit from the first. There are data now from MD Anderson from a randomized study comparing just melphalan alone as a conditioning regimen to busulfan with melphalan.

A. Keith Stewart, MB, ChB: Yes, let’s talk about that.

Robert Orlowski, MD, PhD: Which may be better in terms of efficacy, although it has some toxicity associated with it. So, if we re-transplant folks, we often will do a combination conditioning regimen like that. I did want to briefly go back to this question of re-treating with daratumumab because before we, as a panel, anoint that as a standard of care, there are absolutely no rigorous data to prove that continuing this expensive drug, which over time reduces CD38 expression on the myeloma cells, is of benefit. What you would need to do is, for example, if you progress on daratumumab/lenalidomide/dexamethasone, compare in a randomized fashion bortezomib/dexamethasone versus daratumumab/bortezomib/dexamethasone. Literally, we have case reports now. So, I actually don’t continue daratumumab if patients do progress on daratumumab.

A. Keith Stewart, MB, ChB: Actually, thank you for bringing us back to reality there, but I completely agree with you. We have this notion that going back to weekly is somehow magical. But we really have no evidence that this is the case.

Cristina Gasparetto, MD: We don’t.

Parameswaran Hari, MD, MRCP, MS: And I agree that we should actually follow it up with CD38 expression if it is, and then strategies to improve CD38 expression might be the way to go.

Robert Orlowski, MD, PhD: But it could also be that some kind of T cell, NK cell, or macrophage exhaustion is the mechanism for resistance, in which case coming in with another antibody that depends on ADCC may not really be of benefit.


Transcript Edited for Clarity 

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Transcript: 

A. Keith Stewart, MB, ChB: What about elotuzumab, Hari, where do you use that?

Parameswaran Hari, MD, MRCP, MS: I tend to use elotuzumab in just 1 setting: where a person is on lenalidomide maintenance, either posttransplant or nontransplant eligible, and thereby chemically their numbers are going up, but they feel exceptionally well. And I just don’t want to wait on that disease. I try to get more mileage for the lenalidomide by adding in elotuzumab and going up on the lenalidomide. And it works in some cases, and it might prolong the next big regimen that we have to use.

A. Keith Stewart, MB, ChB: Noopur, you’re using elotuzumab?

Noopur Suresh Raje, MD: I’m using elotuzumab less and less. I think it’s hard to find a place for elotuzumab. I do think elotuzumab is a drug that should be used early on in the disease and probably as a maintenance strategy, the way Bob is using it in his trial. We just don’t have the data to speak to that just yet, but my patient, who is somebody I’m treating with lenalidomide, with a low-risk relapse would be where I would add elotuzumab.

A. Keith Stewart, MB, ChB: Is everybody in agreement with that? That’s the general use of elotuzumab?

Robert Orlowski, MD, PhD: There were up-front studies with elotuzumab-based combos. Through SWOG, we did a combination with elotuzumab/lenalidomide/bortezomib/dexamethasone versus RVd for high-risk patients, and we don’t have the data yet because they haven’t really read out yet.

A. Keith Stewart, MB, ChB: In relapse or in newly diagnosed?

Robert Orlowski, MD, PhD: This was frontline, and there was actually an abstract from Jacob Laubach at this meeting looking at elotuzumab/RVd frontline, which was actually a little concerning because there were quite a few infections, probably because of the lymphocytopenia. So, it’s definitely a regimen that one has to be careful about, and I’m not sure about its role in the up-front setting at this point.

A. Keith Stewart, MB, ChB: People who are getting daratumumab in the frontline setting, do you think elotuzumab will be an antibody we use at relapse or do you think we’d re-treat with daratumumab?

Cristina Gasparetto, MD: I think re-treatment with daratumumab. I was actually waiting for the results of their study in the maintenance. I was very interested to see how the high-risk patients behaved with the addition of elotuzumab after transplant. That will be interesting. Rather than combine with a proteasome inhibitor, going with elotuzumab. But I think in relapse, I will go ahead and re-treat with daratumumab.

A. Keith Stewart, MB, ChB: In patients who are on daratumumab and they’re beginning to progress, is anybody changing the schedule? I’ve heard this bandied around as one strategy. Noopur, what?

Noopur Suresh Raje, MD: I think all of us have done that.

A. Keith Stewart, MB, ChB: And describe what you do for the audience.

Noopur Suresh Raje, MD: So, typically what happens with a daratumumab-based regimen is you give weekly daratumumab for the first 8 weeks, then you go every other week for the next 4 months, and then you go to monthly. So, if somebody is progressing on monthly, I have gone back to a more intensive daratumumab regimen, which is either start off weekly or sometimes every other week. And we do recapture responses in that. Again, those may not be long-lived responses but we’ve done that.

A. Keith Stewart, MB, ChB: Hari?

Parameswaran Hari, MD, MRCP, MS: I do exactly the same thing. There are probably data that are coming soon about drugs that can increase antigen expression, including things like cyclophosphamide at low doses and metronomic doses of cyclophosphamide/ATRA (all-trans retinoic acid)
 
A. Keith Stewart, MB, ChB: When you treat your patients with, let’s say, daratumumab/pomalidomide/dexamethasone at relapse, is your plan in a younger patient to use a second transplant or are you using that as a risk-adapted, depending on the response, strategy? Christina, do you retransplant people?

Cristina Gasparetto, MD: It depends on the duration of the first remission. And I think our cutoff was 18 months, 24 months. However, now with the maintenance, I think we need to revisit that cutoff because we see even the high-risk patient going longer. And so, if they’re going to benefit from a second autologous transplant, it isn’t clear to me yet. So, we need to revisit that in the transplant world. But yes, if I have a patient in remission for 4 to 5 years, I rechallenge with another transplant, reset the clock in that way. What is confusing right now is what we do in the maintenance in that situation, right? Are we going to go with the pomalidomide? Are we going to go back with pomalidomide/daratumumab? Is the transplant allowing us to achieve the depth and then continuation? So, a little bit of confusion in that setting.

A. Keith Stewart, MB, ChB: Bob, what do you think about second transplants?

Robert Orlowski, MD, PhD: I agree. I think it’s reasonable in people who have had a good benefit from the first. There are data now from MD Anderson from a randomized study comparing just melphalan alone as a conditioning regimen to busulfan with melphalan.

A. Keith Stewart, MB, ChB: Yes, let’s talk about that.

Robert Orlowski, MD, PhD: Which may be better in terms of efficacy, although it has some toxicity associated with it. So, if we re-transplant folks, we often will do a combination conditioning regimen like that. I did want to briefly go back to this question of re-treating with daratumumab because before we, as a panel, anoint that as a standard of care, there are absolutely no rigorous data to prove that continuing this expensive drug, which over time reduces CD38 expression on the myeloma cells, is of benefit. What you would need to do is, for example, if you progress on daratumumab/lenalidomide/dexamethasone, compare in a randomized fashion bortezomib/dexamethasone versus daratumumab/bortezomib/dexamethasone. Literally, we have case reports now. So, I actually don’t continue daratumumab if patients do progress on daratumumab.

A. Keith Stewart, MB, ChB: Actually, thank you for bringing us back to reality there, but I completely agree with you. We have this notion that going back to weekly is somehow magical. But we really have no evidence that this is the case.

Cristina Gasparetto, MD: We don’t.

Parameswaran Hari, MD, MRCP, MS: And I agree that we should actually follow it up with CD38 expression if it is, and then strategies to improve CD38 expression might be the way to go.

Robert Orlowski, MD, PhD: But it could also be that some kind of T cell, NK cell, or macrophage exhaustion is the mechanism for resistance, in which case coming in with another antibody that depends on ADCC may not really be of benefit.


Transcript Edited for Clarity 
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