The Impact of Evolving Treatment Options in Multiple Myeloma, Part 5

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Joseph Mikhael, MD, reviews the phase 2 GRIFFIN trial evaluating the use of quadruplet therapy, daratumumab plus VRd, in patients with multiple myeloma, and the panel comments on the use of quadruplet therapy.

Bruce A. Feinberg, DO: The GRIFFIN trial introduces what could be the first mainstream quadruplet therapy. Joe, can you take us through it and give us a sense of what the trial was built on? What were we achieving in terms of efficacy? What’s the next goal there?

Joseph Mikhael, MD: The GRIFFIN trial is sentinel in our next phase of approaching frontline therapy for myeloma, in particular, for those who are going to transplant, but ultimately over time, even those patients who are not going to transplant. It’s a phase 2 randomized trial where we’ve added daratumumab, or a CD38 antibody, to that VRd [bortezomib, lenalidomide, dexamethasone] platform that we discussed earlier: bortezomib, lenalidomide, and dexamethasone.

What was interesting about the design of this study was the daratumumab was added for 4 cycles before the transplant, for 2 cycles after, as an additional consolidation, and then for up to 2 years alongside lenalidomide in the maintenance therapy. It was really looking at the A-to-Z addition of a daratumumab, or a CD38 antibody, with the goal of trying to determine the initial impact on the depth of response, and progression-free survival.

It’s a preview to the phase 3 trials that are going to be looking at this, with perhaps slightly different outcomes. It may be looking at taking off the maintenance at MRD [minimal residual disease] negativity, for example, as opposed to just a timeframe.

The short message from the GRIFFIN study is that we can get a deeper response before transplant, after transplant, and in maintenance when we add a CD38 antibody. I think this is why there’s so much excitement for it, and why places like Emory Winship Cancer Institutehave started to adopt this in a fraction of patients.

It goes back to this notion of biology, that myeloma’s a complicated disease that often has multiple bits to it, and 1 or 2 mechanisms of action may not be sufficient. As we put all 4 together, we may have the best chance of controlling the disease. Now we’re seeing MRD negativity rates in over two-thirds of patients that we never saw before in our VRd-like platform. We’re upgrading the depth of response by about 15% or 20% by adding the daratumumab to the VRd.

Bruce A. Feinberg, DO: Were these levels of MRD achieved with the transplant?

Joseph Mikhael, MD: The transplant helped. Think of the transplant as part of that process, but it wasn’t always the biggest bump along the way. Now people are getting a much deeper response even before transplants. The transplant in both arms of GRIFFIN continued to deepen response. It further reminded us that at least in our current world, transplant still has a place. But there was as much benefit from the novel treatment as there was from the transplant, if not more. The transplant was not the be-all and end-all, but it also still had an additional deepening effect on the response.

Bruce A. Feinberg, DO: Do we have any parallels with CML [chronic myeloid leukemia] in this degree of MRD negativity, whereby now we have CML where we actually can discontinue therapy in patients, and a number of them don’t relapse? Are we getting to that kind of level of disease reduction that we think that’s directionally where we’re moving?

Joseph Mikhael, MD: I am exclusively a myeloma doctor, I don’t spend a lot of time in CML, but we are moving in that direction. The difference, I would argue, with no disrespect to my CML colleagues, is CML is a pretty simple genetic disease; you’re dealing with 1 chromosome, the Philadelphia chromosome. I think it’s a little early for us to make that immediate connection because what we are starting to learn, even with MRD negativity, is that there’s a difference between reaching MRD negativity once, and reaching it twice.

Myeloma is more of a hybrid disease than just a CML. If we look at the very aggressive lymphomas and the very indolent lymphomas, myeloma’s kind of a mix of the 2 to some extent. Some patients’ disease behaves more like the indolent, while others behave more like high risk. I think with time, MRD status, along with other features, will help guide whether we can have that stopping rule to discontinue. We are definitely seeing MRD rates that historically were unheard of in myeloma, let alone complete remission [CR] rates, too. In the past, we’d be happy to get a small fraction of our patients into true CR, and now we’re seeing two-thirds, three-quarters, over 80% of them achieving them with these quadruplets.

Transcript Edited for Clarity