Shared insight on approved quadruplet vs triplet induction regimens for patients with transplant-eligible, newly diagnosed multiple myeloma, evaluated in the GRIFFIN, MASTER and GMMG-HD7 trials.
Noopur Raje, MD: RVd [lenalidomide, bortezomib, dexamethasone]-daratumumab is not the only quadruplet around. We’ve seen other quadruplets. Omar, we saw nice data presented by Luciano Costa, [MD, PhD,] at the ASCO [American Society of Clinical Oncology] meeting, as well as at ASH [American Society of Hematology]. This was using KRd [carfilzomib, lenalidomide, and dexamethasone] with daratumumab based on the MASTER trial. Can you give us an overview of the MASTER data?
Omar Nadeem, MD: Sure. This was a great study presented by Dr Costa looking at this quadruplet regimen of daratumumab-KRd as you mentioned. But interestingly, this trial is unique because they did therapy based on MRD [minimal residual disease] status; it was a response-adaptive trial design. This trial used 4 cycles of induction therapy with daratumumab-KRd followed by transplant, and then additional cycles of consolidation were given depending on your MRD status. The goal was to get patients to be MRD negative 2 times in a row, and at that time they could come off of therapy, which is a question we have in our field. As Jacob pointed out, we’re seeing impressive and deep responses with these quadruplets. Is there a subset of patients for whom we can tailor therapy based on that response? I think that’s still an open question.
This trial showed that this quadruplet regimen was very effective, potent, and had high rates of MRD negativity, similar to the GRIFFIN trial, and many patients converted to that MRD negative status, being able to come off of therapy. They broke down the presentation based on the risk of disease. They had patients with chromosomal abnormalities that were considered high risk and demonstrated that patients had similar rates of MRD negativity across the different subgroups. However, we still saw those high-risk patients relapse. The patients who were progressing within the time of the follow-up were those ultra-high-risk patients with several cytogenetic abnormalities. This trial said a few things. One is that this regimen is effective in achieving those deep responses, but it didn’t answer the question that we’re looking for, is there a subgroup of patients we can comfortably take off of therapy based on response? Longer follow-up with this study and other studies that are using response-adaptive therapy will hopefully answer that.
Noopur Raje, MD: You bring up important points, Omar. When we start thinking about using quadruplets, the next question is when do we start de-escalating? Jacob, you brought up the point about deepening responses beyond 2 years. We’ve seen the MASTER trial, which is a great hypothesis-generating trial as to when can you start taking patients off. The way they defined MRD-SURE [treatment-free observation and MRD surveillance] was 12 weeks apart, and they stopped treatment maybe too early, but like you said, Omar, it’s still an open question as to when can we de-escalate treatment. There may be a subset of patients with myeloma where, after we see sustained MRD negativity, we consider dropping some of the therapies because treatment fatigue is something that is underappreciated.
Before we talk about how to think about which regimen to pick, I don’t want to leave the other quadruplet out. Andrew, this was presented at last year’s ASH meeting. This is the GMMG-HD7 study. As you know, they used isatuximab, the CD38 monoclonal antibody, with RVd. Your thoughts on the initial presentation of isatuximab-RVd?
Andrew J. Yee, MD: Thanks, Noopur. The GMMG-HD7 study was the first presentation of the anti-CD38 monoclonal antibody isatuximab with RVd vs RVd alone. It’s great to see that we have more treatment options available for our patients in terms of anti-CD38 monoclonal antibodies. The structure of this trial was very similar to the GRIFFIN study. They both used an RVd backbone, and in this case they used isatuximab instead of daratumumab. One of the key differences is that this was a phase 3 study, so the number of patients was higher. It was about 660 patients compared to the GRIFFIN study, which had about 200 patients. The primary end point was looking at MRD negativity rate. At the recent ASH meeting, they presented some of those findings from the MRD negativity rate. It depends on how you determine the cycle, but to keep it simple, let’s say these are 3-week cycles. So at the end of six 3-week cycles, the MRD negativity rate for the isatuximab-containing arm was about 50%. That’s impressive for that depth of response after your initial therapy. But bear in mind—I like to compare trials—so the comparison will come, how does this compare to the GRIFFIN study vs the GMMG-HD7 study? One of the differences is that this was after 6 cycles, whereas in GRIFFIN it was after 4 cycles. The second point would be the modality used was different. In GRIFFIN they used next-generation sequencing, and in the GMMG they used next-generation flow cytometry. As we have more mature data, we’ll have a better chance to see how this plays out in terms of depth of response and progression-free survival [PFS].
We’re also looking forward to seeing the results of the PERSEUS study; it’s like taking the GRIFFIN study but powered, I believe progression-free survival is the primary end point. That will more definitively answer the question about PFS since the GRIFFIN study wasn’t powered to answer that. The key difference is that isatuximab is given intravenously, whereas in US practice, daratumumab is given subcutaneously as a standard. We’ll must see how this evolves in terms of the different CD38 antibodies.
Noopur Raje, MD: The bottom line, which the 3 of you have highlighted, is the quadruplets are well-tolerated—we were worried about tolerability—and we are seeing incredibly high response rates, sustained response rates. The PFS follow-up with the GRIFFIN trial is unprecedented, we’ve never seen that kind of a PFS benefit.
Transcript edited for clarity.