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Emerging Agents 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: Thursday, Jul 27, 2017



Transcript:

Keith Stewart, MB, ChB:
Let’s move on from the cellular therapies to other agents of interest. Isatuximab is a monoclonal antibody. You’ve been heavily engaged with that, Tom. Tell us about it.

Thomas G. Martin, MD: Isatuximab is an anti-CD38 monoclonal antibody. And like daratumumab, it does show single-agent activity upwards of 30%. Also, like daratumumab, it shows increased efficacy when combined with an IMiD immunomodulatory imide drug and dexamethasone. That was just published in Blood, showing that in lenalidomide-refractory patients, response rates were in the order of 50%-plus.

At the current time, isatuximab is being combined with pomalidomide and dexamethasone. It looks to be a very active combination. The response rates were 60% to 70% in relapsed and refractory patients, and they’ve launched a phase III trial of isatuximab, pomalidomide, and dexamethasone versus pomalidomide and dexamethasone. I think that is the avenue for isatuximab to get, hopefully, FDA-approved sometime in the next 2 to 3 years.

Keith Stewart, MB, ChB: Bendamustine, does anybody use it? There is an abstract from the 2017 ASCO Annual Meeting that talked about bendamustine and pomalidomide. Is anybody using bendamustine?

Saad Z. Usmani, MD: No.

Keith Stewart, MB, ChB: No, I didn’t think so. There is more of a European flavor to that drug, although our lymphoma colleagues seem to like it. Why are we not so enthused? Do we just have other better alternatives?

Sagar Lonial, MD: We use melphalan. It’s the same thing.

Keith Stewart, MB, ChB: What about other drugs that are coming out? Let’s spend a few minutes on those. What has got you excited that’s on the horizon, Gareth?

Gareth Morgan, MD, PhD: I’m most excited about the bispecific antibodies—the CAR T-cell therapies, really. I think that our challenge over the next year is to find groups of patients where these are really indicated—for properly, well-defined, high-risk disease using gp70 or p53 biallelic inactivation. Those are really a significant challenge. I think those agents, in that group of patients, will be beneficial.

Keith Stewart, MB, ChB: Small molecule drugs. Venetoclax, has anybody got experience with that? Saad, what do you think? Tom, I know you’ve used it, too.

Saad Z. Usmani, MD: Venetoclax is probably the most exciting small molecule drug we have right now.

Keith Stewart, MB, ChB: Why is that?

Saad Z. Usmani, MD: It’s an oral BCL-2 antagonist, and it has a single-agent activity—specifically, in the translocation 11;14 patients of about 40%, which is quite impressive and probably leads the way to developing a predictive biomarker-driven therapy in myeloma, which would be a first. I think that’s exciting. And then, with the bortezomib combination, the overall response rate reaches north of 80% in the 1 to 3-prior-lines-of-treatment patients. Even in bortezomib-refractory patients, there appears to be activity.

Keith Stewart, MB, ChB: It’s almost 90%, as I recall.

Saad Z. Usmani, MD: Yes. I believe you’re right.

Keith Stewart, MB, ChB: Tom, because I talked you into this last year, I know that you’ve been using some venetoclax.

Thomas G. Martin, MD: You did talk us into it last year.

Keith Stewart, MB, ChB: Can you tell me about it?

Thomas G. Martin, MD: We’ve had trouble with the daratumumab-refractory patients. Those patients, in our hands, have already seen carfilzomib, have already seen daratumumab, and we needed another agent. So, we started them on venetoclax and bortezomib, and we did it in both the patients who had an 11;14 translocation and those who did not have an 11;14 translocation. We’ve had good responses in both groups. It’s certainly been better in the 11;14 translocation group, but we’ve seen response rates in the order of 20% to 30% in truly penta-refractory patients, which is pretty dramatic at this current time.

Gareth Morgan, MD, PhD: I think it’s remarkable. I think it’s the start of precision medicine for myeloma. It’s the drug “par excellence,” which will allow us to segment myeloma into different subgroups. Once venetoclax is approved and we’re using it, we’ll fall in line and have a way forward for bringing in more drugs to the myeloma space.

Sagar Lonial, MD: We might. The one caveat to that is that MCL-1 inhibitors may actually treat both.

Gareth Morgan, MD, PhD: Yes, absolutely.

Sagar Lonial, MD: If you have an active MCL-1 inhibitor—and that’s a target we’re certainly very excited about, and there are a number of ones—it may supplant venetoclax.

Keith Stewart, MB, ChB: But not in trials. You are just starting trials.

Sagar Lonial, MD: Yes.

Saad Z. Usmani, MD: We are just starting trials right now.

Keith Stewart, MB, ChB: My own experience with venetoclax has been very positive. Even as a single agent, I’ve had some very nice, deep and long remissions in my patients. I’m actually pretty keen on that one.

Thomas G. Martin, MD: Patients tolerate it really well, also.

Keith Stewart, MB, ChB: Yes, and it’s approved for CLL, so it’s actually out there on the market if you work with your insurance company. What about selinexor? This is an interesting drug with a new mechanism of action. Ivan, your center has been working with selinexor. I know you’ve had some decent experiences with that agent. Tell us a little bit about that.

Ivan M. Borrello, MD: I could tell you about experiences with my patients that I’ve put on the study. It is an agent that now is in fifth-line penta-refractory patients and clearly has seen very dramatic responses. The patients who I’ve had experiences with have also been complicated by extreme nausea, to the point that, for the first time in my experience, I’ve had patients actually beg of me to come off study despite the fact that they’ve been having such a good response. And these 3 or 4 patients were patients for whom standard antiemetics were not even coming close to treating them. My understanding is that this has possibly improved with subsequent patients that have gone on with therapy.

Keith Stewart, MB, ChB: I think that’s been a universal experience. In the trial that has been reported recently, the overall response rate was about 20%; it was 21% to be precise. I think there was a high incidence of nausea, but with appropriate management, apparently, many patients were able to stay on the drug. Does anyone have any experience with this over on this side of the table?

Sagar Lonial, MD: I think nausea certainly can be an issue, but with aggressive pre-medication ahead of time, you can mitigate that. What really struck me was the data, both in terms of bortezomib- and carfilzomib-refractory patients, when you combine it with selinexor. The response rates were really good, and the gastrointestinal toxicities dropped significantly—almost in half. It’s almost like the best antiemetic for selinexor is a proteasome inhibitor.

Saad Z. Usmani, MD: Wasn’t there a difference in dosing of selinexor, as well, when combined with the PIs?

Sagar Lonial, MD: Not at the outset. Subsequently, you could reduce the dose.

Ivan M. Borrello, MD: My experience was with single-agent selinexor.

Sagar Lonial, MD: The dexamethasone certainly makes it better.

Keith Stewart, MB, ChB: We’ll watch that space. It’s a drug that’s still in clinical trials.

Transcript Edited for Clarity

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Transcript:

Keith Stewart, MB, ChB:
Let’s move on from the cellular therapies to other agents of interest. Isatuximab is a monoclonal antibody. You’ve been heavily engaged with that, Tom. Tell us about it.

Thomas G. Martin, MD: Isatuximab is an anti-CD38 monoclonal antibody. And like daratumumab, it does show single-agent activity upwards of 30%. Also, like daratumumab, it shows increased efficacy when combined with an IMiD immunomodulatory imide drug and dexamethasone. That was just published in Blood, showing that in lenalidomide-refractory patients, response rates were in the order of 50%-plus.

At the current time, isatuximab is being combined with pomalidomide and dexamethasone. It looks to be a very active combination. The response rates were 60% to 70% in relapsed and refractory patients, and they’ve launched a phase III trial of isatuximab, pomalidomide, and dexamethasone versus pomalidomide and dexamethasone. I think that is the avenue for isatuximab to get, hopefully, FDA-approved sometime in the next 2 to 3 years.

Keith Stewart, MB, ChB: Bendamustine, does anybody use it? There is an abstract from the 2017 ASCO Annual Meeting that talked about bendamustine and pomalidomide. Is anybody using bendamustine?

Saad Z. Usmani, MD: No.

Keith Stewart, MB, ChB: No, I didn’t think so. There is more of a European flavor to that drug, although our lymphoma colleagues seem to like it. Why are we not so enthused? Do we just have other better alternatives?

Sagar Lonial, MD: We use melphalan. It’s the same thing.

Keith Stewart, MB, ChB: What about other drugs that are coming out? Let’s spend a few minutes on those. What has got you excited that’s on the horizon, Gareth?

Gareth Morgan, MD, PhD: I’m most excited about the bispecific antibodies—the CAR T-cell therapies, really. I think that our challenge over the next year is to find groups of patients where these are really indicated—for properly, well-defined, high-risk disease using gp70 or p53 biallelic inactivation. Those are really a significant challenge. I think those agents, in that group of patients, will be beneficial.

Keith Stewart, MB, ChB: Small molecule drugs. Venetoclax, has anybody got experience with that? Saad, what do you think? Tom, I know you’ve used it, too.

Saad Z. Usmani, MD: Venetoclax is probably the most exciting small molecule drug we have right now.

Keith Stewart, MB, ChB: Why is that?

Saad Z. Usmani, MD: It’s an oral BCL-2 antagonist, and it has a single-agent activity—specifically, in the translocation 11;14 patients of about 40%, which is quite impressive and probably leads the way to developing a predictive biomarker-driven therapy in myeloma, which would be a first. I think that’s exciting. And then, with the bortezomib combination, the overall response rate reaches north of 80% in the 1 to 3-prior-lines-of-treatment patients. Even in bortezomib-refractory patients, there appears to be activity.

Keith Stewart, MB, ChB: It’s almost 90%, as I recall.

Saad Z. Usmani, MD: Yes. I believe you’re right.

Keith Stewart, MB, ChB: Tom, because I talked you into this last year, I know that you’ve been using some venetoclax.

Thomas G. Martin, MD: You did talk us into it last year.

Keith Stewart, MB, ChB: Can you tell me about it?

Thomas G. Martin, MD: We’ve had trouble with the daratumumab-refractory patients. Those patients, in our hands, have already seen carfilzomib, have already seen daratumumab, and we needed another agent. So, we started them on venetoclax and bortezomib, and we did it in both the patients who had an 11;14 translocation and those who did not have an 11;14 translocation. We’ve had good responses in both groups. It’s certainly been better in the 11;14 translocation group, but we’ve seen response rates in the order of 20% to 30% in truly penta-refractory patients, which is pretty dramatic at this current time.

Gareth Morgan, MD, PhD: I think it’s remarkable. I think it’s the start of precision medicine for myeloma. It’s the drug “par excellence,” which will allow us to segment myeloma into different subgroups. Once venetoclax is approved and we’re using it, we’ll fall in line and have a way forward for bringing in more drugs to the myeloma space.

Sagar Lonial, MD: We might. The one caveat to that is that MCL-1 inhibitors may actually treat both.

Gareth Morgan, MD, PhD: Yes, absolutely.

Sagar Lonial, MD: If you have an active MCL-1 inhibitor—and that’s a target we’re certainly very excited about, and there are a number of ones—it may supplant venetoclax.

Keith Stewart, MB, ChB: But not in trials. You are just starting trials.

Sagar Lonial, MD: Yes.

Saad Z. Usmani, MD: We are just starting trials right now.

Keith Stewart, MB, ChB: My own experience with venetoclax has been very positive. Even as a single agent, I’ve had some very nice, deep and long remissions in my patients. I’m actually pretty keen on that one.

Thomas G. Martin, MD: Patients tolerate it really well, also.

Keith Stewart, MB, ChB: Yes, and it’s approved for CLL, so it’s actually out there on the market if you work with your insurance company. What about selinexor? This is an interesting drug with a new mechanism of action. Ivan, your center has been working with selinexor. I know you’ve had some decent experiences with that agent. Tell us a little bit about that.

Ivan M. Borrello, MD: I could tell you about experiences with my patients that I’ve put on the study. It is an agent that now is in fifth-line penta-refractory patients and clearly has seen very dramatic responses. The patients who I’ve had experiences with have also been complicated by extreme nausea, to the point that, for the first time in my experience, I’ve had patients actually beg of me to come off study despite the fact that they’ve been having such a good response. And these 3 or 4 patients were patients for whom standard antiemetics were not even coming close to treating them. My understanding is that this has possibly improved with subsequent patients that have gone on with therapy.

Keith Stewart, MB, ChB: I think that’s been a universal experience. In the trial that has been reported recently, the overall response rate was about 20%; it was 21% to be precise. I think there was a high incidence of nausea, but with appropriate management, apparently, many patients were able to stay on the drug. Does anyone have any experience with this over on this side of the table?

Sagar Lonial, MD: I think nausea certainly can be an issue, but with aggressive pre-medication ahead of time, you can mitigate that. What really struck me was the data, both in terms of bortezomib- and carfilzomib-refractory patients, when you combine it with selinexor. The response rates were really good, and the gastrointestinal toxicities dropped significantly—almost in half. It’s almost like the best antiemetic for selinexor is a proteasome inhibitor.

Saad Z. Usmani, MD: Wasn’t there a difference in dosing of selinexor, as well, when combined with the PIs?

Sagar Lonial, MD: Not at the outset. Subsequently, you could reduce the dose.

Ivan M. Borrello, MD: My experience was with single-agent selinexor.

Sagar Lonial, MD: The dexamethasone certainly makes it better.

Keith Stewart, MB, ChB: We’ll watch that space. It’s a drug that’s still in clinical trials.

Transcript Edited for Clarity
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