Emerging Treatment Options in Relapsed Refractory Multiple Myeloma - Episode 6

Clinical Significance of DKd Dosing Flexibility

Key opinion leaders discuss the clinical significance of dosing flexibility for the CANDOR trial regimen, as studied in the EQUULEUS trial.

C. Ola Landgren, MD, PhD: The once-weekly and twice-weekly regimen for the DKd, daratumumab, carfilzomib, DEX [dexamethasone] was approved as a result of the CANDOR [trial], and there was also a phase 1b EQUULEUS trial. What is the clinical significance of adding different dosing options, Luciano, once a week, twice a week? I think Ajai said that he liked once a week. What do you like, and why?

Luciano Costa, MD, PhD: Once a week. I think Ajai can speak with great property of the once a week data; I think he was the first author on that publication. We’re never going to solve the question of whether 70 [mg] once a week is better than, or not worse than, 56 [mg] twice weekly. It’s one of those things, that is a very busy field, and other factors like convenience play a role. Now that there are so many options that are oral, subcutaneous and IV [intravenous] treatment already have a disadvantage from the convenience standpoint. Weekly is such an attractive proposition that I think even if there’s a little bit of compromise in efficacy, which I don’t believe there is, I think patients and physicians are willing to take it. We literally abolished biweekly the morning after the ARROW study.

C. Ola Landgren, MD, PhD: What is your dose of carfilzomib together with daratumumab and dexamethasone?

Luciano Costa, MD, PhD: I use 70 mg. We tend to use 56 mg when combining with an IMiD [immunomodulatory imide drug], with some concerns about cardiovascular toxicity. With the combination with alkylators or a single agent, or with monoclonal, we usually go with 70 mg.

C. Ola Landgren, MD, PhD: What about you Rafael; what dose do you give for the once a week carfilzomib with daratumumab, if you do that?

Rafael Fonseca, MD: The 70 mg; I think there’s some nuance that people need to know whether you use it alone or in combination, regarding the IMiDs, with the lower dose. I’m going to build on a comment you said before. I do use carfilzomib for frontline therapy. I have had some serious problems with peripheral neuropathy with a weekly subcutaneous under close monitoring with bortezomib. Now what I realize, it just dawned on me at this meeting; I do have my practice full of patients with peripheral neuropathy and the consequences years later. I don’t have my practice full of patients full of heart failure or related problems. A lot of this, and we have published on this and I think others have observed it too as well; part of it is fluid, and part of it is reversible. I don’t minimize the toxicity, but I think the tradeoffs are ones that need to be discussed directly with the patient.

C. Ola Landgren, MD, PhD: Ajai, I know that you are more in favor of bortezomib than carfilzomib. What is your thinking there? Do you think that bortezomib is a better option because of the cardiovascular [impacts], or for other reasons? What is your perspective in the newly diagnosed setting?

Ajai Chari, MD: We’ve looked at all these cardiac data that have been published that have better analysis, and I think it’s important to start with the fact that both the ASPIRE and ENDEAVOR trial not only had a PFS [progression-free survival] benefit, but an OS [overall survival] benefit. You can’t be blaming the heart if people are living longer. I think that’s an important starting point, which then puts the toxicities into context; it’s basically the number needed to treat versus the number needed to harm. Overall you clearly have a benefit. We also have to keep in mind that just because ENDEAVOR showed that Kd [carfilzomib and dexamethasone] at 56 mg is better than Bd [bortezomib and dexamethasone] twice weekly, it doesn’t mean that we can apply that to every disease segment and every patient population, because we have ENDURANCE and CLARION frontline studies that were both not superior in efficacy.

In study after study, if you look at that older subgroup, we see there are more cardiac issues; not because it’s a different drug, but because people are coming to the table with more cardiac issues. In that older patient population that risk benefit is slightly different. Partner drugs matter, which has already been alluded to. With an IMiD, you can’t give 56 mg twice weekly and 70 mg weekly without having to think about the cardiopulmonary issues.

Finally, the newly diagnosed segment might have a higher propensity for thrombotic issues because of the protein burden, performance status, renal failure, all of those other components. We have to be nuanced in making blanket statements that one drug is better than the other. However, for the relapsed setting, I think across the board there’s really no reason to be using bortezomib. In the frontline setting where you definitely need an IMiD, you definitely have comorbidities, and we don’t have data to support; the only data we have is the ENDURANCE [trial], which was not superior, and CLARION was negative. That’s the only reason in the frontline setting I use DVRd [daratumumab, bortezomib, lenalidomide, dexamethasone]. Not to mention, we haven’t talked about cost; I was going to make a point with Luciano talking about the 2 different DKd [daratumumab, carfilzomib, dexamethasone] dosing schedules.

We did a recent matched pair analysis, and if you compare it, whether you give once or twice weekly, CANDOR or EQUULEUS, you get comparable results. Two things that we forget is 210 mg/m2 per month for weekly; it’s over 336 [mg] for twice weekly 56 [mg]. It’s actually more carfilzomib for 56 [mg] twice weekly, which comes at a higher cost and less compliance, and yet you’re getting comparable efficacy. I think it’s hard to beat, and the FORTE study, for example recently Francesca Gay, [MD,] said that in the maintenance setting they had to modify twice weekly/every other week maintenance for compliance to once weekly. If we’re all saying it’s important to treat to progression, let’s make it easy for patients and not ask them to be coming in twice weekly. I believe that DKd [daratumumab, carfilzomib, dexamethasone] once weekly for relapse is the regimen go-to if you’re going to use DKd [daratumumab, carfilzomib, dexamethasone].

C. Ola Landgren, MD, PhD: At what dosing are you using for weekly DKd [daratumumab, carfilzomib, dexamethasone], for carfilzomib?

Ajai Chari, MD: Seventy [mg] weekly.