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Addressing Treatment of Myeloma-Related Comorbidity

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 13, 2018



Transcript: 

A. Keith Stewart, MB, ChB: Let’s talk about bone disease in myeloma. We’ve had bisphosphonates for a decade or longer. We recently saw a study with denosumab, and maybe one of you would like to explain to the audience what we learned from that study. Who’s feeling lively? There are you, you smiled, you got it.

Ajai Chari, MD: So, I think the most impressive thing about the study is actually the size. It was, I think, almost 1800 patients and newly diagnosed, all of whom got chemotherapy and were randomized to either receive denosumab, the RANK ligand inhibitor, or zoledronic acid. And it was noninferiority in terms of results. There was no difference in skeletal-related events. I think the toxicity profile was kind of interesting in terms of comparable rates of osteonecrosis of the jaw but slightly higher rates of renal toxicity with the zoledronic acid, slightly higher hypocalcemia in the denosumab arm. But the kind of unexpected finding was the PFS improvement with denosumab, almost 10 months.

A. Keith Stewart, MB, ChB: Amazing.

Ajai Chari, MD: Yes.

A. Keith Stewart, MB, ChB: Do you believe it? Because I don’t see why people wouldn’t, but some people have challenged it.

Ajai Chari, MD: It’s important that this was a randomized double-blinded trial, because you could argue, did physicians maybe not image as much? Whenever you see bony events, I think there’s always the question of how frequently they were being imaged and what kind of imaging. But I think the fact that it was randomized, patients were getting both IV and subQ, so that no one knew, I think it speaks to probably being real.

A. Keith Stewart, MB, ChB: Tom?

Thomas Martin, MD: So, I’m not sure I’m a believer on the 10.5-month improvement in the PFS, and I don’t have a good reason for why. Just same thing with the UK study, the oral versus IV, the 5.5 months. Is it access to drugs? It’s so hard to tell when it’s not just a United States study because access to drugs are very different in Europe, etc. That said, I do think that in patients who have renal insufficiency, I do use denosumab. It’s a small percentage of patients, but certainly for those patients, I think denosumab is the right drug. For everybody else, I still use the cost-saving zoledronic acid.

A. Keith Stewart, MB, ChB: I should have mentioned it, we did get FDA approval for denosumab earlier this year. Has it changed your practice at all now that it’s FDA approved, Sagar?

Sagar Lonial, MD, FACP: Yes, I think our main area of use is in patients with renal insufficiency where it’s tougher to give the bisphosphonates. I think the question that I’ve posed to our group is if somebody develops new bone lesions and they’re on zoledronic acid, is that rationale to switch, just as you switch therapy when they progress? Because I think that, to me, is a really interesting question. The PFS difference, it’s really hard to get because if the incidence of bone progression was the same between the 2 arms, bone progression should mean that you’re hitting your PFS endpoint. So, I’m not sure I understand that for this trial, but certainly there was a clear safety signal in terms of renal patients to get the drug.

A. Keith Stewart, MB, ChB: Ed, what do you think?

Edward A. Stadtmauer, MD: Well, I think we also have to pair this study with the other recent study that compared monthly zoledronic acid with every-3-monthly, showing there was a similar outcome for those different doses and schedules. So, many of us have moved to an every-3-monthly schedule, and yet the study that is presented, which I definitely do believe shows noninferiority of denosumab, it was a monthly schedule for that. And so, can we then extrapolate to every-3-monthly denosumab versus every-3-monthly zoledronic acid? So, I also have been cautious in my use and primarily use it for patients who have had toxicity to zoledronic acid or who have renal insufficiency. I think there was also some, at least, earlier reports of increased osteonecrosis with the denosumab, but I think with the larger study that may not be as clear.

A. Keith Stewart, MB, ChB: Renal failure, you mentioned there. Let’s talk about renal failure a little bit in myeloma. Does that change your therapeutic approach in relapse if somebody is on hemodialysis or acute renal failure? We talked about daratumumab, Kyprolis (carfilzomib), Velcade (bortezomib), and Pomalyst (pomalidomide). What does the presence of renal failure do to you in that setting?

Amrita Krishnan, MD, FACP: Well, I think the nice thing is most of these drugs you could use in patients with renal failure. Obviously, it’s just challenging if a patient is on dialysis and scheduling, but you can use daratumumab, you can use carfilzomib, you can use pomalidomide, which is very nice in regard to the pomalidomide versus lenalidomide.

A. Keith Stewart, MB, ChB: Let me just stop you there. The carfilzomib, are you comfortable using that in somebody if they’re not on hemodialysis yet, are you worried about that?

Amrita Krishnan, MD, FACP: I’m less worried about it. I think you have to maintain hydration and use it and be watchful in terms of tumor lysis. I personally think, yes, there is some carfilzomib toxicity—I think it was microangiopathy. Some of it I think was early tumor lysis, and I think you can mitigate certainly against tumor lysis. With hydration, I’ve really not seen a big renal signal.

A. Keith Stewart, MB, ChB: Is that everybody’s experience with it? What about lenalidomide? There’s some thinking that that’s a harder drug to give in renal failure. Do you use lenalidomide in renal failure or do you switch to something else?

Thomas Martin, MD: I would use lenalidomide in renal failure, but you have to dose appropriately. And I think especially in myeloma, it’s an aging population. You really have to do the creatinine clearance. Just take out your calculator, calculate the creatinine clearance, and dose the lenalidomide appropriately. As long as you dose it appropriately.

A. Keith Stewart, MB, ChB: I can’t believe you have a calculator. Most of us would use a computer.

Thomas Martin, MD: Not that kind of a calculator. I use the iPhone.

Edward A. Stadtmauer, MD: A slide rule. Use a slide rule.

Thomas Martin, MD: Take out your iPhone. Get your creatinine clearance and dose it appropriately. It’s right on the package insert, and that’s really the most important thing for dosing of lenalidomide. You can use it in renal insufficiency. You just have to dose it appropriately.

Sagar Lonial, MD, FACP: I think that presumes a relatively stable level of renal function. So, in the newly diagnosed setting where you don’t know what’s going to happen to renal function over the course of the first cycle, we actually use thalidomide, so VTd becomes our go-to. But once you’ve got stable renal function, then lenalidomide or pomalidomide. Pomalidomide is a little bit easier to use.

Transcript Edited for Clarity 

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Transcript: 

A. Keith Stewart, MB, ChB: Let’s talk about bone disease in myeloma. We’ve had bisphosphonates for a decade or longer. We recently saw a study with denosumab, and maybe one of you would like to explain to the audience what we learned from that study. Who’s feeling lively? There are you, you smiled, you got it.

Ajai Chari, MD: So, I think the most impressive thing about the study is actually the size. It was, I think, almost 1800 patients and newly diagnosed, all of whom got chemotherapy and were randomized to either receive denosumab, the RANK ligand inhibitor, or zoledronic acid. And it was noninferiority in terms of results. There was no difference in skeletal-related events. I think the toxicity profile was kind of interesting in terms of comparable rates of osteonecrosis of the jaw but slightly higher rates of renal toxicity with the zoledronic acid, slightly higher hypocalcemia in the denosumab arm. But the kind of unexpected finding was the PFS improvement with denosumab, almost 10 months.

A. Keith Stewart, MB, ChB: Amazing.

Ajai Chari, MD: Yes.

A. Keith Stewart, MB, ChB: Do you believe it? Because I don’t see why people wouldn’t, but some people have challenged it.

Ajai Chari, MD: It’s important that this was a randomized double-blinded trial, because you could argue, did physicians maybe not image as much? Whenever you see bony events, I think there’s always the question of how frequently they were being imaged and what kind of imaging. But I think the fact that it was randomized, patients were getting both IV and subQ, so that no one knew, I think it speaks to probably being real.

A. Keith Stewart, MB, ChB: Tom?

Thomas Martin, MD: So, I’m not sure I’m a believer on the 10.5-month improvement in the PFS, and I don’t have a good reason for why. Just same thing with the UK study, the oral versus IV, the 5.5 months. Is it access to drugs? It’s so hard to tell when it’s not just a United States study because access to drugs are very different in Europe, etc. That said, I do think that in patients who have renal insufficiency, I do use denosumab. It’s a small percentage of patients, but certainly for those patients, I think denosumab is the right drug. For everybody else, I still use the cost-saving zoledronic acid.

A. Keith Stewart, MB, ChB: I should have mentioned it, we did get FDA approval for denosumab earlier this year. Has it changed your practice at all now that it’s FDA approved, Sagar?

Sagar Lonial, MD, FACP: Yes, I think our main area of use is in patients with renal insufficiency where it’s tougher to give the bisphosphonates. I think the question that I’ve posed to our group is if somebody develops new bone lesions and they’re on zoledronic acid, is that rationale to switch, just as you switch therapy when they progress? Because I think that, to me, is a really interesting question. The PFS difference, it’s really hard to get because if the incidence of bone progression was the same between the 2 arms, bone progression should mean that you’re hitting your PFS endpoint. So, I’m not sure I understand that for this trial, but certainly there was a clear safety signal in terms of renal patients to get the drug.

A. Keith Stewart, MB, ChB: Ed, what do you think?

Edward A. Stadtmauer, MD: Well, I think we also have to pair this study with the other recent study that compared monthly zoledronic acid with every-3-monthly, showing there was a similar outcome for those different doses and schedules. So, many of us have moved to an every-3-monthly schedule, and yet the study that is presented, which I definitely do believe shows noninferiority of denosumab, it was a monthly schedule for that. And so, can we then extrapolate to every-3-monthly denosumab versus every-3-monthly zoledronic acid? So, I also have been cautious in my use and primarily use it for patients who have had toxicity to zoledronic acid or who have renal insufficiency. I think there was also some, at least, earlier reports of increased osteonecrosis with the denosumab, but I think with the larger study that may not be as clear.

A. Keith Stewart, MB, ChB: Renal failure, you mentioned there. Let’s talk about renal failure a little bit in myeloma. Does that change your therapeutic approach in relapse if somebody is on hemodialysis or acute renal failure? We talked about daratumumab, Kyprolis (carfilzomib), Velcade (bortezomib), and Pomalyst (pomalidomide). What does the presence of renal failure do to you in that setting?

Amrita Krishnan, MD, FACP: Well, I think the nice thing is most of these drugs you could use in patients with renal failure. Obviously, it’s just challenging if a patient is on dialysis and scheduling, but you can use daratumumab, you can use carfilzomib, you can use pomalidomide, which is very nice in regard to the pomalidomide versus lenalidomide.

A. Keith Stewart, MB, ChB: Let me just stop you there. The carfilzomib, are you comfortable using that in somebody if they’re not on hemodialysis yet, are you worried about that?

Amrita Krishnan, MD, FACP: I’m less worried about it. I think you have to maintain hydration and use it and be watchful in terms of tumor lysis. I personally think, yes, there is some carfilzomib toxicity—I think it was microangiopathy. Some of it I think was early tumor lysis, and I think you can mitigate certainly against tumor lysis. With hydration, I’ve really not seen a big renal signal.

A. Keith Stewart, MB, ChB: Is that everybody’s experience with it? What about lenalidomide? There’s some thinking that that’s a harder drug to give in renal failure. Do you use lenalidomide in renal failure or do you switch to something else?

Thomas Martin, MD: I would use lenalidomide in renal failure, but you have to dose appropriately. And I think especially in myeloma, it’s an aging population. You really have to do the creatinine clearance. Just take out your calculator, calculate the creatinine clearance, and dose the lenalidomide appropriately. As long as you dose it appropriately.

A. Keith Stewart, MB, ChB: I can’t believe you have a calculator. Most of us would use a computer.

Thomas Martin, MD: Not that kind of a calculator. I use the iPhone.

Edward A. Stadtmauer, MD: A slide rule. Use a slide rule.

Thomas Martin, MD: Take out your iPhone. Get your creatinine clearance and dose it appropriately. It’s right on the package insert, and that’s really the most important thing for dosing of lenalidomide. You can use it in renal insufficiency. You just have to dose it appropriately.

Sagar Lonial, MD, FACP: I think that presumes a relatively stable level of renal function. So, in the newly diagnosed setting where you don’t know what’s going to happen to renal function over the course of the first cycle, we actually use thalidomide, so VTd becomes our go-to. But once you’ve got stable renal function, then lenalidomide or pomalidomide. Pomalidomide is a little bit easier to use.

Transcript Edited for Clarity 
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