Frontline Quadruplet Therapy in NDMM: GRIFFIN and MASTER Studies


Expert perspectives on frontline daratumumab-containing quadruplet regimens in the context of recent clinical trials in newly diagnosed multiple myeloma.


Shaji Kumar, MD: Welcome to this CancerNetwork® Around the Practice program, “Advances in Multiple Myeloma: Insights From Experts at Mayo Clinic on Translating Evidence to Clinical Practice.” I am Dr Shaji Kumar, professor of medicine and chair of the Myeloma, Amyloidosis, Dysproteinemia Group at Mayo Clinic in Rochester, Minnesota....I would like to invite my esteemed fellow panelists to introduce themselves.

Morie Gertz, MD: I am Morie Gertz. I am a consultant in the Division of Hematology within the Myeloma, Amyloidosis, Dysproteinemia Group at Mayo Clinic.

David Dingli, MD: My name is David Dingli. I am also a professor of medicine at Mayo Clinic and a consultant in the Division of Hematology within the Myeloma, Amyloidosis, Dysproteinemia Group.

Prashant Kapoor, MD: I am Prashant Kapoor, also in the Division of Hematology in at Mayo Clinic. I also work in the Myeloma, Amyloidosis, Dysproteinemia Group.

Shaji Kumar, MD: We are going to discuss several key data updates in multiple myeloma from recent meetings. We will review these data in the context of the current multiple myeloma treatment landscape and discuss how we can apply this emerging body of evidence to a clinical practice to improve patient outcomes. The treatment of multiple myeloma has changed over the past few years with the introduction of new therapies. With the introduction of EMID [evolutionary metabolic infectious disease], we used doublets for the initial therapy of newly diagnosed myeloma and subsequently moved on to triplets. It is clear across the cancer spectrum that using multiple different drugs in combination, especially with a different mechanism of action, leads to deeper responses and better outcomes. The concept of using 4 drugs has been around for some time, and the combination of cyclophosphamide, bortezomib, and dexamethasone was tried but without any significant improvement in outcomes. More recently, with monoclonal antibodies, there has been an increased interest in trying to develop 4-drug regimens for treatment of multiple myeloma to see whether that would improve outcomes in patients with newly diagnosed disease. Clearly, there have been some exciting data. Morie, do you want to talk about the GRIFFIN trial updates?

Morie Gertz, MD: The GRIFFIN trial was an important first step in understanding the role of quadruplets. It was a randomly assigned trial in transplant-eligible patients of daratumumab, bortezomib, and LenDex [lenalidomide and dexamethasone] compared with bortezomib and LenDex. When they did their most recent update, the 36-month progression-free survival in the DARA [daratumumab]-containing arm was 89% statistically better than the non–DARA-containing arm, and the percentage of patients with results of greater than equal to complete response was 61%. It really spoke volumes in terms of response depth, and the subset of the CRs [complete responses] will be MRD [minimal residual disease] negative. We don’t have overall survival data. We are not able to say that it impacts that, but generally speaking, response depth is a good surrogate in terms of anticipating what will ultimately be seen in both progression-free survival.

Shaji Kumar, MD: I think the 4-drug regimens are going to have a profound impact, but one of the questions that always comes up is: When you are using the 4 drugs, are we able to give these patients a limited duration of therapy, then hopefully stop treatment and give patients a treatment-free interval? To that extent, the data from the MASTER trial are quite illuminating. Do you want to speak to that, David?

David Dingli, MD: Yes, absolutely. Up until now, the paradigm has been that the patients are treated continuously with therapy from the time of diagnosis. The MASTER trial is opening new ground because it is asking a very important question: Can we use MRD data to inform decisions on how long to give therapy? This was a phase 2 trial with approximately 125 patients. The patients were transplant eligible. They included patients who were in their early 70s. These patients were all treated with a quadruplet regimen: daratumumab, carfilzomib, lenalidomide, and dexamethasone. Intentionally, in this group, they were reaching for patients with high-risk disease and divided patients into standard risk and high risk with single-hit, double-hit or higher-risk disease. The patients received 4 cycles of therapy, went on to transplant, and then received 0, 4, or 8 cycles of consolidation with the same quadruplet. The patients were tested at specific points for MRD negativity: prior to transplant, meaning after 4 cycles of induction, then immediately after transplant, and then every 4 months. They showed that the number of patients who developed complete responses and MRD-negative states at the level of 10 to –5 progressively increased. The study was designed in such a way that if a patient had results of 2 consecutive MRD-negative states, effectively separated by 4 months, therapy could be held and the patient could go into an observation. The medium follow-up is not very long; it is about 18 months. However, we can already see that the patients with standard-risk disease, who were about 43% of the patients in the study, have not progressed. The problem is with the patients with double-hit multiple myeloma. Although the response rates were similar to those of standard-risk patients with respect to CR and MRD negativity, in this study, the progression-free survival of therapy is lower with high-risk disease. At the time of reporting, 27% of patients with double-hit multiple myeloma who were off therapy had progressed. What we can conclude is that it may be possible to consider the idea of withholding therapy in patients with very deep responses, but we probably need to do more for patients with high-risk disease.

Shaji Kumar, MD: The ideal duration of maintenance question still remains unanswered to some extent, especially in the context of these therapies. Talking about a daratumumab-KRd [carfilzomib, lenalidomide, and dexamethasone] regimen, are there certain occasions or patient types where you would prefer that over a daratumumab-VRd [bortezomib, lenalidomide, and dexamethasone] regimen, like in the GRIFFIN trial?

David Dingli, MD: The question of whether carfilzomib versus bortezomib is superior is something that is still being explored. We know that in standard-risk patients, there is no superiority with respect to carfilzomib versus bortezomib. The question remains as to whether carfilzomib will be a superior drug in high-risk patients. In general, I prefer bortezomib-based regimens because they are simpler. I would consider carfilzomib for some patients with high-risk disease or patients with preexisting neuropathy, but I would generally try to avoid carfilzomib for patients with cardiac comorbidities or severe hypertension.

Shaji Kumar, MD: Morie, as a follow-up on the GRIFFIN trial, in your practice, are you using the daratumumab maintenance post transplant when you use the quadruplet, or do you tend to look at the data from the CASSIOPEIA trial and extrapolate from there?

Morie Gertz, MD: Again, it’s these cross-trial comparisons, but my concern is that when the comparison between daratumumab, bortezomib, thalidomide, and dexamethasone versus bortezomib, thalidomide, and dexamethasone was published, it didn’t appear that if patients received daratumumab as part of induction therapy, its addition outside of the study to maintenance immunomodulatory drugs was better than the immunomodulatory drug alone. Outside of a trial, I think the standard for maintenance, at the very least in the standard-risk patients, is still single-agent lenalidomide. It gets debatable about whether 2 agents should be considered in high-risk patients. That isn’t something that has been fully validated in trial settings to justify double treatment.

Transcript edited for clarity.

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