Sequencing Therapies for Multiple Myeloma

Transcript:Keith Stewart, MD, CHB: We have three randomized trials that show that the addition of either ixazomib, elotuzumab, or carfilzomib to lenalidomide/dexamethasone have improved at least progression-free survival on all three trials. What’s the role of ixazomib in this setting then, Bill? Would you use that on a younger patient, an older patient, indolent relapse, or aggressive relapse? Where’s your thinking?

William I. Bensinger, MD: Ixazomib is the oral proteasome inhibitors, the first one of its type approved. The data from the TOURMALINE study did show a benefit for the three-drug combination over lenalidomide/dexamethasone alone, about a 6-month difference in PFS. The drug combination was well tolerated. I think we aren’t sure about when to use this drug though. Because I wanted to point out that both this trial and the trial with elotuzumab specifically excluded patients who were on lenalidomide maintenance and progressed. Those were determined to be refractory patients. Now, that was not true of the ASPIRE study, which did allow patients who progressed on maintenance lenalidomide to go on the trial. So, I think they were different populations and we don’t really know, I think, how true lenalidomide-refractory patients would do by adding in ixazomib or adding in elotuzumab.

Keith Stewart, MD, CHB: I don’t know if I got an answer there but when would you use ixazomib?

William I. Bensinger, MD: I would certainly consider ixazomib for a patient who was responding, or who had responded to lenalidomide in the past and was then relapsing. And the same goes for elotuzumab.

Keith Stewart, MD, CHB: There are some others. I think the reason people are voting for carfilzomib is the depth of response. Is that important or is it durability of response, or they go hand in hand? What do you think?

C. Ola Landgren, MD, PhD: I think durability is the reflection of depth of response. And I think we are kind of walking around the problem we addressed here before, that for aggressive relapse you need powerful therapy. For indolent relapse, the question is, is it good enough to do a less powerful therapy and then sequence to more powerful therapy later? Or is it better to use the more powerful therapy up front? And it’s the same question as we addressed in the newly diagnosed setting—shall you use your best drugs right away? If you say yes to that, then you should ask the question, should you use your best drugs for relapse?

Keith Stewart, MD, CHB: Are you using carfilzomib/lenalidomide/dexamethasone in the newly diagnosed patient?

C. Ola Landgren, MD, PhD: Right.

Keith Stewart, MD, CHB: Well, you’re doing it relapsed when that disease comes back.

C. Ola Landgren, MD, PhD: We would use carfilzomib/pomalidomide/dexamethasone. I think that’s a very powerful combination. Keith Stewart, MD, CHB: What’s happened if they’ve had intolerance of carfilzomib, or they don’t want to come in every week because of work issues, or they’ve actually progressed on carfilzomib therapy? What’s your plans for then?

C. Ola Landgren, MD, PhD: Our default would probably be the carfilzomib/pomalidomide/dexamethasone. But we would go over all these options that we have just heard Jatin and Bill talking about here. And I think I have this conversation with my patients. I say that basically there’s the more convenient approach. Patients have been on lenalidomide maintenance for a long time. They almost forgot they have myeloma. And now I show the problem. I say, “It’s coming back,” and they feel great. They don’t want to come back for infusions. So, you have basically two options. Either you keep on taking tablets as a convenient approach and maybe that works, or maybe you do a couple of months with infusional therapy and that’s more likely to work. And you have to have that conversation. I think I have that conversation with every patient.

Keith Stewart, MD, CHB: Let me ask, the ENDEAVOR clinical trial didn’t use an IMiD, it just used high-dose carfilzomib with dexamethasone. Very impressive results compared to bortezomib/dexamethasone alone. So, this was carfilzomib, 56 mg/m² with dexamethasone. Impressive. No IMiDs, just two drugs. What do you think of that, Rafael, and how does that change your practice?

Rafael Fonseca, MD: I think the ENDEAVOR clearly establishes that carfilzomib is a more potent proteasome inhibitor. There are some caveats that need to be discussed. There’s a higher dose than what’s on label. But the question is, what is the right dose for carfilzomib? We don’t know that. It went up to 56 mg/m². Even amongst patients who have prior exposure to bortezomib, the results of the trial were positive. I think all of what we’re discussing are real-world reasons why you may go with one versus another. And I think those real-world reasons are fundamental in how we choose the selection of the different regimens for patients. I’ll give you an example. I have a patient who’s willing to drive 200-plus miles every week for infusions because he cannot get oncologic care next to his community. Well, that’s a person that I’m very fortunate now that I have an oral proteasome inhibitor for induction therapy. And I think we can go in through anecdotes, each one of us, why in specific circumstances each one of those agents is going to be useful. But back to your point. If you just lined them up and you look at all the drugs that are currently in the proteasome inhibitor category, there’s really no question that carfilzomib is the most potent.

Keith Stewart, MD, CHB: Jatin?

Jatin P. Shah, MD: I agree. I think there’s probably just two things I want to quickly comment on. Number one is that when we think about the right dosing schedule of carfilzomib, probably what I’ve thought about is that carfilzomib 56 mg/m² is full-dose therapy and not high-dose therapy because I think that’s a misnomer. And then you dose attenuate if you’re combining it with something else, like we do with everything else. Or, if you’re going to do it in later lines of therapies, you dose attenuate. So, you start off with a full dose in the relapse setting as a doublet of 56 mg/m². If you combine it—which we often do with lenalidomide or pomalidomide—then you need to dose reduce, as opposed to saying that 27 mg is full dose and that it is high dose. I think that to me is a different way of thinking about it.

Keith Stewart, MD, CHB: But economically this might be quite useful to just be able to give carfilzomib with steroids with another drug.

Jatin P. Shah, MD: Exactly. I think that does open up options for patients who, for example, are lenalidomide-refractory. That’s carfilzomib/dexamethasone based on that ENDEAVOR data, which I think is rather powerful data as well.

Keith Stewart, MD, CHB: Panobinostat, what do you think of that? We have another positive phase III trial with PANORAMA, with panobinostat/bortezomib versus bortezomib alone. Bill?

William I. Bensinger, MD: Panobinostat is another oral drug and the trial that showed benefit unfortunately paired it with a parenteral drug, bortezomib. So, you had to use it; you have one oral drug but you’re still having to give shots to a patient. It did show benefit. The drug may not be optimally dosed in that study. There was a fair amount of GI toxicity, and I’ve heard of regimens where instead of giving the drug every week, you give it every other week. It seems to be better tolerated. I think we need to learn more about how to use that drug. But I think it does have benefit in the right patient population.

Keith Stewart, MD, CHB: Jatin, didn’t you have RFVD, vorinostat, panobinostat …

Jatin P. Shah, MD: Panobinostat. We have a fair amount of experience at MD Anderson with panobinostat. So, I think what I’d highlight here is coming back to what I said about transplant. Until you can cure the disease, use every therapeutic option. Though we’re excited about some of these novel therapies, panobinostat is still an active drug. So, make sure you don’t forget about that for our community physicians, that it’s still an active drug, and for an incurable disease, that’s an important option for patients.

Keith Stewart, MD, CHB: Do you use subcutaneous bortezomib with it?

Jatin P. Shah, MD: Yes. That’s a great question. I think that the phase III trial did show actually a pretty impressive hazard ratio for patients who had a prior IMiD and a proteasome inhibitor. The progression-free survival improved from 4 months to 12 months, so it was actually a significant improvement in that subset of patients. What we’ve done now is two trials with panobinostat. One, we did RVD plus panobinostat up front. I think that was important, again, just speaking to the oncologic principles that we’re able to get a high depth of response with 50% of our patients getting a CR after 4 months. And that’s consistent with what we’ve seen with panobinostat globally, that when you combine it with other proteasome inhibitors and IMiDs, you improve the depth of response.

And number two, we’ve combined it with carfilzomib, and importantly, I think, Ajai Chari combined it with lenalidomide. It’s very different when you combine those with carfilzomib and lenalidomide, and that 20%-plus grade 3 and grade 4 GI toxicity essentially resolve. And so we actually see almost no grade 3 and 4 GI toxicity or cytopenias that we see when we combine it with the bortezomib. So, I think the partner drug consistently now when you combine it with Ajai Chari’s experiences plus our experience.

Keith Stewart, MD, CHB: And he’s, Dr. Chari, is at Mount Sinai?

Jatin P. Shah, MD: He’s out in Mount Sinai. And so the data from Sarah Cannon also combines it with carfilzomib—very similar experience. I think globally we’re seeing now multiple data sets that when you combine panobinostat with carfilzomib, or lenalidomide, actually it’s an active combination that’s well tolerated. Very different than what we see with a panorama when you combine it with weekly bortezomib.

Keith Stewart, MD, CHB: So, other experiences with panobinostat?

C. Ola Landgren, MD, PhD: We are not using it a whole lot right now. But I think those data are interesting. And I agree, of course, with Jatin that until we have a cure, we need every drug.

Transcript Edited for Clarity