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Dosing Strategies in Relapsed-Refractory MM
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Dosing Strategies in Relapsed-Refractory MM

A review of the dosing strategies based on data from the ARROW study, for relapsed or refractory multiple myeloma.


Keith Stewart, MB, ChB: If you’re using Kyprolis, or carfilzomib, at relapse, what dosing schedule are you using?

Rafael Fonseca, MD: For the most part I’d use it in combination. Certainly at the minimum, go to 36 [mg/m2]. The real question I think right now is go up to the weekly schedule versus the biweekly, and perhaps we can perhaps talk a little bit more about that.

Keith Stewart, MB, ChB: There was a clinical trial called ARROW that examined that.

Andrzej Jakubowiak, MD, PhD: The data [were] very convincing with some comments to be made that [about] weekly schedule, and I will maybe summarize the study. Evaluated efficacy of weekly 70 mg/m2 carfilzomib, which is double 36 [mg/m2] in a way, versus twice-weekly traditional approved in the combination, both with dex [dexamethasone]. And it was eventually evaluated in the relapsed setting, which is a double. And surprisingly outcome was better for weekly, which to some extent on a very superficial way have indicated maybe weekly is better than twice weekly.

Keith Stewart, MB, ChB: Would you move to weekly then throughout?

Andrzej Jakubowiak, MD, PhD: I have, for the most part, although I have to say that you know the jury is still out in regards to how to do that, because when you push weekly to 70 [mg/m2], which is what we think—and the combination is probably the right dose, 36 times 2—then you’re getting to maybe a little bit slightly higher rate of cardiovascular toxicities, and that’s the balance we need to find.

Keith Stewart, MB, ChB: Would you use 70 [mg/m2] weekly even in combination? Or would you use 56 [mg/m2] weekly in combination?

Andrzej Jakubowiak, MD, PhD: I have trials when I’m using 70 [mg/m2] in weekly in combination with KRd [carfilzomib, pomalidomide, dexamethasone] and antibody, which I think is ongoing, so [it is] too early to really discuss it. I think that the field, it appears to me, is going to be moving to 56 [mg/m2] in combination

Keith Stewart, MB, ChB: I think so.

Rafael Fonseca, MD: Andrzej, when you talk about cardiac toxicity, are you talking about the subtle changes, or are you talking the more serious one? Because [in] the ARROW study, [which shows] very similar toxicity, I think CHAMPION originally had brought up some concerns—[CHAMPION 1] was the first study of once-a-week carfilzomib. But I think this is important information because I see myself moving to weekly. Is it the more serious 1 that you’re concerned [with] or the more subtle changes you were describing?

Andrzej Jakubowiak, MD, PhD: Maybe I am repeating what is being reported to us rather than [speaking] from experience. And I agree, [the] ARROW study actually showed no difference in toxicity with even higher dose...of a single agent, carfilzomib.

Keith Stewart, MB, ChB: Single agent.

Andrzej Jakubowiak, MD, PhD: Single agent. And the combination, it has been a concern from some of the emerging data and studies that was 70 [mg/m2] combined with, in triplets, for example, lenalidomide and dex [dexamethasone]. Seventy [mg/m2] may be 1 level dose too high, and I don’t know enough to really comment in more specific ways. I’m actually comfortable using 70 [mg/m2] in triplets and quadruplets. But I think that is something [that] needs to be continuously watched.

Keith Stewart, MB, ChB: Yeah, I think I’m a little uncomfortable going that high in combination therapy. What were your feelings?

Rafael Fonseca, MD: Yeah, I do have the discomfort too. I want to see a little more data. I think it really depends on the myeloma. I think you know if the person [is] a slow relapser, [and] there’s not a progressive disease, I think it’s probably better to err a little bit on the lower side on safety. Which by the way, I was going to say, if there’s any community provider [who] is hearing [us], I’ve seen circumstances where patients have stayed on 20 [mg/m2] forever. And that is used because we know everyone leads a busy life, and the orders were there and there was no switch to either at the minimum 27, 36 [mg/m2]. So I’ve seen a few patients like that. And I think it’s important.

Keith Stewart, MB, ChB: There’s a lot still, 20, 27 [mg/m2] because the FDA label...

Rafael Fonseca, MD: Right, I think there is some merit in [these] slightly higher doses of the carfilzomib as long as they’re well tolerated.

Andrzej Jakubowiak, MD, PhD: But do you have a treatment plan, which is extended and which includes carfilzomib, then potentially moving to weekly. It’s almost a must thing to do, and there’s no way that you can continue twice weekly for, for many months, forever.

Keith Stewart, MB, ChB: Do you give it every week or 3 of 4 weeks?

Andrzej Jakubowiak, MD, PhD: Three out of the 4.

Keith Stewart, MB, ChB: I’d like to give it every week, but our orders—it’s too complicated to change them.

Rafael Fonseca, MD: I override them. I do it every week.

Keith Stewart, MB, ChB: You have to teach me how to do that. Any cost implications on going weekly, or [does] it pretty much end up being the same?

Rafael Fonseca, MD: Well, you’re going to have less infusional cost. I mean, from a payer perspective, you know, [fewer] visits potentially…[means less] laboratory right. And from the patient perspective, 1 of the aspects of the cost considerations is that it’s not only the patient but the caregiver. If someone has to drive you to the clinic, it’s going to take a half day of their work. So many of them are going to have to take the full day off work. There’s 2 days of lost wages versus 1.

Keith Stewart, MB, ChB: That’s very good; so the drug costs the same once weekly, but all the other benefits of [fewer] visits, less time off work.

Mary E. DeRome: And just more convenience...

Andrzej Jakubowiak, MD, PhD: Outside clinical trial in a patient who has long [been] on a twice-weekly schedule—say, 27 [mg/m2]—we pretty much move all these patients to a weekly schedule at 56 [mg/m2], which is the same dose but weekly. For those who are on 36 [mg/m2], I have discussion [about] whether it’s the right thing to do and sometimes test the waters and select the best...to dose.

Keith Stewart, MB, ChB: What are you hearing from patients taking carfilzomib? Are you hearing [from] a lot of people? Are they happy with it? Are they unhappy with it?

Mary E. DeRome: I think people understand that it’s a very effective therapy, which they like, and certainly everyone is very happy that the schedule is moving to once weekly, and that’s just great news for patients. Because there’s no change in efficacy, but it’s certainly much more convenient for them and for many of the reasons that Rafael mentioned too.

Keith Stewart, MB, ChB: And if we’re going to give it in combination with daratumumab, do you give it the same day? Just yes or no.

Rafael Fonseca, MD: Yes.

Keith Stewart, MB, ChB: Same day? OK. And so you’re not hearing [many] people calling in and saying they’ve had significant toxicity from it?

Mary E. DeRome: No, but we haven’t actually had people say that they’re very interested in that drug because of the neuropathy of the alternative, right?

Keith Stewart, MB, ChB: Right.

 
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