Ajai Chari, MD: The second point I want to address was Nina’s point about the KRd versus the quad, and I think the challenge is, we do a lot of these cross-trial comparisons, and you saw some of the oral presentations; they showed all these regimens. We have to get in to the granularity of details, which is, VRd [bortezomib, lenalidomide, and dexamethasone] is a 21-day regimen. If you do 6 cycles of VRd, that is different than 8 cycles of KRd [Kyprolis, lenalidomide, and dexamethasone], which is a 28-day cycle. It’s almost double the amount of chemo. When we do these cross-study comparisons with varying amounts of chemo at differing time points, I don’t know what to make of all that.

Nina Shah, MD: I agree.

Paul Richardson, MD: I think the only other key point, in my view, is that, obviously, we have to be aware of financial cost. For example, when we look at wholesale acquisition cost of KRd/DARA [daratumumab] for 12 weeks of therapy, it’s almost $200 000.

Nina Shah, MD: Which is 2 transplants.

Paul Richardson, MD: The RVd [bortezomib, lenalidomide, and dexamethasone] platform is half the price.

Nina Shah, MD: Yeah.

Paul Richardson, MD: I think we need to bear that in mind. I wanted to pick up on a point that Sagar made about overall survival. I so agree with you, Sagar, that we need PFS [progression-free survival] and MRD [minimal residual disease] in clinical trials and so forth. The sobering thing about OS [overall survival], for me anyway—and it’s a slightly different context of the up-front setting—is of course the BELLINI trial, which showed a loss of OS despite the striking PFS benefit. I’m a little bit cautious about that in different settings. I appreciate that.

Sagar Lonial, MD, FACP: Relapsed and refractory disease—it’s a different discussion.

Paul Richardson, MD: I agree.

Sagar Lonial, MD, FACP: I’m just saying, early in the disease course, I personally struggle with using OS.

Ajai Chari, MD: To follow up on your point, I think there’s a difference between expecting an improvement in OS without hoping, not hurting the OS. Those are different.

Paul Richardson, MD: I agree.

Ajai Chari, MD: And so like PEMBRO [pembrolizumab] studies and BELLINI all tell us that we should never stop looking at OS because we want to make sure…

Paul Richardson, MD: Dr Ajai Chari, that’s a great point. I just want to make sure for our audience that no one is saying, “abandon OS”.

Ajai Chari, MD: Correct.

Paul Richardson, MD: Absolutely. In the interest of time, I’m wanting to move on because we’ve got a lot of fantastic stuff to discuss. Ajai, if I may, I’m going to ask you to build on safety and tolerability, kind of relevant to what you just said. What are we seeing with the DARA-based approaches?

Ajai Chari, MD: I think one of the most striking things, as Nina mentioned about the CASSIOPEIA study, is that we have this increased depth of response with very short follow-up of only 18 months already translated into PFS benefit. I think that’s what’s kind of interesting and we’ll have to see with the GRIFFIN study whether the same holds up. Because the VRd arm is so good, it’s going to be even harder to show that PFS benefit than VTd [bortezomib, thalidomide, and dexamethasone]. I think some of the questions are going to be—we discussed early and I, like Sagar, I have a lot of issues with MRD and we’ll talk about that more. This is where we need MRD in a very controlled clinical trial.

If you’re looking at all the standard myeloma serologies, imaging, and then you’re getting this early readout of MRD-negativity deepening—that’s a potential window into the future for the study—again, not necessary for the real world. I think one of the things that we want to look at, in addition to the efficacy, is the safety. When you add DARA, what happens to these patients? Generally, we’re not seeing a lot of additive adverse events. Neutropenia, certainly, because CD38 is also expressed on myeloid precursors, so particularly with IMiD [immunomodulatory imide]-containing regimens, we do see higher rates of neutropenia. We do see higher rates of all-grade infection, but typically grade 3 infections are controlled.

I think some of the other questions that came up with the GRIFFIN study, in particular—I think comparison to the CASSIOPEIA study is kind of interesting—is the stem cell issue, right? We know that we have to hold LEN [lenalidomide], and we generally don’t want to give more than 4 to 6 cycles of LEN before collecting. The question is, “what does DARA do to that profile”? What we saw in the GRIFFIN study is there is a slightly lower median yield of CD34 in the DARA-containing arm.

Paul Richardson, MD: Exactly.

Ajai Chari, MD: I think what this tells us is DARA may add a little bit, and I do think—I’m curious to hear from the panel—but in my practice I am trying to collect more stem cells from patients because of the need for possible CAR T [chimeric antigen receptor T cell] marrow failure rescues. I do think we need to think about these issues, and I think the last is, of course, the biggest kind of deterrent to using DARA is the infusion reaction. I think certainly you can do for right now, IV [intravenous] split dosing, etcetera, if somebody is pressed for time.

But, clearly, what everybody is excited about is subq [subcutaneous administration]. It’s rare in medicine when you have a drug that works just as well—that is more safe in terms of allergic, infusion-related reactions, or typically less than 10%—with subq, compared to 50% with dose 1. So equal efficacy, safer, and more convenient, 5 minutes instead of many hours. I think that will really change the, I think, uptake of DARA once it gets approved. I think that’s kind of why the—hopefully especially with these CASSIOPEIA and GRIFFIN and the DARA subq formulation—will make it that much easier.

Amrita Krishnan, MD: If I could comment on 2 things.

Paul Richardson, MD: Yes, of course, Amrita.

Amrita Y. Krishnan, MD: It’s a little bit misleading because no one collected data. Yeah, you can collect, I think it was 8 million versus 6 million, the RVd versus, but you don’t say how many days of collection you need, for example. I could keep you going for a week to collect that 8 million.

Nina Shah, MD: Each institution does it differently, right? You all have your different SOPs [standard operating procedures] about when you give plerixafor and all that.

Transcript Edited for Clarity