Next-Generation Regimens for Multiple Myeloma - Episode 8

Sequencing Through Multiple Lines of Therapy


A. Keith Stewart, MB, ChB: So, we’ve glossed over the CASTOR and POLLUX studies of daratumumab because they weren’t really updated at this meeting. Have they established, along with your study now, that daratumumab is going to be incorporated with pretty much every regimen we use, you think? Is that where we’re heading here?

Amrita Krishnan, MD, FACP: Yes, I would say.

Sagar Lonial, MD, FACP: I think the data in first relapse are so strong for daratumumab. I think the question is, what’s the partner? And you mentioned 15 months for KdD (carfilzomib [Kyprolis], dexamethasone, and daratumumab). For the pomalidomide/daratumumab/dexamethasone that Jay from our center presented in first relapse, it was about 14 to 17 months with the PFS. So, it really is, what partner do you want to choose?

A. Keith Stewart, MB, ChB: With the duration of therapy at relapse, we’re using these triplet regimens. When do you decide to stop? You all have had very high response rates, 80% and higher. What makes you stop or start to cut back on?

Edward A. Stadtmauer, MD: The discontinuation of therapy is driven by response and by toxicity more so than a set endpoint. I am so impressed with how well—beyond what I anticipated, for instance—the daratumumab is tolerated by patients. I quiz them on this every time I see them. And once they get to once a month, they are impressed; they are impressively comfortable with doing that. And as you alluded to earlier, it’s sometimes even more difficult to give lenalidomide for long-term or bortezomib.

A. Keith Stewart, MB, ChB: Actually, that was Tom. I didn’t say that, just to be clear.

Edward A. Stadtmauer, MD: Well, usually it’s Tom.

A. Keith Stewart, MB, ChB: California over there.

Thomas Martin, MD: So, I would say out of the triplet regimens that we use, the most toxic drug is dexamethasone. In fact, that’s probably the drug that I decrease the dose in first and also get them off first. And then between the other 2 partner drugs, both tend to be potent these days. We have really potent drugs, and it’s really what do I attribute the toxicity to, this drug. Drug A or drug B? And whichever it is, that’s the one I’ll reduce and the other one I’ll just continue. It’s kind of fun, and I think you can get to a very tolerable regimen that patients can take year in and year out.

A. Keith Stewart, MB, ChB: Is there a stopping point for relapse therapy or is it really until progression? Is there any point where we should say enough’s enough other than toxicity?

Ajai Chari, MD: I would just make a caveat, that in high-risk patients I’m not as prone to discontinue it because I think response rates should be distinguished from PFS. And high-risk patients may respond well, but we know that they relapse faster. And there, I try to maintain them on both of the active drugs, not necessarily the steroid. But I think for other patients, I think what you’ve been hearing over and over is we have a dearth of MRD-negative decision-making studies. If you tame it, how many drugs do you need and for how long? That’s, I think, what we really need.

A. Keith Stewart, MB, ChB: I guess that’s the question for me. If you use daratumumab/carfilzomib and you’re MRD-negative, do you really need to go forever? Do you drop one of the drugs and just continue one? Those are the things we just don’t know the answer to.

Edward A. Stadtmauer, MD: In our current circumstance, our relapsed regimens may be even more potent than our initial regimens.

A. Keith Stewart, MB, ChB: Exactly.

Edward A. Stadtmauer, MD: But that may change over time as we move to these more potent regimens.

A. Keith Stewart, MB, ChB: Second transplants versus continuing the drugs? It’s certainly cheaper.

Edward A. Stadtmauer, MD: It has become cheaper. There definitely is a role for a second transplant. A lot of it depends on the behavior after the first transplant and durability of response, toxicities, etc.

A. Keith Stewart, MB, ChB: We’re going to get really complicated. What happens at third relapse? You’ve now used 6 different drugs. Are you just recycling things or is it time to move on to novel mechanisms of action? Sagar, what do you think?

Sagar Lonial, MD, FACP: For us, it would be daratumumab/pomalidomide in first relapse and then second relapse would usually be carboplatin/cyclophosphamide. So, we go old school in that situation.

A. Keith Stewart, MB, ChB: That was some shade thrown at me, by the way. I got that.

Sagar Lonial, MD, FACP: And then, again, start to think about recycling as well and looking more closely at genetics. For instance, I’m not going to argue that mutation-driven therapy should take over a third-line therapy, but a lot of people weren’t testing 5 and 6 years ago for 11;14. And that’s a great opportunity, if they’re 11;14, to think about something like venetoclax.

A. Keith Stewart, MB, ChB: Any other thoughts on sequencing therapies and how we choose our regimens on way to relapse, Amrita?

Amrita Krishnan, MD, FACP: Well, I think it’s shifting so quickly, as everyone alluded to, because now we’re going to use a lot more pomalidomide on first relapse. We’re using daratumumab first relapse.

A. Keith Stewart, MB, ChB: So, up front.

Amrita Krishnan, MD, FACP: Exactly. I think by the time you get to third relapse, you really are just mixing all the ingredients. But we’ve used a lot more venetoclax now in combination with bortezomib. There’s a phase II trial published showing about 80% response rate.

A. Keith Stewart, MB, ChB: Yes, I think we might come to that a little later in our discussion, but venetoclax is certainly a drug that’s beginning to appear in our conversation. Anything else that’s…?

Ajai Chari, MD: I think the 2 sequencing issues. Again, this is a dearth of issue because we really have very little sequencing studies. “If you do this, then you should do that.” But the 2 things I would say is elotuzumab has a sequencing issue because it’s only on label with lenalidomide.

A. Keith Stewart, MB, ChB: Thank you for mentioning that.

Ajai Chari, MD: So, if somebody is not lenalidomide sensitive, there is really no on-label use of elotuzumab right now. I’m sure we’re going to get to this more, but the BCMA is now becoming an issue as well.

A. Keith Stewart, MB, ChB: Actually, I’m glad you mentioned elotuzumab, and I apologize we haven’t talked about that before. Is that a good choice when daratumumab has been used and maybe failed? Would you consider elotuzumab?

Ajai Chari, MD: I think the elotuzumab struggles with having lack of single-agent activity, but it’s strength is its excellent tolerability. And I think that those of us who have done the elotuzumab study, we all have patients who have been out many, many years; 6 or 7 years we had patients on ERd (elotuzumab, Revlimid [lenalidomide], and dexamethasone) without really any problem. I think the question is, who is the right patient? And I think somebody with perhaps a biochemical relapse and lenalidomide sensitivity or maybe low-dose lenalidomide maintenance, I think that’s one role for elotuzumab. But once they’ve progressed on lenalidomide and are progressing, I don’t think there’s a role for elotuzumab.

Sagar Lonial, MD, FACP: But if daratumumab moves up front, then elotuzumab may have an opportunity in the relapsed setting.

A. Keith Stewart, MB, ChB: I guess that’s why I was asking. It opens the door for elotuzumab to come in.

Thomas Martin, MD: And then there are other regimens with elotuzumab now. So, there’s elotuzumab/pomalidomide/dexamethasone and there will be elotuzumab/ixazomib/dexamethasone. There will be other combinations that we can see if there’s a good response rate that can be part of the sequence. The other thing I would add is when we’re done with PIs and IMiDs and daratumumab, at that point in time, I think the options are really alkylator-based therapy. That’s when I tend to think about, am I going to do a second transplant? Sometimes I’ll give them chemotherapy to get them into remission and then do a second transplant at that point in time, or the other drug that I do get some responses from is bendamustine as an “alkylator-based” regimen. And that’s really kind of down the road. I think all of us practice that those patients are on our next immunotherapy clinical trial, because that’s the eligibility now for all the clinical trials. But for other people in practice, I think those are things that they can do, they can use the alkylator-based therapies.

Amrita Krishnan, MD, FACP: Can I make a case? The other thing for second transplant, because we talk about tolerability of these regimens long term, which is fine in terms of neuropathy and cardiac. But the one thing you can’t mitigate against is hematologic toxicity.

Thomas Martin, MD: Right.

Amrita Krishnan, MD, FACP: And that is actually often a case where we end up doing a second transplant to reconstitute counts. Maybe you’re also having some resetting of the immune microenvironment.

Edward A. Stadtmauer, MD: It becomes a bridge to another therapy.

A. Keith Stewart, MB, ChB: All right, well I think we’ve heard that treating relapse is complex. We’re using pomalidomide, and carfilzomib, and daratumumab at first relapse these days in various combinations and cocktails based on prior response, patient characteristics, relapse. But, clearly, any of those combinations are improving outcomes for our patients, and we need to learn a little bit more about how to best combine them and for how long to use them.

Transcript Edited for Clarity