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Emerging Therapies in Myeloma: Venetoclax

Panelists: A. Keith Stewart, MB, ChB, The Mayo Clinic in Phoenix Arizona; Thomas Martin, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Faith Davies, MD, MBBCh, MRCP, FRCPath, University of Arkansas for Medical Sciences; Rafael Fonseca, MD, The Mayo Clinic in Phoenix Arizona; Adriana Rossi, MD, Weill Cornell Medical College
Published: Thursday, Feb 28, 2019



Transcript:

A. Keith Stewart, MB, ChB:
Maybe we should segue, then, into those patients—who we’ve talked about—who have a first relapse for whom we’re seeing a lot of pomalidomide use, like daratumumab, elotuzumab emerging again in different combinations. What are some of the new drugs you’ve heard about at this meeting [the American Society of Hematology Annual Meeting and Exposition], or at ASCO [American Society of Community Oncology]? Adriana, what’s got you excited?

Adriana Rossi, MD: Rafael has mentioned a couple of times venetoclax, specifically for the t(11;14) patients.

A. Keith Stewart, MB, ChB: Let’s talk about that now. What do you know about that drug? What should you tell the audience?

Adriana Rossi, MD: It does have a response rate. I would remind everyone it’s not only for the t(11;14) patients. It just seems to be a much higher, deeper response for the t(11;14) patients. It is an oral medication, and it does combine well with other medications. And again, the data come out in little bits.

A. Keith Stewart, MB, ChB: Tom, you were an early adopter of venetoclax. It’s approved for CLL [chronic lymphocytic leukemia] but not approved yet for myeloma. We should be clear. But you’ve been able to access it for some of your patients?

Thomas Martin, MD: It is a very expensive drug, and therefore, in patients who make less than a certain amount of money, the company will actually provide it for you for patients with myeloma, which is great. So we use it in quite a few patients. It is a BCL-2 inhibitor, which nobody thought would really work so well in myeloma. But there are probably a quarter of patients who present, or more, who actually do have overexpression of BCL2 pathway proteins. And this drug works quite well. It seems that the biomarker is t(11;14), but not everybody with t(11;14) responds, and some people who don’t have the t(11;14) also respond.

A. Keith Stewart, MB, ChB: It’s an important point for the audience to note that because we have this drug available now, a lot of the FISH [fluorescence in situ hybridization] labs don’t routinely test for t(11;14). We certainly need to encourage for that to happen.

Faith Davies, MD, MBBCh, MRCP, FRCPath: The other point is the dose is slightly different from myeloma.

A. Keith Stewart, MB, ChB: It’s a lot higher, right?

Faith Davies, MD, MBBCh, MRCP, FRCPath: Yes.

A. Keith Stewart, MB, ChB: About 800 mg is the final dose and not a lot of tumor lysis.

Faith Davies, MD, MBBCh, MRCP, FRCPath: In terms of adverse effects, it’s very well tolerated.

A. Keith Stewart, MB, ChB: What dose do you start at then?

Faith Davies, MD, MBBCh, MRCP, FRCPath: I’ve gone with what the clinical studies go in at. Well, the initial clinical studies had a ramp-up, and then the later clinical studies just went in at 800. So I’ve been going in at 800.

A. Keith Stewart, MB, ChB: Are you impressed with activity?

Faith Davies, MD, MBBCh, MRCP, FRCPath: I’ve had some amazing, amazing responses.

A. Keith Stewart, MB, ChB: In t(11;14) only?

Faith Davies, MD, MBBCh, MRCP, FRCPath: In the t(11;14) patients. We also took part in the study that was presented this morning with carfilzomib and venetoclax, and we’ve had some good responses in that study as well.

A. Keith Stewart, MB, ChB: Yeah, tell us about that.

Faith Davies, MD, MBBCh, MRCP, FRCPath: So that study was for all comers. It had a dosage-finding part, and then they went in with the 70 mg/m2 of the carfilzomib once a week and venetoclax at 800. And amazing responses. As you’d expect, I think 100% of the t(11;14)s responded. But there was a group of other patients that also responded. And that’s going to be the key question moving forward: can you identify which patients are going to be the ones that have that great response?

A. Keith Stewart, MB, ChB: Rafael, there’s been both bortezomib and venetoclax and now a very exciting…100% response rate in carfilzomib- and venetoclax-treated patients with t(11;14). Do you think this is a drug that’s beyond t(11;14), or are you not sure yet?

Rafael Fonseca, MD: I’m not sure yet. I think that the important group is t(11;14). I think it might help other patients, but I want to see more data, because a lot of those patients respond to proteasome inhibitors as well. But I think the data, just as Dr Davies was mentioning, are impressive. I had patients who had relapsed or refractory myeloma progress on every single combination I could think of who are on CRs [complete remissions] now with a very good quality of life. By the way, the toxicity profile is very good. It’s a very well-tolerated drug.

A. Keith Stewart, MB, ChB: Unfortunately, it doesn’t last forever. My initial feeling that I’d cured everybody didn’t pan out. They all started to relapse at 12, 18 months. So I think it’s probably not a single-agent drug, eventually, but you mentioned earlier perhaps it’s a maintenance, or even a t(11;14) up-front drug 1 day?

Rafael Fonseca, MD: I think it should be up front. I think for t(11;14), you know, with the caveat that we’re still finding this out, it should be up front. It should be a sensitizer. And if we’re going to use K [carfilzomib], or are we going to use bortezomib up front? I think venetoclax should be there. It should be part of maintenance. When you look at t(11;14), over the many years it used to be a good prognostic factor. And then it didn’t move because the other agents helped all the other versions of myeloma, but t(11;14) was not helped. I’ve always believed that because they have smaller cells, so they’re more lymphoid biology, they don’t have the stress in the protein. So we need to do better for those patients. And even some series now show a more aggressive course for t(11;14).

Adriana Rossi, MD: There was an abstract presented at the meeting. I don’t know if it was presented yet, but in reviewing the abstract, it showed that t(11;14)s don’t seem to do quite as well as other standard risks. So even though we clump it in the standard risk, they do deserve the special attention.

A. Keith Stewart, MB, ChB: And I think that’s the point Rafael is making. It used to be low risk. But as the other categories improved with the new drugs, it kind of got left alone. So we now have a drug for that.

Transcript edited for clarity.

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Transcript:

A. Keith Stewart, MB, ChB:
Maybe we should segue, then, into those patients—who we’ve talked about—who have a first relapse for whom we’re seeing a lot of pomalidomide use, like daratumumab, elotuzumab emerging again in different combinations. What are some of the new drugs you’ve heard about at this meeting [the American Society of Hematology Annual Meeting and Exposition], or at ASCO [American Society of Community Oncology]? Adriana, what’s got you excited?

Adriana Rossi, MD: Rafael has mentioned a couple of times venetoclax, specifically for the t(11;14) patients.

A. Keith Stewart, MB, ChB: Let’s talk about that now. What do you know about that drug? What should you tell the audience?

Adriana Rossi, MD: It does have a response rate. I would remind everyone it’s not only for the t(11;14) patients. It just seems to be a much higher, deeper response for the t(11;14) patients. It is an oral medication, and it does combine well with other medications. And again, the data come out in little bits.

A. Keith Stewart, MB, ChB: Tom, you were an early adopter of venetoclax. It’s approved for CLL [chronic lymphocytic leukemia] but not approved yet for myeloma. We should be clear. But you’ve been able to access it for some of your patients?

Thomas Martin, MD: It is a very expensive drug, and therefore, in patients who make less than a certain amount of money, the company will actually provide it for you for patients with myeloma, which is great. So we use it in quite a few patients. It is a BCL-2 inhibitor, which nobody thought would really work so well in myeloma. But there are probably a quarter of patients who present, or more, who actually do have overexpression of BCL2 pathway proteins. And this drug works quite well. It seems that the biomarker is t(11;14), but not everybody with t(11;14) responds, and some people who don’t have the t(11;14) also respond.

A. Keith Stewart, MB, ChB: It’s an important point for the audience to note that because we have this drug available now, a lot of the FISH [fluorescence in situ hybridization] labs don’t routinely test for t(11;14). We certainly need to encourage for that to happen.

Faith Davies, MD, MBBCh, MRCP, FRCPath: The other point is the dose is slightly different from myeloma.

A. Keith Stewart, MB, ChB: It’s a lot higher, right?

Faith Davies, MD, MBBCh, MRCP, FRCPath: Yes.

A. Keith Stewart, MB, ChB: About 800 mg is the final dose and not a lot of tumor lysis.

Faith Davies, MD, MBBCh, MRCP, FRCPath: In terms of adverse effects, it’s very well tolerated.

A. Keith Stewart, MB, ChB: What dose do you start at then?

Faith Davies, MD, MBBCh, MRCP, FRCPath: I’ve gone with what the clinical studies go in at. Well, the initial clinical studies had a ramp-up, and then the later clinical studies just went in at 800. So I’ve been going in at 800.

A. Keith Stewart, MB, ChB: Are you impressed with activity?

Faith Davies, MD, MBBCh, MRCP, FRCPath: I’ve had some amazing, amazing responses.

A. Keith Stewart, MB, ChB: In t(11;14) only?

Faith Davies, MD, MBBCh, MRCP, FRCPath: In the t(11;14) patients. We also took part in the study that was presented this morning with carfilzomib and venetoclax, and we’ve had some good responses in that study as well.

A. Keith Stewart, MB, ChB: Yeah, tell us about that.

Faith Davies, MD, MBBCh, MRCP, FRCPath: So that study was for all comers. It had a dosage-finding part, and then they went in with the 70 mg/m2 of the carfilzomib once a week and venetoclax at 800. And amazing responses. As you’d expect, I think 100% of the t(11;14)s responded. But there was a group of other patients that also responded. And that’s going to be the key question moving forward: can you identify which patients are going to be the ones that have that great response?

A. Keith Stewart, MB, ChB: Rafael, there’s been both bortezomib and venetoclax and now a very exciting…100% response rate in carfilzomib- and venetoclax-treated patients with t(11;14). Do you think this is a drug that’s beyond t(11;14), or are you not sure yet?

Rafael Fonseca, MD: I’m not sure yet. I think that the important group is t(11;14). I think it might help other patients, but I want to see more data, because a lot of those patients respond to proteasome inhibitors as well. But I think the data, just as Dr Davies was mentioning, are impressive. I had patients who had relapsed or refractory myeloma progress on every single combination I could think of who are on CRs [complete remissions] now with a very good quality of life. By the way, the toxicity profile is very good. It’s a very well-tolerated drug.

A. Keith Stewart, MB, ChB: Unfortunately, it doesn’t last forever. My initial feeling that I’d cured everybody didn’t pan out. They all started to relapse at 12, 18 months. So I think it’s probably not a single-agent drug, eventually, but you mentioned earlier perhaps it’s a maintenance, or even a t(11;14) up-front drug 1 day?

Rafael Fonseca, MD: I think it should be up front. I think for t(11;14), you know, with the caveat that we’re still finding this out, it should be up front. It should be a sensitizer. And if we’re going to use K [carfilzomib], or are we going to use bortezomib up front? I think venetoclax should be there. It should be part of maintenance. When you look at t(11;14), over the many years it used to be a good prognostic factor. And then it didn’t move because the other agents helped all the other versions of myeloma, but t(11;14) was not helped. I’ve always believed that because they have smaller cells, so they’re more lymphoid biology, they don’t have the stress in the protein. So we need to do better for those patients. And even some series now show a more aggressive course for t(11;14).

Adriana Rossi, MD: There was an abstract presented at the meeting. I don’t know if it was presented yet, but in reviewing the abstract, it showed that t(11;14)s don’t seem to do quite as well as other standard risks. So even though we clump it in the standard risk, they do deserve the special attention.

A. Keith Stewart, MB, ChB: And I think that’s the point Rafael is making. It used to be low risk. But as the other categories improved with the new drugs, it kind of got left alone. So we now have a drug for that.

Transcript edited for clarity.
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