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Immunotherapy for 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: Wednesday, Jul 19, 2017


Transcript:

Keith Stewart, MB, ChB:
Let’s move on and talk about some of the emerging agents in myeloma. Like everybody else in cancer, we’re in the early years of a revolution of the use of immunotherapy. Ivan, you’ve been most active in this area of all of us. Tell us about the rationale for immunotherapy in myeloma—particularly, the potential for using checkpoint inhibitors.

Ivan M. Borrello, MD: I think, obviously, checkpoint inhibitors have revolutionized many solid tumors—melanoma, lung, etc—and I think their history in myeloma has been very interesting because, as single agents, they had absolutely zero activity. Certainly, nivolumab did, and pembrolizumab was never really checked. They’re very similar antibodies, I think, but they have shown significant activity with the incorporation of IMiDs (immunomodulatory imide drugs).

The pembrolizumab-lenalidomide data, which are being updated here at the 2017 ASCO Annual Meeting, are showing a 44% response rate. The thing that’s actually very interesting is that they looked at patients who were Revlimid-refractory compared to those who weren’t, and there was equivalent response rates in both arms, with a significant duration of response of over 20 months. Actually, 25 months in the Revlimid-refractory patients.

Keith Stewart, MB, ChB: I was very impressed by that. What would you expect in that population without pembrolizumab?

Ivan M. Borrello, MD: These are patients who are Revlimid-refractory and are getting a 20-month duration of response with Revlimid plus pembrolizumab. Without pembrolizumab, I think the response would be zero. What this is really speaking to is the immunomodulation of IMiDs in combination with various immunotherapies.

In this case, we’re looking at checkpoint inhibitors. I think the clinical data speak clearly that these combinations are essential for maximizing a tumor-specific immune response. But I can tell you that we have also looked at combinations with vaccines, and there have been papers published about combining IMiDs with CAR (chimeric antigen receptor) T-cell or adoptive T-cell therapy. And that really speaks to the ability of this class of drugs to increase immuno-stimulation. What’s also emerging now is increasing the synapse between the tumor and the T cell itself. It’s probably mediating some of this immune activity.

Keith Stewart, MB, ChB: Let me get a broader reaction on checkpoint inhibitors. I must admit, I was a little skeptical when I saw that there was really no single-agent activity. Was my skepticism unfounded, Gareth, or is the jury still out? Are you convinced?

Gareth Morgan, MD, PhD: I think the jury is still out. The absence of single-agent activity has to make you concerned. We’ve seen a number of cases where drugs that don’t have single-agent activity don’t make it. The mode of action—the PD-1, the PD-L1 inhibition, that checkpoint—is going to be important. It’s just a question of, how do we learn how to use it? Which patients do you put it in? What governs of response do we have?

Keith Stewart, MB, ChB: 18 months is long for that.

Sagar Lonial, MD: Single-agent activity is a relative term, I think. There’s no question that there’s synergy between the IMiD agents and immunotherapy across the board. I will tell you, we’ve had patients who have been in that same refractory/relapsed, 5 lines-of-therapy group, and we’ve treated them with elotuzumab-nivolumab-pomalidomide, and they didn’t respond initially. Then, they got a dose of radiation to a plasmacytoma. They developed responses all over their body and autoimmune myocarditis. So, I think there is something about this. I think it’s a very fine balance, and that’s what I worry a little bit about.

Keith Stewart, MB, ChB: I was at a meeting yesterday where I was amazed at how many people were using these drugs already. I confess, I haven’t used them very much outside of clinical trials. Are you experimenting outside of trials?

Thomas G. Martin, MD: We are. One of our common solid regimens is pembrolizumab and pomalidomide.

Keith Stewart, MB, ChB: You’re a believer, then?

Thomas G. Martin, MD: Again, the PFS (progression-free survival) of 17 months in the pembrolizumab-pomalidomide data and 20 months here speaks for itself. These are patients who are refractory. You would expect, on the next line of therapy, maybe 5 to 7 months PFS, but not 17- and 20-month PFS.

Gareth Morgan, MD, PhD: The scientist in me asks, what governs the response? It’s becoming more and more apparent that we have no idea about the microenvironment in multiple myeloma. We’ve never really looked at it. And one of the key things to do is to look at that microenvironment in the context of these agents—to work out how they are working and in which patients they respond.

Keith Stewart, MB, ChB: We need phase III trials.

Saad Z. Usmani, MD: Yes, I agree. They’re ongoing, so we may have an answer. We have to understand that the PFS is very impressive. For the same population, you would expect a 3- or a 4-month PFS and an overall survival of 8 to 9 months. You’re essentially getting a lot of benefit from this checkpoint inhibition/IMiD combination.

Ivan M. Borrello, MD: But I would like to make a comment. I have data, here, that the PFS was 6.3 months but the duration of response was significantly longer. I think this gets back to a point that we were making earlier.

Keith Stewart, MB, ChB: With pembrolizumab-lenalidomide-dexamethasone, the PFS is only 6.3.

Ivan M. Borrello, MD: But the duration of the response is 24 months. This gets back to the point of MRD (minimal residual disease). What we’re seeing with a lot of immunotherapeutic approaches is immune equilibrium. You don’t necessarily need to eradicate the disease as long as you can maintain a constant degree of immune surveillance. This is happening in checkpoint inhibition. We’re seeing this in other forms of immunotherapy that we’re looking at, maybe with the exception of CAR T cells where it’s a 1-time shot and you have to eradicate it if you’re going to cure it. But certainly, with these chronic immunotherapeutic approaches, MRD may not be the endpoint. Clearly, duration of response and time to next therapy, as I think many people at Arkansas have professed in the past, is much more relevant.

Transcript Edited for Clarity
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Transcript:

Keith Stewart, MB, ChB:
Let’s move on and talk about some of the emerging agents in myeloma. Like everybody else in cancer, we’re in the early years of a revolution of the use of immunotherapy. Ivan, you’ve been most active in this area of all of us. Tell us about the rationale for immunotherapy in myeloma—particularly, the potential for using checkpoint inhibitors.

Ivan M. Borrello, MD: I think, obviously, checkpoint inhibitors have revolutionized many solid tumors—melanoma, lung, etc—and I think their history in myeloma has been very interesting because, as single agents, they had absolutely zero activity. Certainly, nivolumab did, and pembrolizumab was never really checked. They’re very similar antibodies, I think, but they have shown significant activity with the incorporation of IMiDs (immunomodulatory imide drugs).

The pembrolizumab-lenalidomide data, which are being updated here at the 2017 ASCO Annual Meeting, are showing a 44% response rate. The thing that’s actually very interesting is that they looked at patients who were Revlimid-refractory compared to those who weren’t, and there was equivalent response rates in both arms, with a significant duration of response of over 20 months. Actually, 25 months in the Revlimid-refractory patients.

Keith Stewart, MB, ChB: I was very impressed by that. What would you expect in that population without pembrolizumab?

Ivan M. Borrello, MD: These are patients who are Revlimid-refractory and are getting a 20-month duration of response with Revlimid plus pembrolizumab. Without pembrolizumab, I think the response would be zero. What this is really speaking to is the immunomodulation of IMiDs in combination with various immunotherapies.

In this case, we’re looking at checkpoint inhibitors. I think the clinical data speak clearly that these combinations are essential for maximizing a tumor-specific immune response. But I can tell you that we have also looked at combinations with vaccines, and there have been papers published about combining IMiDs with CAR (chimeric antigen receptor) T-cell or adoptive T-cell therapy. And that really speaks to the ability of this class of drugs to increase immuno-stimulation. What’s also emerging now is increasing the synapse between the tumor and the T cell itself. It’s probably mediating some of this immune activity.

Keith Stewart, MB, ChB: Let me get a broader reaction on checkpoint inhibitors. I must admit, I was a little skeptical when I saw that there was really no single-agent activity. Was my skepticism unfounded, Gareth, or is the jury still out? Are you convinced?

Gareth Morgan, MD, PhD: I think the jury is still out. The absence of single-agent activity has to make you concerned. We’ve seen a number of cases where drugs that don’t have single-agent activity don’t make it. The mode of action—the PD-1, the PD-L1 inhibition, that checkpoint—is going to be important. It’s just a question of, how do we learn how to use it? Which patients do you put it in? What governs of response do we have?

Keith Stewart, MB, ChB: 18 months is long for that.

Sagar Lonial, MD: Single-agent activity is a relative term, I think. There’s no question that there’s synergy between the IMiD agents and immunotherapy across the board. I will tell you, we’ve had patients who have been in that same refractory/relapsed, 5 lines-of-therapy group, and we’ve treated them with elotuzumab-nivolumab-pomalidomide, and they didn’t respond initially. Then, they got a dose of radiation to a plasmacytoma. They developed responses all over their body and autoimmune myocarditis. So, I think there is something about this. I think it’s a very fine balance, and that’s what I worry a little bit about.

Keith Stewart, MB, ChB: I was at a meeting yesterday where I was amazed at how many people were using these drugs already. I confess, I haven’t used them very much outside of clinical trials. Are you experimenting outside of trials?

Thomas G. Martin, MD: We are. One of our common solid regimens is pembrolizumab and pomalidomide.

Keith Stewart, MB, ChB: You’re a believer, then?

Thomas G. Martin, MD: Again, the PFS (progression-free survival) of 17 months in the pembrolizumab-pomalidomide data and 20 months here speaks for itself. These are patients who are refractory. You would expect, on the next line of therapy, maybe 5 to 7 months PFS, but not 17- and 20-month PFS.

Gareth Morgan, MD, PhD: The scientist in me asks, what governs the response? It’s becoming more and more apparent that we have no idea about the microenvironment in multiple myeloma. We’ve never really looked at it. And one of the key things to do is to look at that microenvironment in the context of these agents—to work out how they are working and in which patients they respond.

Keith Stewart, MB, ChB: We need phase III trials.

Saad Z. Usmani, MD: Yes, I agree. They’re ongoing, so we may have an answer. We have to understand that the PFS is very impressive. For the same population, you would expect a 3- or a 4-month PFS and an overall survival of 8 to 9 months. You’re essentially getting a lot of benefit from this checkpoint inhibition/IMiD combination.

Ivan M. Borrello, MD: But I would like to make a comment. I have data, here, that the PFS was 6.3 months but the duration of response was significantly longer. I think this gets back to a point that we were making earlier.

Keith Stewart, MB, ChB: With pembrolizumab-lenalidomide-dexamethasone, the PFS is only 6.3.

Ivan M. Borrello, MD: But the duration of the response is 24 months. This gets back to the point of MRD (minimal residual disease). What we’re seeing with a lot of immunotherapeutic approaches is immune equilibrium. You don’t necessarily need to eradicate the disease as long as you can maintain a constant degree of immune surveillance. This is happening in checkpoint inhibition. We’re seeing this in other forms of immunotherapy that we’re looking at, maybe with the exception of CAR T cells where it’s a 1-time shot and you have to eradicate it if you’re going to cure it. But certainly, with these chronic immunotherapeutic approaches, MRD may not be the endpoint. Clearly, duration of response and time to next therapy, as I think many people at Arkansas have professed in the past, is much more relevant.

Transcript Edited for Clarity
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