Next-Generation Regimens for Multiple Myeloma - Episode 7

Selecting a Proteasome Inhibitor in Multiple Myeloma


A. Keith Stewart, MB, ChB: So, we’ve talked about switching class, switching immunomodulating drugs. Let’s talk about proteasome inhibitors next. We have some choices. We have ixazomib and we have carfilzomib, once bortezomib has been used in the past. What kind of patient would you use either of those 2 new proteasome inhibitors in, and how do you select them?

Ajai Chari, MD: I think the biggest difference obviously between these 2 is the administration: oral versus IV. So, for patients where that’s going to be an issue, I think ixazomib would win for convenience. But beyond that, I think the ixazomib data have only been done in patients with prior bortezomib sensitivity or are bortezomib-naïve, as opposed to carfilzomib. There are studies that have shown activity even in bortezomib-refractory patients, albeit perhaps a little bit less. And I think the head-to-head study of ENDEAVOR—“K” (carfilzomib) at 56 mg/m2 versus Vd (Velcade/dexamethasone)—showed superiority in terms of response, PFS…

A. Keith Stewart, MB, ChB: So, what kind of patients are you thinking for either drug?

Ajai Chari, MD: I think it’s somebody who has an aggressive disease, more than just a biochemical relapse. I would probably use “K” over “I” (ixazomib); if it was somebody who had more of a biochemical and it was a convenience issue, then I would use that.

A. Keith Stewart, MB, ChB: Any difference of opinion with that? Is it all about tempo and aggressiveness? Is age and comorbidity factoring into your choices, Amrita?

Amrita Krishnan, MD, FACP: I think Tom alluded to the fact you can give carfilzomib in elderly patients, but it doesn’t necessarily mean you have to. I probably would prefer an elderly patient try ixazomib first.

Thomas Martin, MD: And it could be an oral, it’s really convenient. I have a lot of patients where I present them, “Here, you can take an oral pill, you can come once or twice a week for an IV,” and they all select the oral pill. But like Ajai said, it really needs to be in patients who are bortezomib-sensitive and carfilzomib-sensitive. If they’re refractory to any other PI, then ixazomib is probably not the right choice.

Edward A. Stadtmauer, MD: That’s how I make the decision. If I’m thinking bortezomib, then I use that as an option. If I’m thinking that I wouldn’t use bortezomib in this setting, then I think carfilzomib.

A. Keith Stewart, MB, ChB: OK. Let’s talk about the ARROW study. Who wants to take a stab and explain to the audience what they heard yesterday? Amrita, why don’t we pick on you.

Amrita Krishnan, MD, FACP: So, the ARROW study looked at the standard biweekly dosing of carfilzomib at 20 mg/m2 and then 27 mg/m2 compared with a weekly dosing of 70 mg/m2. It actually showed equal tolerability, which surprised me in terms of cardiovascular events. It was about 3% to 4% with the weekly 70 mg/m2. And it actually showed a better PFS for the weekly.

So, I think it will be practice-changing because it will make us more comfortable to use 70 mg/m2 weekly, including in older patients. And, frankly, as Tom alluded to, the biggest barrier I think for patients getting carfilzomib has been the dosing schedule.

A. Keith Stewart, MB, ChB: Any other reactions to that study? Sagar, what do you think?

Sagar Lonial, MD, FACP: Yes. I think certainly the toxicity data are what really struck me. Because sometimes 70 mg/m2 once a week can be a little bit tough to give. I think it’s clear, both from ENDEAVOR at 56 mg/m2 twice a week and ARROW at 70 mg/m2 once a week, that you can give these higher doses of carfilzomib with dexamethasone as the partner. We don’t often do that. And so, if you’re going to partner it with lenalidomide or pomalidomide or daratumumab, how safe is it to do that? And we have some trials that speak to that.

A. Keith Stewart, MB, ChB: What a great intro to Dr. Chari’s trial. Because there has been this notion that 70 mg/m2 weekly is not going to be the dose you can combine with lenalidomide or cyclophosphamide, you have to use a lower dose. But you showed some compelling data yesterday combining carfilzomib/daratumumab. Do you want to tell us about that a little bit?

Ajai Chari, MD: Sure. This is the daratumumab/carfilzomib/dexamethasone arm of the MMY1001 study, which is a phase I study comparing the addition of daratumumab with various backbone drugs. And it showed that it was very safe. Really, we didn’t see a lot of additional toxicities than you would expect from each drug. The rate of neutropenia was relatively modest. Grade 3/4 was about 20%, so I think that was an interesting safety signal.

A. Keith Stewart, MB, ChB: I asked you this already, but you didn’t see an increasing in infection? Because I’ve been impressed with the hypogammaglobulinemia you get with those 2 drugs, but you didn’t see any…

Ajai Chari, MD: We didn’t see significant infection.

A. Keith Stewart, MB, ChB: How many patients were there on that study?

Ajai Chari, MD: There were 85. And I think the interesting data also were that the PFS for the entire group was not even reached with a median follow-up of 12 months. But specifically, as Tom alluded to, in the lenalidomide-refractory population, the medium PFS was 14 months, which I think in the context of the other data that we have with DPd, DVd from CASTOR, and Kd from ENDEAVOR, this is a pretty encouraging result. And I think it adds to the ARROW study, which was the same weekly 70 mg/m2, and this is the same weekly 70 mg/m2 with the addition of daratumumab.

A. Keith Stewart, MB, ChB: Is everybody switching to weekly carfilzomib? Is it done using it twice weekly? Are we still going to try that in some patients?

Thomas Martin, MD: Well, immediately after the session yesterday, I sent an email to all the myeloma practitioners at UCSF, including our pharmacists, and said, “Let’s go to weekly for everybody. Let’s get an APEX build and a Beacon build for the 70 mg/m2 weekly.” Because I do think it is certainly way more convenient than twice weekly. And patients will be very happy, I think, to go to that. I was very surprised also on the safety signal, that there wasn’t a safety signal between the 70 mg/m2 versus the 27 mg/m2 2 times a week.

A. Keith Stewart, MB, ChB: Yes, I think we were all a bit surprised by that. Some real-life experience.

Sagar Lonial, MD, FACP: The other thing that struck me from that trial, which you can say is neither here nor there, the 20 mg/m2-27 mg/m2 PFS was identical to Vd in every other phase III trial. So, I think if you know there are differences between the proteasome inhibitors, but if you look at the lower dose of carfilzomib, it’s basically equivalent to Vd.

Ajai Chari, MD: I think that’s really an important point because the carfilzomib is not the same drug at different doses. Carfilzomib 20 mg/m2-27 mg/m2 versus the ENDEAVOR 56 mg/m2, I think you can extrapolate that it’s the same. And to see that potency of higher doses is really what I think is an important finding.

Amrita Krishnan, MD, FACP: I think the other point is sort of what you alluded to, it’s still the same story as bortezomib, right? When we show studies in bortezomib, we had a lot of neuropathy because we didn’t know how to use it. With carfilzomib, we’re recognizing that you have to mitigate all these other factors first before you start a patient. So, before you suddenly jump to 70 mg/m2, you really need to make sure all your ducks are in a row, especially in terms of hypertension.

Transcript Edited for Clarity