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Emerging Therapies for Relapsed/Refractory Multiple Myeloma

Panelists: Sagar Lonial, MD, FACP, Winship Cancer Institute of Emory University; Amrita Y. Krishnan, MD, City of Hope Comprehensive Cancer Center; Thomas G. Martin, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Krina K. Patel, MD, MSc, University of Texas MD Anderson Cancer Center; Saad Z. Usmani, MD, FACP, Levine Cancer Institute
Published: Tuesday, Jul 16, 2019



Transcript: 

Sagar Lonial, MD, FACP: Let’s talk a little bit about emerging therapies. Tom, do you want to get us started off talking about how genetics and other subsets in the relapsed setting might help shape what we’re doing or how we think about treatments we have available in the relapsed setting?

Thomas G. Martin, MD: Sure. In contrast to upfront therapy, cytogenetic abnormalities, the high-risk abnormalities, obviously have been associated with worse prognosis, but when the patients receive a daratumumab-based regimen, they in fact do better. So Jonathan Kaufman, MD, presented at ASCO [American Society of Clinical Oncology annual meeting] looking at data from the POLLUX study, and Katja Weisel, MD, also presented data looking at it from the CASTOR study. And in both of those studies patients who had high-risk disease did better, much better in fact, if they got daratumumab plus the doublet—either lenalidomide and dexamethasone or bortezomib and dexamethasone—than you would have expected based on the frontline data. It’s pretty interesting. In fact, the patients who are high risk and got the triplet did better than the standard-risk patients who got the doublet. But it didn’t completely eliminate having high-risk disease. They didn’t do as well as patients who were standard risk getting the triplet. But it made it a lot better. And so there is a little difference there between newly diagnosed and early relapsed patients.

I do think that if somebody has high-risk cytogenetics and has early relapse, going to a daratumumab-based regimen, one of these regimens—DVd [daratumumab/bortezomib/dexamethasone] or DRd [daratumumab/lenalidomide/dexamethasone], or even DPd [daratumumab/pomalidomide/dexamethasone]—would actually be OK, and I do think actually a carfilzomib-based regimen would be fine in addition, a triplet.

Sagar Lonial, MD, FACP: So how do we reconcile what Saad was saying earlier in terms of ALCYONE, CASSIOPEIA, and MAIA where you don’t get the benefit from adding daratumumab, and what you’re saying with POLLUX and CASTOR where you do seem to get the benefit? I’m trying to figure that out.

Saad Z. Usmani, MD, FACP: So are we. I think it will have to be longer follow-up. I think my critique of MAIA is the small proportion of high-risk patients that they have, it’s only about 14%. So that’s roughly 26 or 27-odd patients on each arm. And it could be just the luck of God that we’re not getting the same answer. But again, with longer follow-up, the answer may be a little different. I think ALCYONE read out with a follow-up of around 16½-months, something like that? And I don’t think we’re going to see major differences in PFS [progression-free survival] for high-risk patients that early. But we’ll definitely see it by 3 years.

Sagar Lonial, MD, FACP: Yes, it certainly could be that the truly high risk falls out early and they never even get to the relapsed trials.

Saad Z. Usmani, MD, FACP: Right.

Sagar Lonial, MD, FACP: And so what we’re calling high risk in relapse is not the same as high risk in frontline.

Thomas G. Martin, MD: High risk out of the gate is probably really bad, but like you were saying, high risk down the road isn’t as bad as right out of the gate, without any other therapy, without any selection, etcetera. But again, we’ll learn more over time for sure.

Sagar Lonial, MD, FACP: Let’s get to a happier topic, you want to talk about OPTIMISMM. Let’s talk about OPTIMISMM, Saad.

Saad Z. Usmani, MD, FACP: OPTIMISMM was a randomized phase III trial that compared pomalidomide/Velcade/dexamethasone versus Velcade/dexamethasone. And when I looked at the abstract I thought the “P” stood for panobinostat because the data looked very similar, but in an earlier relapsed setting. In the United States most of our patients do become lenalidomide refractory fairly early, and we always struggle with the best options for those patients. I think from that perspective looking at that first relapsed population where pomalidomide/Velcade actually did have almost 21 months of PFS benefit compared with 11 months, I think it’s a reasonable option. Will we be giving Velcade the same that it was given in the clinical trial? Probably not. So I think it’s a decent option for our patients who are lenalidomide refractory.

One abstract that I didn’t see here is ICARIA-MM, it might be the next one that we talk about, so I’ll just leave it at that. I think that will be an important option to discuss in the same space. With pomalidomide/Velcade/dexamethasone, I think both high-risk and standard-risk patients benefited in the subgroup analysis. So again, even though they might not be the same high risk but they’re in the front line, that’s an important distinction, especially for deletion 17p patients I think.

Sagar Lonial, MD, FACP: Amrita, you led a trial of pomalidomide/ixazomib/dexamethasone. Do you want to talk about some other pomalidomide-based approaches that were discussed here?

Amrita Y. Krishnan, MD: You know Saad referenced the ICARIA trial so there are other anti-CD38 monoclonal antibodies, such as isatuximab, and this is a large trial phase III comparing isatuximab/pomalidomide/dexamethasone versus pomalidomide/dexamethasone alone. And not surprisingly it showed higher response rates with the isatuximab/pomalidomide/dexamethasone, better PFS with the isatuximab/pomalidomide/dexamethasone. So I don’t think there’s any argument about a third drug, and I do think the antibody/pomalidomide combination is probably one of the best combinations we have. I think the question, which I’m sure you’re going to ask everyone is, what do you do with that in the setting of daratumumab? And I didn’t come away with an answer for that from this trial.

Sagar Lonial, MD, FACP: All right, what do people think? So we’ve got daratumumab, we will likely have isatuximab, I think based on this trial, it’s clearly a positive trial. I think there were some discussions around whether there is any ability of one to work when the other doesn’t work. I don’t know, what do you all think?

Thomas G. Martin, MD: We’ve done that in a number of patients. We’ve treated a lot of patients on isatuximab at UCSF [Helen Diller Family Comprehensive Cancer Center], and then when we tried to go to daratumumab afterward, we really haven’t had a long benefit. Probably a very short PFS, and vice versa too. I would say we’ve tried a small number of patients who received daratumumab, to give isatuximab….

Sagar Lonial, MD, FACP: Yes.

Thomas G. Martin, MD: Again, we didn’t really see a huge benefit there. I think that’s going to be difficult. I think if you’re going to give 2 CD38 antibodies, they have to be separated by a period of time to potentially allow for CD38 expression to recover on some of these myeloma cells.

In terms of the phase III data, it’s really good phase III data. It’s a large study, it’s 11.5 months PFS. In terms of antibody plus pomalidomide/dexamethasone, it’s the longest of all the studies that have been published at the current time, so it actually works really well. With daratumumab coming into the frontline setting, I think this would be a reasonable strategy. And this study was for people who had 2 prior lines of therapy. So they get daratumumab frontline, they get a second line of therapy, and then this would be a reasonable thing for third-line, and that would be 2 prior lines of therapy. But I do think they were partly interchangeable in terms of regimens they can be used with.

Saad Z. Usmani, MD, FACP: I think we didn’t touch upon ELO/POM/DEX [elotuzumab/pomalidomide/dexamethasone] as a potential option, and I honestly was discounting elotuzumab in a post-daratumumab exposed or refractory patient. But I’ve been pleasantly surprised with some of our experience with elotuzumab/pomalidomide/dexamethasone in daratumumab-exposed or refractory patients. So if you’re thinking about a monoclonal in a post-daratumumab, at first relapse, I find that the elotuzumab/pomalidomide/dexamethasone data are fairly similar to what we see with isatuximab/pomalidomide/dexamethasone. So again, the struggle is, are these drugs equal? And if they are, is it better to change the target with a monoclonal antibody? I think that’s what we’re going to be struggling with clinically.

Amrita Y. Krishnan, MD: I would be curious, in terms of your elotuzumab/pomalidomide/dexamethasone patients, with those immediately after progressing on daratumumab who you switched to elotuzumab, did you see responses?

Saad Z. Usmani, MD, FACP: Right now most of our data usage is in the first or second relapse setting. Then for our patients who are progressing on daratumumab, and as we’re thinking about different MOAs [monoclonal antibodies], and if we’ve already exhausted our PI [proteasome inhibitor] options with the previous lines of treatment, then we’re left with elotuzumab/pomalidomide/dexamethasone, and we have been pleasantly surprised. We salvaged some patients where we thought it wouldn’t be possible.

Sagar Lonial, MD, FACP: Yes, if you’re using an IMiD [immunomodulatory drug], that NK [natural killer] cell concern that is there with daratumumab goes away, because you get nice recovery of NK cells with an IMiD. So I think that’s certainly one way to think about it.

Transcript Edited for Clarity

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Transcript: 

Sagar Lonial, MD, FACP: Let’s talk a little bit about emerging therapies. Tom, do you want to get us started off talking about how genetics and other subsets in the relapsed setting might help shape what we’re doing or how we think about treatments we have available in the relapsed setting?

Thomas G. Martin, MD: Sure. In contrast to upfront therapy, cytogenetic abnormalities, the high-risk abnormalities, obviously have been associated with worse prognosis, but when the patients receive a daratumumab-based regimen, they in fact do better. So Jonathan Kaufman, MD, presented at ASCO [American Society of Clinical Oncology annual meeting] looking at data from the POLLUX study, and Katja Weisel, MD, also presented data looking at it from the CASTOR study. And in both of those studies patients who had high-risk disease did better, much better in fact, if they got daratumumab plus the doublet—either lenalidomide and dexamethasone or bortezomib and dexamethasone—than you would have expected based on the frontline data. It’s pretty interesting. In fact, the patients who are high risk and got the triplet did better than the standard-risk patients who got the doublet. But it didn’t completely eliminate having high-risk disease. They didn’t do as well as patients who were standard risk getting the triplet. But it made it a lot better. And so there is a little difference there between newly diagnosed and early relapsed patients.

I do think that if somebody has high-risk cytogenetics and has early relapse, going to a daratumumab-based regimen, one of these regimens—DVd [daratumumab/bortezomib/dexamethasone] or DRd [daratumumab/lenalidomide/dexamethasone], or even DPd [daratumumab/pomalidomide/dexamethasone]—would actually be OK, and I do think actually a carfilzomib-based regimen would be fine in addition, a triplet.

Sagar Lonial, MD, FACP: So how do we reconcile what Saad was saying earlier in terms of ALCYONE, CASSIOPEIA, and MAIA where you don’t get the benefit from adding daratumumab, and what you’re saying with POLLUX and CASTOR where you do seem to get the benefit? I’m trying to figure that out.

Saad Z. Usmani, MD, FACP: So are we. I think it will have to be longer follow-up. I think my critique of MAIA is the small proportion of high-risk patients that they have, it’s only about 14%. So that’s roughly 26 or 27-odd patients on each arm. And it could be just the luck of God that we’re not getting the same answer. But again, with longer follow-up, the answer may be a little different. I think ALCYONE read out with a follow-up of around 16½-months, something like that? And I don’t think we’re going to see major differences in PFS [progression-free survival] for high-risk patients that early. But we’ll definitely see it by 3 years.

Sagar Lonial, MD, FACP: Yes, it certainly could be that the truly high risk falls out early and they never even get to the relapsed trials.

Saad Z. Usmani, MD, FACP: Right.

Sagar Lonial, MD, FACP: And so what we’re calling high risk in relapse is not the same as high risk in frontline.

Thomas G. Martin, MD: High risk out of the gate is probably really bad, but like you were saying, high risk down the road isn’t as bad as right out of the gate, without any other therapy, without any selection, etcetera. But again, we’ll learn more over time for sure.

Sagar Lonial, MD, FACP: Let’s get to a happier topic, you want to talk about OPTIMISMM. Let’s talk about OPTIMISMM, Saad.

Saad Z. Usmani, MD, FACP: OPTIMISMM was a randomized phase III trial that compared pomalidomide/Velcade/dexamethasone versus Velcade/dexamethasone. And when I looked at the abstract I thought the “P” stood for panobinostat because the data looked very similar, but in an earlier relapsed setting. In the United States most of our patients do become lenalidomide refractory fairly early, and we always struggle with the best options for those patients. I think from that perspective looking at that first relapsed population where pomalidomide/Velcade actually did have almost 21 months of PFS benefit compared with 11 months, I think it’s a reasonable option. Will we be giving Velcade the same that it was given in the clinical trial? Probably not. So I think it’s a decent option for our patients who are lenalidomide refractory.

One abstract that I didn’t see here is ICARIA-MM, it might be the next one that we talk about, so I’ll just leave it at that. I think that will be an important option to discuss in the same space. With pomalidomide/Velcade/dexamethasone, I think both high-risk and standard-risk patients benefited in the subgroup analysis. So again, even though they might not be the same high risk but they’re in the front line, that’s an important distinction, especially for deletion 17p patients I think.

Sagar Lonial, MD, FACP: Amrita, you led a trial of pomalidomide/ixazomib/dexamethasone. Do you want to talk about some other pomalidomide-based approaches that were discussed here?

Amrita Y. Krishnan, MD: You know Saad referenced the ICARIA trial so there are other anti-CD38 monoclonal antibodies, such as isatuximab, and this is a large trial phase III comparing isatuximab/pomalidomide/dexamethasone versus pomalidomide/dexamethasone alone. And not surprisingly it showed higher response rates with the isatuximab/pomalidomide/dexamethasone, better PFS with the isatuximab/pomalidomide/dexamethasone. So I don’t think there’s any argument about a third drug, and I do think the antibody/pomalidomide combination is probably one of the best combinations we have. I think the question, which I’m sure you’re going to ask everyone is, what do you do with that in the setting of daratumumab? And I didn’t come away with an answer for that from this trial.

Sagar Lonial, MD, FACP: All right, what do people think? So we’ve got daratumumab, we will likely have isatuximab, I think based on this trial, it’s clearly a positive trial. I think there were some discussions around whether there is any ability of one to work when the other doesn’t work. I don’t know, what do you all think?

Thomas G. Martin, MD: We’ve done that in a number of patients. We’ve treated a lot of patients on isatuximab at UCSF [Helen Diller Family Comprehensive Cancer Center], and then when we tried to go to daratumumab afterward, we really haven’t had a long benefit. Probably a very short PFS, and vice versa too. I would say we’ve tried a small number of patients who received daratumumab, to give isatuximab….

Sagar Lonial, MD, FACP: Yes.

Thomas G. Martin, MD: Again, we didn’t really see a huge benefit there. I think that’s going to be difficult. I think if you’re going to give 2 CD38 antibodies, they have to be separated by a period of time to potentially allow for CD38 expression to recover on some of these myeloma cells.

In terms of the phase III data, it’s really good phase III data. It’s a large study, it’s 11.5 months PFS. In terms of antibody plus pomalidomide/dexamethasone, it’s the longest of all the studies that have been published at the current time, so it actually works really well. With daratumumab coming into the frontline setting, I think this would be a reasonable strategy. And this study was for people who had 2 prior lines of therapy. So they get daratumumab frontline, they get a second line of therapy, and then this would be a reasonable thing for third-line, and that would be 2 prior lines of therapy. But I do think they were partly interchangeable in terms of regimens they can be used with.

Saad Z. Usmani, MD, FACP: I think we didn’t touch upon ELO/POM/DEX [elotuzumab/pomalidomide/dexamethasone] as a potential option, and I honestly was discounting elotuzumab in a post-daratumumab exposed or refractory patient. But I’ve been pleasantly surprised with some of our experience with elotuzumab/pomalidomide/dexamethasone in daratumumab-exposed or refractory patients. So if you’re thinking about a monoclonal in a post-daratumumab, at first relapse, I find that the elotuzumab/pomalidomide/dexamethasone data are fairly similar to what we see with isatuximab/pomalidomide/dexamethasone. So again, the struggle is, are these drugs equal? And if they are, is it better to change the target with a monoclonal antibody? I think that’s what we’re going to be struggling with clinically.

Amrita Y. Krishnan, MD: I would be curious, in terms of your elotuzumab/pomalidomide/dexamethasone patients, with those immediately after progressing on daratumumab who you switched to elotuzumab, did you see responses?

Saad Z. Usmani, MD, FACP: Right now most of our data usage is in the first or second relapse setting. Then for our patients who are progressing on daratumumab, and as we’re thinking about different MOAs [monoclonal antibodies], and if we’ve already exhausted our PI [proteasome inhibitor] options with the previous lines of treatment, then we’re left with elotuzumab/pomalidomide/dexamethasone, and we have been pleasantly surprised. We salvaged some patients where we thought it wouldn’t be possible.

Sagar Lonial, MD, FACP: Yes, if you’re using an IMiD [immunomodulatory drug], that NK [natural killer] cell concern that is there with daratumumab goes away, because you get nice recovery of NK cells with an IMiD. So I think that’s certainly one way to think about it.

Transcript Edited for Clarity
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