Proteasome Inhibitors in Relapsed-Refractory Myeloma

Transcript:A. Keith Stewart, MB, ChB: Let me come back to you in a minute. I just want to just refocus this a little bit on the proteasome inhibitor question. So my understanding from market research is that 70% of patients are still getting bortezomib up front, and only about 10% are getting carfilzomib. Although it sounds like in the academic setting that’s starting to switch. The vast majority of our patients we’re seeing have had bortezomib. So the choices are really carfilzomib or ixazomib if you’re going to use a proteasome inhibitor. What are you using at relapse, Tom?

Thomas Martin, MD: Yes. So carfilzomib for sure. I think ixazomib, especially if patients are bortezomib-refractory, has a very low response rate. I don’t think ixazomib is a good choice. But carfilzomib, yes. And actually Dr Luciano J. Costa presented data today [at the American Society of Hematology Annual Meeting and Exposition] with a really neat combination of carfilzomib with venetoclax.

A. Keith Stewart, MB, ChB: Let’s save that one too. We’re going to get to venetoclax in a bit.

Thomas Martin, MD: OK.

A. Keith Stewart, MB, ChB: We alluded to the ARROW study, which showed that once weekly carfilzomib could be used effectively. Do you want to comment on that, Faith?

Faith Davies, MD, MBBCh, MRCP, FRCPath: Yeah. Certainly the once-weekly carfilzomib is at the higher dose. So we’re at the 70 mg/m², rather than the 36 mg/m².

A. Keith Stewart, MB, ChB: Is that a dose you’re comfortable using?

Faith Davies, MD, MBBCh, MRCP, FRCPath: I’ve used it quite a lot. I think that maybe for older, less fit patients I do a bit of extrapolation, and we can then argue that I don’t have a clinical study to support my once-weekly dosing at the lower dose. But I may come down to 56 or 36, to really going on what we were talking about earlier as being tolerable and maintaining patients on treatment for a long period of time.

A. Keith Stewart, MB, ChB: Rafael, are you using weekly carfilzomib? Do you worry about cardiac issues?

Rafael Fonseca, MD: I actually have changed my practice for most of my patients with carfilzomib, just because of the ARROW study. I was a bit uncomfortable with the CHAMPION-1 study before. But I think the ARROW study has the numbers, and actually comparisons with CHF [congestive heart failure] are quite comparable between both arms. So I am confident. I think comments that Dr Davies makes are very important. So I do use that 70; unless they’re in combination, I go down to 56, even in the fit patients. So 56 if we’re going to use KPD [carfilzomib, pomalidomide, and dexamethasone] or KRD [carfilzomib, lenalidomide, and dexamethasone].

A. Keith Stewart, MB, ChB: Weekly.

Rafael Fonseca, MD: On the weekly schedule, yeah. And I think 1 of the things people always talk about is high-dose. We don’t know the right dose for carfilzomib. It’s like saying you have a car that can go faster, just don’t push down on the gas pedal, right? Carfilzomib is more active at higher doses. We saw that with ENDEAVOR when they were using it at the 56 dose in a head-to-head comparison with bortezomib. We’re kind of ganging up on bortezomib, but it’s a better drug and I think it’s well tolerated. So the 70 dose as a single agent—I don’t use a lot of that; 56 in combination, once weekly.

Faith Davies, MD, MBBCh, MRCP, FRCPath: Do you ever use the dose of 27 nowadays?

Rafael Fonseca, MD: When I forget not to use the right dose.

A. Keith Stewart, MB, ChB: I do sometimes if it’s an elderly patient, particularly in combination. I think it’s too low of a dose on its own, but in combination, yes.

So the ARROW trial, just for the audience, compared the standard FDA dosing of 27 with 70 weekly. I was part of the study and the intent was really just to show you could give a more convenient dose with equivalence. But in fact, the weekly dose was actually slightly better, in terms of response rate and progression-free survival. So this is probably a good thing for patients all around.

It’s probably important that we clarify the carfilzomib dosing because there’s a little bit of confusion around that. So the FDA-approved dosage initially for relapse was 20 mg/m² in the first 2 days and then 27 mg/m² thereafter, on the twice-weekly dosing schedule. Now your understanding, Tom, for the next approval, which was from the ENDEAVOR study, which was carfilzomib and dexamethasone in relapse. What was the dosing there? Could you remind us?

Thomas Martin, MD: Yeah, sure. It was 20 mg, again, for day 1 and 2 for cycle 1. But at days 8, 9, 15, and 16, it was 56 mg/m² of carfilzomib. So then ongoing twice weekly at 56 mg/m².

A. Keith Stewart, MB, ChB: And the third study that went to the FDA is the once weekly, which compared 20, 27 with 20 to start, but then 70 weekly. And again, that would be the weekly dosing schedule for those patients.

Up front, Rafael, you alluded to the fact that the dosage is slightly different again?

Rafael Fonseca, MD: Yes.

A. Keith Stewart, MB, ChB: In combination.

Rafael Fonseca, MD: To clarify, in patients that we use carfilzomib weekly in combination, I scale down from that 70 to 56 if we combine, say, with an IMiD [immunomodulatory drug], which is the most common combination with lenalidomide at that point.

A. Keith Stewart, MB, ChB: In weekly dosing.

Rafael Fonseca, MD: In weekly dosing, yeah. And I’d like to put in a comment here for colleagues in the community. Occasionally, because of how the treatment plans are designed, we do see some patients who occasionally are kept at 20. So it’s important to make sure there’s that escalation beyond that 20 that you get on, right at the beginning of treatment.

A. Keith Stewart, MB, ChB: And the 20 is really sort of a test dose to make sure nothing bad happens, and then you immediately escalate up.

Rafael Fonseca, MD: Exactly.

A. Keith Stewart, MB, ChB: Do you use a lot of hydration with your carfilzomib, Faith?

Faith Davies, MD, MBBCh, MRCP, FRCPath: Certainly in the first couple of days I do hydration.

A. Keith Stewart, MB, ChB: How much do you give?

Faith Davies, MD, MBBCh, MRCP, FRCPath: I’m not entirely sure what the FDA and the label say, but I tend to give half a liter beforehand.

A. Keith Stewart, MB, ChB: I give a little bit less, actually 250 [mL] maybe.

Adriana Rossi, MD: Yeah. Our standard is 250, but I think patients either have more renal involvement, and I’m concerned and will go up to 500, or if I have any concern for cardiac tolerance, I will cut back.

A. Keith Stewart, MB, ChB: And the last dose we should mention, which was during the ASPIRE clinical trial, was a combination of carfilzomib, lenalidomide, dexamethasone. The dosing there was 36 mg/m² after the first test dose of 20. Sorry, it was 27, I’m getting confused again. It was 27 mg/m² in combination with lenalidomide, but many of us would use 36 mg/m² in those patients because I think that’s a tolerable dose.

Thomas Martin, MD: Going forward, I think our plan is really to switch to the weekly carfilzomib dosing. So it’s really 20, cycle 1, day 1; and then, subsequently, if it’s in combination, it’s 56 mg/m² weekly; or if it’s just with dexamethasone, it’s 70 mg/m². We actually have data with daratumumab that you could still keep it at 70 mg/m². With IMiDs, it’s 56; with everything else, it’s 70 weekly.

A. Keith Stewart, MB, ChB: I think that’s the best way to clarify it. If they already moved to weekly, we really just have 2 doses now, which makes life easier.

Transcript edited for clarity.