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Newly Diagnosed MM: Is RVd Still Standard of Care?

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: Tuesday, Jul 17, 2018



Transcript: 

A. Keith Stewart, MB, ChB: Thank you for joining this OncLive® Peer Exchange®, which will feature a clinical discussion on mixed-generation regimens for treatment of multiple myeloma. Optimizing therapy for patients with newly-diagnosed multiple myeloma remains a work in progress, particularly for patients with high-risk disease. We continue to develop new regimens with the goals of obtaining deeper and more durable control of myeloma, as well as improving options for patients with relapsed and refractory disease. In this OncLive® Peer Exchange®, my colleagues and I will look at a way to start up from the ASCO 2018 Annual Meeting. We’ll provide our personal perspective on the new research, new agents and new combinations that are being applied and considering how they will fit into current clinical care.

I am Dr. Keith Stewart,  Vasek and Anna Maria Polak Professor of Cancer Research for the Mayo Clinic based in Scottsdale, Arizona. Participating today on our distinguished panel are Dr. Ajai Chari, an associate professor of medicine, hematology and medical oncology at Mount Sinai Hospital in New York, New York; Dr. Amrita Krishnan, director of the Judy and Bernard Briskin Center for Multiple Myeloma Research, and a professor of hematology and hematopoietic cell transplantation at City of Hope Cancer Center in Duarte, California; Dr. Sagar Lonial, chair and professor of the Department of Hematology and Medical Oncology, and chief medical officer of the Winship Cancer Institute, Emory University School of Medicine in Atlanta, Georgia; Dr. Tom Martin, co-director of the Myeloma Program at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, California; and Dr. Ed Stadtmauer, the President’s Distinguished Professor and Section Chief of Hematologic Malignancies at the Abramson Cancer Center of Penn Medicine in Philadelphia, Pennsylvania. Thank you so much for joining us, and let’s get started.

We’re going to begin with a discussion of treatment approaches for newly diagnosed multiple myeloma. And Dr. Lonial, you have published that the combination of lenalidomide/bortezomib/dexamethasone, or RVd, is standard of care in your institution. Is that true do you think nationally now? And if it is not RVd, what alternatives exist?

Sagar Lonial, MD, FACP: Yes, I think that’s a great question. And I think after years and years of experience with RVd, it’s pretty clear that RVd is a standard, probably the one with one of the largest clinical trial data supporting its use for newly-diagnosed myeloma. I think the competitors in that space, if you will, use KRd, or carfilzomib in combination with lenalidomide and dexamethasone, which also has some really encouraging data in small phase II studies, but so far, we don’t really have phase III data at this time point to really compare it head-to-head.

A. Keith Stewart, MB, ChB: Tell us a little bit of what we could expect with RVd. What kind of response rate and progression-free survival are you seeing, or even complete response rate?

Sagar Lonial, MD, FACP: If you begin to look at the overall response rate of patients receiving RVd, it’s probably somewhere between 90% and 100%, depending upon which series you look at. And I think if you look at if CR rates are better, it’s probably somewhere around 40%, certainly for the first 4 cycles of treatment. And if you look at KRd, it’s probably not that different in terms of depth of response at 4 cycles. The real advantage that carfilzomib brings to the table is less peripheral neuropathy, and the ability to potentially stay on KRd for a longer period of time when you could stay on VRd with fewer side effects.

A. Keith Stewart, MB, ChB: I was just going to switch over to you, Tom. Is RVd appropriate in the more elderly patient or is it just for younger people?

Thomas Martin, MD: I think for the transplant-eligible, RVd for sure is the number 1 regimen that we use here in the United States. For the transplant-ineligible, you have to make small changes in the RVd. So, we call it RVd-lite and it’s a published regimen. And essentially, the regimen has lower doses of Revlimid, or lenalidomide, and lower doses of dexamethasone. Typically, we give weekly bortezomib. And it’s based on a 35-day schedule instead of a 21- or 28-day schedule with whatever you use. There are different regimens. So, with a 35-day regimen with RVd, it’s very well tolerated, even in the transplant-ineligible, even in the frail patients. And I think essentially for almost every patient with newly diagnosed myeloma, you can use an RVd-type regimen as induction and get the response rates that Dr. Lonial was saying—90% response rate, 100% response rates, which is really great. I have a question for all you guys, and that is, when you do it in the transplant eligible, how many cycles do you give before you take them to transplant?

A. Keith Stewart, MB, ChB: Good question. Ed, do you want to respond to that?

Edward A. Stadtmauer, MD: Well, there are no great data for this, though most of the studies took patients and gave them 4 to 6 cycles of therapy. I think that most of the data suggest that you want to have a nice response. The number of cycles is really based more on how the patients are tolerating the regimen and what kind of responses they’re having. But in the old days, we used to maybe take 2 cycles and then send them to transplant. It’s also looking like maybe a little bit more is better, but somewhere in the neighborhood of 4 to 6 cycles is usually what we’re seeing.

A. Keith Stewart, MB, ChB: AJ, you’ve published on carfilzomib in the newly diagnosed setting. Tell us a little bit about your thoughts about replacing bortezomib with carfilzomib and whether you’re doing that or not.

Ajai Chari, MD: I think KRd has been shown to be a very effective regimen. I would add that outside of clinical trials and real-world practice, we’re not fixed to picking 1 regimen and sticking with it with a fixed cycle. You can start with VRd and if you’re getting a suboptimal response or you’re getting neuropathy, switch to KRd.

But with the KRd data, people talk a lot about the toxicity but it’s important to really evaluate toxicity. You can’t do that from a single-arm study. And when you look at controlled studies, yes, there is a signal, but we have neuropathy, secondary malignancies, and myelosuppression with other drugs, and we’re comfortable managing that. And I think the key is in the randomized study, how common is it and does it affect the survival? And both ENDEAVOR, Kd versus Vd, and ASPIRE, KRd versus RV, showed an OS benefit, showing that even if there is a cardiopulmonary issue, it’s not so high that it’s overcoming the benefit.

And I think the ways to kind of mitigate that are really looking at the patient and doing a baseline risk assessment, if they have a cardiac history, and basically being a good doctor by monitoring their symptoms and signs after each cycle, minimizing fluids after the first dose, and minimizing steroid use. But at the end of the day, I think it’s a very effective drug. I think it’ll be interesting. Probably the question coming up next would be, if these are the triplets, how is the addition of monoclonal antibodies, particularly CD38?

A. Keith Stewart, MB, ChB: We’re going to get to there. Before we get there, Amrita, are you using carfilzomib? And if so, what kind of patient would you select for that?

Amrita Krishnan, MD, FACP: For the newly diagnosed, I’m using it in high-risk patients, younger patients. I’m pretty comfortable giving it to them.

A. Keith Stewart, MB, ChB: Is that sort of the consensus of the group? Anybody considering a more elderly frail patient for carfilzomib, or is that a step too far today?

Thomas Martin, MD: I think for the start of therapy, the RVd, especially in the elderly or specifically the frail patient, that’s a good regimen to start with. If they are having neuropathy or they’re having side effects that we can attribute to bortezomib, then I have no problems actually switching them over to carfilzomib. And like Ajai has said, you just have to control their blood pressure really well and control their fluids, and these guys can tolerate it fine.

Edward A. Stadtmauer, MD: And for the older or frailer patient, I think sometimes less is more. You can use a lower starting dose of lenalidomide, a lower or a less frequent bortezomib. As you were saying, the VRd-lite. And it’s more than just getting these medicines into patients. It’s being able to continue these therapies for a long period of time.

Ajai Chari, MD: I think the other issue with the elderly patients, it’s not that the carfilzomib is a different drug, the host factors are tremendously different. As you get older, you have a lot more cardiopulmonary-baseline comorbidities, and that’s the nuance that interplays with carfilzomib.

A. Keith Stewart, MB, ChB: So, it’s important to remind the viewers that there is a big randomized trial happening right now in the United States, many hundreds of patients are receiving a VRd or KRd. I think until that matures and we see some of that data, we’re in a transition phase with these drugs.

Transcript Edited for Clarity 

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Transcript: 

A. Keith Stewart, MB, ChB: Thank you for joining this OncLive® Peer Exchange®, which will feature a clinical discussion on mixed-generation regimens for treatment of multiple myeloma. Optimizing therapy for patients with newly-diagnosed multiple myeloma remains a work in progress, particularly for patients with high-risk disease. We continue to develop new regimens with the goals of obtaining deeper and more durable control of myeloma, as well as improving options for patients with relapsed and refractory disease. In this OncLive® Peer Exchange®, my colleagues and I will look at a way to start up from the ASCO 2018 Annual Meeting. We’ll provide our personal perspective on the new research, new agents and new combinations that are being applied and considering how they will fit into current clinical care.

I am Dr. Keith Stewart,  Vasek and Anna Maria Polak Professor of Cancer Research for the Mayo Clinic based in Scottsdale, Arizona. Participating today on our distinguished panel are Dr. Ajai Chari, an associate professor of medicine, hematology and medical oncology at Mount Sinai Hospital in New York, New York; Dr. Amrita Krishnan, director of the Judy and Bernard Briskin Center for Multiple Myeloma Research, and a professor of hematology and hematopoietic cell transplantation at City of Hope Cancer Center in Duarte, California; Dr. Sagar Lonial, chair and professor of the Department of Hematology and Medical Oncology, and chief medical officer of the Winship Cancer Institute, Emory University School of Medicine in Atlanta, Georgia; Dr. Tom Martin, co-director of the Myeloma Program at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, California; and Dr. Ed Stadtmauer, the President’s Distinguished Professor and Section Chief of Hematologic Malignancies at the Abramson Cancer Center of Penn Medicine in Philadelphia, Pennsylvania. Thank you so much for joining us, and let’s get started.

We’re going to begin with a discussion of treatment approaches for newly diagnosed multiple myeloma. And Dr. Lonial, you have published that the combination of lenalidomide/bortezomib/dexamethasone, or RVd, is standard of care in your institution. Is that true do you think nationally now? And if it is not RVd, what alternatives exist?

Sagar Lonial, MD, FACP: Yes, I think that’s a great question. And I think after years and years of experience with RVd, it’s pretty clear that RVd is a standard, probably the one with one of the largest clinical trial data supporting its use for newly-diagnosed myeloma. I think the competitors in that space, if you will, use KRd, or carfilzomib in combination with lenalidomide and dexamethasone, which also has some really encouraging data in small phase II studies, but so far, we don’t really have phase III data at this time point to really compare it head-to-head.

A. Keith Stewart, MB, ChB: Tell us a little bit of what we could expect with RVd. What kind of response rate and progression-free survival are you seeing, or even complete response rate?

Sagar Lonial, MD, FACP: If you begin to look at the overall response rate of patients receiving RVd, it’s probably somewhere between 90% and 100%, depending upon which series you look at. And I think if you look at if CR rates are better, it’s probably somewhere around 40%, certainly for the first 4 cycles of treatment. And if you look at KRd, it’s probably not that different in terms of depth of response at 4 cycles. The real advantage that carfilzomib brings to the table is less peripheral neuropathy, and the ability to potentially stay on KRd for a longer period of time when you could stay on VRd with fewer side effects.

A. Keith Stewart, MB, ChB: I was just going to switch over to you, Tom. Is RVd appropriate in the more elderly patient or is it just for younger people?

Thomas Martin, MD: I think for the transplant-eligible, RVd for sure is the number 1 regimen that we use here in the United States. For the transplant-ineligible, you have to make small changes in the RVd. So, we call it RVd-lite and it’s a published regimen. And essentially, the regimen has lower doses of Revlimid, or lenalidomide, and lower doses of dexamethasone. Typically, we give weekly bortezomib. And it’s based on a 35-day schedule instead of a 21- or 28-day schedule with whatever you use. There are different regimens. So, with a 35-day regimen with RVd, it’s very well tolerated, even in the transplant-ineligible, even in the frail patients. And I think essentially for almost every patient with newly diagnosed myeloma, you can use an RVd-type regimen as induction and get the response rates that Dr. Lonial was saying—90% response rate, 100% response rates, which is really great. I have a question for all you guys, and that is, when you do it in the transplant eligible, how many cycles do you give before you take them to transplant?

A. Keith Stewart, MB, ChB: Good question. Ed, do you want to respond to that?

Edward A. Stadtmauer, MD: Well, there are no great data for this, though most of the studies took patients and gave them 4 to 6 cycles of therapy. I think that most of the data suggest that you want to have a nice response. The number of cycles is really based more on how the patients are tolerating the regimen and what kind of responses they’re having. But in the old days, we used to maybe take 2 cycles and then send them to transplant. It’s also looking like maybe a little bit more is better, but somewhere in the neighborhood of 4 to 6 cycles is usually what we’re seeing.

A. Keith Stewart, MB, ChB: AJ, you’ve published on carfilzomib in the newly diagnosed setting. Tell us a little bit about your thoughts about replacing bortezomib with carfilzomib and whether you’re doing that or not.

Ajai Chari, MD: I think KRd has been shown to be a very effective regimen. I would add that outside of clinical trials and real-world practice, we’re not fixed to picking 1 regimen and sticking with it with a fixed cycle. You can start with VRd and if you’re getting a suboptimal response or you’re getting neuropathy, switch to KRd.

But with the KRd data, people talk a lot about the toxicity but it’s important to really evaluate toxicity. You can’t do that from a single-arm study. And when you look at controlled studies, yes, there is a signal, but we have neuropathy, secondary malignancies, and myelosuppression with other drugs, and we’re comfortable managing that. And I think the key is in the randomized study, how common is it and does it affect the survival? And both ENDEAVOR, Kd versus Vd, and ASPIRE, KRd versus RV, showed an OS benefit, showing that even if there is a cardiopulmonary issue, it’s not so high that it’s overcoming the benefit.

And I think the ways to kind of mitigate that are really looking at the patient and doing a baseline risk assessment, if they have a cardiac history, and basically being a good doctor by monitoring their symptoms and signs after each cycle, minimizing fluids after the first dose, and minimizing steroid use. But at the end of the day, I think it’s a very effective drug. I think it’ll be interesting. Probably the question coming up next would be, if these are the triplets, how is the addition of monoclonal antibodies, particularly CD38?

A. Keith Stewart, MB, ChB: We’re going to get to there. Before we get there, Amrita, are you using carfilzomib? And if so, what kind of patient would you select for that?

Amrita Krishnan, MD, FACP: For the newly diagnosed, I’m using it in high-risk patients, younger patients. I’m pretty comfortable giving it to them.

A. Keith Stewart, MB, ChB: Is that sort of the consensus of the group? Anybody considering a more elderly frail patient for carfilzomib, or is that a step too far today?

Thomas Martin, MD: I think for the start of therapy, the RVd, especially in the elderly or specifically the frail patient, that’s a good regimen to start with. If they are having neuropathy or they’re having side effects that we can attribute to bortezomib, then I have no problems actually switching them over to carfilzomib. And like Ajai has said, you just have to control their blood pressure really well and control their fluids, and these guys can tolerate it fine.

Edward A. Stadtmauer, MD: And for the older or frailer patient, I think sometimes less is more. You can use a lower starting dose of lenalidomide, a lower or a less frequent bortezomib. As you were saying, the VRd-lite. And it’s more than just getting these medicines into patients. It’s being able to continue these therapies for a long period of time.

Ajai Chari, MD: I think the other issue with the elderly patients, it’s not that the carfilzomib is a different drug, the host factors are tremendously different. As you get older, you have a lot more cardiopulmonary-baseline comorbidities, and that’s the nuance that interplays with carfilzomib.

A. Keith Stewart, MB, ChB: So, it’s important to remind the viewers that there is a big randomized trial happening right now in the United States, many hundreds of patients are receiving a VRd or KRd. I think until that matures and we see some of that data, we’re in a transition phase with these drugs.

Transcript Edited for Clarity 
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