Carfilzomib As Part of Upfront Therapy in Multiple Myeloma

Transcript:Keith Stewart, MD, CHB: You brought up carfilzomib as an option. What do people think about that? There are some pretty exciting looking data with carfilzomib in the frontline setting. Does anyone want to take a shot at telling us about what that looks like? Bill?

William I. Bensinger, MD: There are data from mainly one center, using a combination of carfilzomib, lenalidomide, and dexamethasone. A lot of treatment, up to 18 to 24 months of treatment, and also combining it with the stem cell transplant. But those patients that they have treated, and reported on, have achieved very high rates of complete response; stringent complete response rates above 85% for these patients. So, the data look promising, but I would still say it’s preliminary and it needs to be validated by other groups and larger numbers of patients. It’s worth pointing out that even though NCCN guidelines allow the use of carfilzomib as up-front therapy, it doesn’t have an FDA label for that.

Keith Stewart, MD, CHB: Have people found that a challenge if they’ve tried to use carfilzomib in a patient?

Jatin P. Shah, MD: That’s a good question. I think for us though—for a newly diagnosed patient that comes in to MD Anderson—the two options that we’ll typically consider are a bortezomib/lenalidomide/dexamethasone combination, and we’re actually transitioning to more and more carfilzomib/lenalidomide/dexamethasone for patients. Again, based on two things: one is that we’ve proven that three drugs is better than two. Number two, we know that depth of response matters, and sticking with that oncologic principle that depth of response matters, we know that when we look at carfilzomib-based therapies, more patients are getting to deeper remissions in MRD than we’ve ever gotten.

Sticking with the oncologic principles helps me say that we can use carfilzomib/lenalidomide/dexamethasone in that setting. And, again, also extrapolating from the ENDEAVOR data, where we showed that carfilzomib had a better depth of response, and duration of response, and doubling the CR (complete remission) rate and PFS (progression-free survival). So, I’m using that to extrapolate into the frontline setting, saying that using my oncologic principles helps me use this combination now.

Keith Stewart, MD, CHB: Given that this is not yet approved by the FDA for frontline use, Bill, you’re on the fence a bit, VRD (bortezomib-lenalidomide-dexamethasone) versus KRD (carfilzomib-lenalidomide-dexamethasone). It sounds like MD Anderson is transitioning a bit to KRD. Ola, what are you doing at Memorial Sloan Kettering Cancer Center?

C. Ola Landgren, MD, PhD: Well, as you know, we have worked with this combination since 2010. I think I personally treated more than 200 patients with this combination. So, I feel comfortable using it. It is NCCN-approved. We have actually implemented that as our default therapy at Memorial Sloan Kettering Cancer Center. We give six cycles of…

Keith Stewart, MD, CHB: Have you had any challenges getting the drug approved given…?

C. Ola Landgren, MD, PhD: I think we have set the stage so we no longer really have those. We had those problems in the beginning, but now that has become our standard-of-care for Memorial. We give six cycles.

William I. Bensinger, MD: What dose of carfilzomib do you use?

C. Ola Landgren, MD, PhD: That’s a very important question. We give 20 mg on day 1 and day 2.

Keith Stewart, MD, CHB: Per meter squared?

C. Ola Landgren, MD, PhD: Yes, per meter squared. So, 20 mg/m2 day 1 and 2, and then we jack up to 36 mg/m2 for every subsequent dose—days 8, 9, 15, 16—and for the subsequent cycles.

Keith Stewart, MD, CHB: But some people have said the issue with using carfilzomib in the frontline setting is these rare, but important, toxicity profiles. Have you had any? What’s your personal experience been with that?

C. Ola Landgren, MD, PhD: The reported issues people have talked about a lot is that there could be cardiac signal, there could be, maybe, renal signal. But the ASPIRE trial that you led, Keith, showed that there was no difference in cardiac adverse events in the randomized trial.

Keith Stewart, MD, CHB: There was a difference; it was just small…

C. Ola Landgren, MD, PhD: A small difference.

Keith Stewart, MD, CHB: Not the small percentage; the actual difference is double the number of events, but it’s 2% versus 4%.

C. Ola Landgren, MD, PhD: In my experience, I probably—as I mentioned—treated 200 to 300 patients with this combination. I probably have seen two or three cardiac events.

Rafael Fonseca, MD: One percent.

C. Ola Landgren, MD, PhD: So, that’s relative.

Keith Stewart, MD, CHB: You feel comfortable using this drug in the frontline setting?

C. Ola Landgren, MD, PhD: I feel very comfortable; yes, I do.

Keith Stewart, MD, CHB: Rafael, what’s your thinking?

Rafael Fonseca, MD: You know, I don’t want to sound like I’m the most conservative in this task, but I do actually like the VRD combination for up-front therapy, and particularly because I agree with the principle. We put the best players up front. But for the first half, I would put VRD. For the second half of the game, I would put KRD. And the reason for that is the data with ASPIRE, which you would agree with, are quite spectacular. When we look at the first relapse, our ability to induce complete responses is very, very high. And I think we’re fortunate—it’s not a good word—but fortunate that we can discuss this minutia of the toxicities, because I think VRD followed by stem cell transplant remains a very powerful combination. And, again, I think this is temporary because just down the line, whether it’s months or years from now, we’ll start seeing blank monoclonal plus VRD, or something else.

Keith Stewart, MD, CHB: So, you brought up monoclonals. I don’t want to spend a lot of time on it because we’ll come back to these, but is that the future? Are we going to be using triplets plus a monoclonal? Can we afford it?

William I. Bensinger, MD: That’s a good question. I think the availability of monoclonal antibodies that target myeloma cells is really a new frontier for us because these have a totally different mechanism of action. And we believe—and I think there are data emerging—that they’re going to be synergistic with many of the other frontline drugs we use. So, I think it’s inevitable they’re going to move into the front line. Whether it’s a three-drug monoclonal or a four-drug monoclonal, there are cost considerations and potential toxicity situations that need to be seen. But I think it’s the future.

Jatin P. Shah, MD: Can I make a comment real quick?

Keith Stewart, MD, CHB: Yes, please.

Jatin P. Shah, MD: Based on—beginning with the oncological principles—yes, I do think that your best therapies are going to move up front. But I just want to actually comment a little bit more on what Ola was talking about, about the side-effect and toxicity profile, if you don’t mind.

Keith Stewart, MD, CHB: No, I don’t mind at all.

Jatin P. Shah, MD: I think that I want to change the conversation a little bit and go a little bit beyond just talking about the percent of cardiac toxicity that we see. And I think it’s important to get a little bit more clinical perspective on that. And so, what I’ve seen, the patients that have had cardiac toxicity, you recognize it, you stop it, but then within several months, their symptoms resolve and their ejection fraction comes back up to normal. I think that’s important, not to say that they get this at a low incidence or doubling the rate, but the clinical relevance of that in the long term… Short term, yes, but long term, these are patients that are not necessarily in the hospital in the cardiac ICU. They have symptoms, you stop therapy, and you manage it. And several months later they recover, which I think is important to complete the story.

Keith Stewart, MD, CHB: That’s been our experience, too. I think the message is monitor; you don’t need to do baseline testing, I don’t think. Monitor for it, be aware of that side effect, stop the drug; it does usually improve.

William I. Bensinger, MD: Is it possible to reuse the drug in those patients?

Keith Stewart, MD, CHB: I think you’d be a bold person to do that but…

Rafael Fonseca, MD: We don’t even have the publications of the natural history. We’re working on that, you know, with the reversibilities. I think our gestalt is that it recovers. And there may be a price to be paid for effective proteasome inhibition.

Keith Stewart, MD, CHB: I don’t want to dwell on this right now. We’ll come back to it because we have the relapse trials to look at. So, I think the summary here is that, use your best drugs at the beginning, use a triplet therapy. Most people around the table say it’s a proteasome inhibitor and immune modulator. If you’re outside the United States, that means probably thalidomide and bortezomib. Here, we’re seeing a transition from bortezomib with lenalidomide and dexamethasone to carfilzomib, lenalidomide, and dexamethasone—gradually happening, it looks like. Ixazomib in this population, we’ll talk about that in a minute when we come to the more elderly patient, but I didn’t get a lot of enthusiasm for that in the newly diagnosed younger patients.

Transcript Edited for Clarity