Quadruplet Induction Therapy in Patients With Transplant-Eligible NDMM


Shared insight on the advent of quadruplet therapy regimens in the induction setting of transplant-eligible newly diagnosed multiple myeloma.


Andrew P. Dalovisio, MD: The success of those triplet trials and the reason I talk about MRD [minimal residual disease] is because of the data that's being reported out in these quadruplet trials. So because of the success of those triplet trials that added to the question of the advent of things like daratumumab, elotuzumab, and monoclonal antibodies, could you then add those to triplet drugs to get deeper responses? We do have a number of randomized trials. Some I'll just mention briefly, and some I'm trying to focus on, namely the GRIFFIN trial [NCT02874742], but the first one was the CASSIOPEIA trial [NCT02541383], which was a randomized trial in a European trial. This took dara/Velcade [daratumumab and bortezomib], thalidomide, and dex [dexamethasone] vs just Velcade/thalidomide/dex. So, obviously, they switched out Revlimid [lenalidomide] for thalidomide, which is still commonly used in Europe. Both groups got autos and both groups got the same consolidation. So if you got 4 drugs up-front, you got 4-drug consolidation. If you got 3 drugs up-front, you got 3-drug consolidation for 2 cycles.

And then there was a second randomization to either receive no maintenance or a maintenance daratumumab for 2 years. What this showed was a much higher MRD rate in the quadruplet arm. Interestingly, it didn't seem to matter if you got daratumumab in maintenance or up-front just that you got daratumumab, because the patients that got daratumumab up-front didn't seem to benefit as much from it in the maintenance setting. So, based on that, you'll sometimes see people saying, “I don't need to do Dara I can just do Revlimid maintenance after.” There was another study called the GMMG HD7 trial [NCT03617731], and what that did was took isatuximab and placed it in place of daratumumab, and essentially had the exact same clinical trial design in the sense that patients got isa-VRd [isatuximab-lenalidomide, bortezomib, and dexamethasone] vs VRd and auto, and then there was a second randomization to either get isa-rituximab- isa-Revlimid [lenalidomide] or Revlimid [lenalidomide] maintenance, and that study also showed very high MRD [minimal residual disease] rates just after induction at 51%.

Now, I really think, for the focus of the study, I want to focus on the GRIFFIN trial [NCT02874742] because I think this has become the standard of care, or arguably the standard of care for our transplant-eligible patients. As the most recent update at the IMS [The International Myeloma Society] meeting in 2022, this was a final analysis of the data from GRIFFIN. What they did was they took transplant-eligible patients, they were given 4 cycles of Dara-VRd vs VRd, and then in consolidation, the quadruplet arms got 4 drugs for 2 cycles, and the triplet arm, got 3 drugs for 2 cycles, and then for maintenance, the quadruplet arm got dara-rev for 2 years, whereas they got just Revlimid in the triplet arm.

Now, interestingly, that data has been reported out after 50 months in completion of the maintenance phase, and 64% of [participants] had reached MRD negativity vs just 35%, and that's at a 10-to-the-5th level in the quadruple or daratumumab arm. So, right now, the PFS [progression-free survival] curves favor the quadruplet arm. There has not been a reported out overall survival advantage yet, but I'd be willing to bet everything I own that that's going to happen as this data continue to be followed out.

Based on the GRIFFIN trial, at 48 months, 87% of [participants] in the quad arm were still progression free, and the 48 months was actually the median PFS in the triplet IFM trial. So clearly, a significant benefit to doing that.

Ryan P. Griffin, MD: Andy, can I ask you a question real quick?

Andrew P. Dalovisio, MD: Yes.

Ryan P. Griffin, MD: For the GRIFFIN trial, for the consolidation cycles, I haven't seen too much of that in the community setting. How much are you all using consolidation after transplant?

Andrew P. Dalovisio, MD: That's a really good question. Generally, my approach has been, if they have not had a deepening of their response, say they had stable disease after transplant or, say they only went from like a VGPR [very good partial response] to a PR [partial response], I will often use consolidation, but if they're MRD negative or close to MRD negative, I generally won't use consolidation.I think you'll find a lot of practice deviation from the study with regard to that, and then also patients that are MRD-negative, a lot of the times, you won't see them doing the full 2 years of dara-rev maintenance, they'll just be doing rev maintenance alone. That was one of the other questions I was actually about to pose to you. Thomas, what's been your approach in your transplant-eligible patients, do you tend to stick with triplets or quads and do you use the GRIFFIN when you treat these patients?

Thomas Atkinson, MD: I definitely prefer to use the quad therapy when I have the option. In my former practice, there were sometimes limitations to getting dara prior to some of this data coming out, but lately, it's been a lot easier. So anytime I have the opportunity, I'm going for the quad.

Andrew P. Dalovisio, MD: Good. And I think that the data played out from GRIFFIN certainly supports that. There are a couple of non-andomized control trials I'd like to mention. It actually incorporated using Kyprolis [carfilzomib] instead of Velcade. Briefly, I'll mention one, the MANHATTAN [NCT04268498], which took dara-KRd [daratumumab, carfilzomib, lenalidomide, and dexamethasone] for 8 cycles with no transplant, and 71% of those patients reached MRD negativity. So you can use alternative proteasome inhibitors, and then the MASTER trial [NCT03224507], which I think is a very important trial, took dara-KRd for 4 cycles, for transplant-eligible patients. They then got a transplant, but after both induction and transplant, they were measured for MRD, and if they had any 2 timepoints where they were MRD negative, they could stop all treatment, but if they were still MRD positive, they went on to get an additional 4 consolidations of dara-KRd, and if still MRD positive, additional 4 after that, and then at that point they would just go onto lenalidomide maintenance.

What we found from that trial was, again, incredibly high MRD rates from induction and transplant, but importantly patients who [were] MRD negative, who had a single high-risk chromosomal abnormality were doing just as well as the patients that had no high-risk chromosome abnormality. So it seems that quad regimens and transplants may abrogate the risk of single genetic abnormalities. But the 2 high-risk genetic abnormality patients still seem to do pretty poorly. So those patients again, are challenging. But I think that was a very important study where you could tell people, you could still be high-risk if you get MRD negative and have 1 lesion you can still do OK.

Kelly Pippin, MD: I had a quick question about your transplant preferences given that you prefer quad therapy going into transplant for most transplant-eligible patients. If they have a very deep response and they get to a CR [complete response] or an MRD negative, at relapse, would you try to reuse that quad regimen and go to a second transplant?

Andrew P. Dalovisio, MD: That's a good question. I think that would be based on their duration of remission. I think if they're relapsing, our general rule is if they're not maintained 18 months they need to at least have gotten an 18-month remission, if they're maintained at least a 3-year remission for a second transplant to be worth it. Generally, within less than 3 years, my gut would be to go with a new regimen rather than retreating them. I absolutely have some late relapse patients who are relapsing their myeloma 10 years after their transplant. Obviously, they wouldn't have gotten daratumumab because it wasn't around then. But I would certainly consider re-adding VRd with dara at that point or drugs like that. So absolutely I think that is a reasonable approach to take.

Transcript edited for clarity.

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