Quadruplet Therapy in Transplant-Eligible NDMM: Implications of GRIFFIN and MASTER Studies


Shared insight on clinical trial results from both the GRIFFIN and MASTER trials, and the key role of frontline quadruplet regimens in transplant-eligible NDMM.

Ajai Chari, MD:
Let’s start with Rafael, because he did bring up something in quads [quadruplet therapy] already. Can you tell us a little about GRIFFIN and what your take was?

Rafael Fonseca, MD: That was a perfect segue. We saw an update at ASH [American Society of Hematology Annual Meeting] and ASCO [American Society of Clinical Oncology Annual Meeting] regarding the GRIFFIN study. GRIFFIN is a randomized phase 2 study of daratumumab–RVd [lenalidomide, bortezomib, dexamethasone] vs RVd [lenalidomide, bortezomib, dexamethasone] as a backbone for induction therapy in patients who get a transplant and subsequent therapy. I said this was a perfect segue because we’re seeing a dramatic difference in the ability to induce deep responses as measured by MRD [minimal residual disease].

I like to remove this aura of a mystique or a very special test. It’s just 1 more test. It’s just more sensitive. That’s what MRD is. If you look at the difference in absolute percentage points, there are 30 absolute percentage points in the difference of attainment of MRD with a quad vs the 3-drug combination. At this ASCO meeting, Cesar Rodriguez made a great update on what happens over time. We saw a little of that at ASH. In reality, first, if you take all comers and you look at patients who get the quad we’re looking at PFS [progression-free survival] that is close to 90% at 4 years. But if you look at ones that are MRD negative and are sustaining MRD negative, there’s still a small fraction of patients, and if you take the stringency of 10-6, you see a flat curve. The writing is on the wall.

Once you start therapy on myeloma, you have to do the best possible and you have to try to put these patients in this MRD-negative status. We’ll talk more about that as we talk about the other abstracts. I don’t know why we’re dancing around the topic, because as long as you do it safely, we get it. You have to do it safely, but if you can do that with quads, this will translate better downstream for patients. As we often say, the first treatment is probably the most important phase of the treatment of myeloma.

Ajai Chari, MD: Your quad and MRD could not be a better segue for Cristina to discuss the MASTER study. To be fair and balanced, there’s more than D-VRd [daratumumab, bortezomib, lenalidomide, dexamethasone].

Cristina Gasparetto, MD: Absolutely. The MASTER trial was very interesting because with daratumumab–KRd [carfilzomib, lenalidomide, dexamethasone] we see a different proteasome inhibitor. What was interesting in the MASTER trial was that the carfilzomib was given only once a week, which I liked because it’s so difficult to bring the clinical trial design to the real world. I always say that. I repeat myself, but it’s the truth, and we love KRd [carfilzomib, lenalidomide, dexamethasone]. We have the FORTE trial with the longer follow-up and the transplant. Another important point in the MASTER trial was that the MRD was guiding treatment, so the patient received induction therapy, transplant, and then based on the MRD status they received additional therapy: 0, 4, or 8 cycles. We want to achieve MRD, but we can’t treat everybody the same way. That’s a very interesting concept.

What I’d like to see in the future—[I wonder if] you guys agree or disagree—is a little differentiation between the standard and the high-risk. The high-risk patients tend to achieve MRD faster, but they also progress faster. We need to push the envelope on these patients. We can’t stop therapy, but with the standard therapy or standard risk, we can do that. We can follow the MRD sequential and eventually stop therapy. I’d like the new design to also think about that because we need to pay attention. We can’t stop therapy completely in patients with high-risk disease because of MRD, the durability of MRD, the sequential MRD, and the sustainability.

Ajai Chari, MD: With those great summaries, let’s go to Krina. Triplet or quad? Which triplet, which quad?

Krina Patel MD: It probably changes every 2 weeks. With the quads, before I would be scared about infections or other comorbidities, but we’ve seen patients do well with our quads. For most of my patients, I do the standard of care, which is now daratumumab–VRd [bortezomib, lenalidomide, dexamethasone]. I have patients who are a little more frail or have horrible neuropathy. For them, I might adjust the V [bortezomib]. Or I go to the MAYA data instead and do DRd [daratumumab, lenalidomide, dexamethasone]. For my high-risk patients, sometimes I throw the K [carfilzomib] in there instead of the V [bortezomib]. It used to be KRd [carfilzomib, lenalidomide, dexamethasone] because I couldn’t get insurance to approve. But with all these data, I’m hopefully going to be able to do more daratumumab-KRd for my high-risk patients. That’s what I want to do.

Ajai Chari, MD: Just to follow up a little, because Cristina alluded to this, the bortezomib in GRIFFIN was twice weekly and a lot of the K [carfilzomib] regimens are twice weekly. What are you doing in clinic?

Krina Patel MD: With my standard-risk patients without any issues, we go with daratumumab–VRd [bortezomib, lenalidomide, dexamethasone]. The V [bortezomib] is twice weekly, but for my patients who are frail or who have baseline neuropathy, we change it to a D-VRd [daratumumab, lenalidomide, bortezomib, dexamethasone] lite. We’re doing it weekly, so we do 4-week cycles with Velcade weekly. With K [carfilzomib], I’m doing it once weekly.

Ajai Chari, MD: What dose are you picking?

Krina Patel MD: It depends on the patient. For K [carfilzomib], I try to get to at least 56 mg/m². If they have a high risk, I try to get to 70 mg/m², but that’s a little harder in terms of cytopenias for some.

Krina Patel MD: If we could go down the line, I’m curious if everybody could just say weekly or twice weekly for V [bortezomib] and K [carfilzomib].

Rafael Fonseca, MD: I’ll make it simple: weekly carfilzomib is my go-to regimen. My main limitation is getting coverage from the insurance companies. But Dr Patel and I are hoping that with all these data, things will be better.

Cristina Gasparetto, MD: I do that too: once a week and in combination. I’m always reluctant to go up to 70 mg/m², so I keep it at 56 mg/m².

Ajai Chari, MD: Omar?

Omar Nadeem, MD: Exactly the same. Weekly 56 mg/m² is the max in most combinations and weekly for bortezomib.

Ajai Chari, MD: The reason I wanted to go through that is because many people, especially in the community, are historically doing weekly. That’s 1 benefit of adding that CD38 up front.

Christina Gasparetto, MD: Absolutely.

Ajai Chari, MD: Historically we were doing twice weekly PIs [proteasome inhibitors] in these studies and once weekly in the real world, but now maybe that synergy comes. The other point that everybody on the panel alluded to but that was never clearly stated is that if you’re giving carfilzomib 70 mg/m² weekly, you can run into more cardiopulmonary issues with giving an IMiD [immunomodulatory imide drug]. We all agree, which is rare. We’ve got 5 myeloma doctors.

Cristina Gasparetto, MD: It’s absolutely true. You want to balance the toxicity.

Ajai Chari, MD: The other part is considering NOACs [novel oral anticoagulants] instead of aspirin because it’s a concurrent.

Cristina Gasparetto, MD: Yes, even in the MASTER trial, there was an increased incidence.

Ajai Chari, MD: It’s always in the footnotes, right? No one talks about it, but we think the initial VTE [venous thromboembolism] risk is higher.

Cristina Gasparetto, MD: Absolutely.

Transcript edited for clarity.

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