Evaluating Frontline Treatment Strategies in NDMM: The DETERMINATION Trial


Expert hematologist-oncologists open their discussion on NDMM management by reviewing frontline data from the recent DETERMINATION trial.


Ajai Chari, MD: Hello, and welcome to this OncLive® Peer Exchange® titled “A New Wave of Progress in the Treatment of Multiple Myeloma: Translating Evidence to Clinical Practice.” My name is Ajai Chari. I’m a professor of medicine and the director of clinical research at the Icahn School of Medicine at Mount Sinai in New York [New York]. It’s my pleasure to have a distinguished panel of experts in multiple myeloma. I’ll let them introduce themselves.

Krina Patel MD: Hi, I’m Krina Patel. I’m an associate professor at [The University of Texas] MD Anderson Cancer Center in Houston, Texas.

Rafael Fonseca, MD: Hi, I’m Rafael Fonseca. I’m a professor of medicine at the Mayo Clinic in Phoenix, Arizona.

Cristina Gasparetto, MD: Hi, I’m Cristina Gasparetto. I’m a professor of medicine at Duke University [School of Medicine in Durham, North Carolina].

Omar Nadeem, MD: Hi, I’m Omar Nadeem. I’m the director of the immune effector cell therapy at Dana-Faber Cancer Institute in Boston [Massachusetts].

Ajai Chari, MD: Welcome, everyone. Thank you for joining me. Let’s get started on our first topic. If we’re true to form, there’s that joke that if you ask 5 myeloma doctors, you’ll get 6 opinions. Let’s see what we come up with. We’re going to start with the newly diagnosed setting, the evolving treatment landscape of newly diagnosed myeloma. Let’s set the stage with what we’re talking about: the choices of regimens for this transplant-eligible population. Historically, we’ve done VRd [bortezomib, lenalidomide, dexamethasone] in the United States. Some have done KRd [carfilzomib, lenalidomide, dexamethasone]. In Europe, we see VTd [bortezomib, thalidomide, dexamethasone], and there’s a question of whether to transplant early vs delayed. The newer questions are quads [quadruplet therapy]: can you add a CD38 up front with VRd [bortezomib, lenalidomide, dexamethasone] or KRd [carfilzomib, lenalidomide, dexamethasone]?

We’re going to go through some of those regimens together, but let me get things started with the exciting update at this year’s ASH [American Society of Hematology Annual Meeting], which was long awaited…. This is the DETERMINATION study. This is the American response, and things take longer here because of slower clinical trial accrual. But there’s also an important difference in the French design. The IFM study, which has been published in the New England Journal of Medicine, was VRd [bortezomib, lenalidomide, dexamethasone] followed by transplant or continuing VRd [bortezomib, lenalidomide, dexamethasone] and then lenalidomide maintenance for 1 year. The American difference is that the lenalidomide was given till progression. A lot of people felt that the criticism of the French study was that you’re going to stack the odds in favor of transplant because the control arm isn’t getting treatment beyond 1 year. What did that show? We see that with the randomized study of about 360 patients, and the follow-up is quite impressive, at 76 months. We see that the primary end point, which is important because people are often going to talk about other end points, was PFS [progression-free survival].

After there was a median follow-up of 76 months, the PFS of the control arm was 46.2 months, and the transplant was 67.6 months. That by itself was very impressive. It translated into a hazard ratio of 1.53, which was statistically significant. There were deeper responses and more MRD [minimal residual disease] negativity. Overall survival at this follow-up wasn’t statistically significantly different. I’m curious to hear people’s takes on that.

Safety is the other question. There was more hematologic toxicity. Quality of life, which is going to be increasingly important when you have so many choices, diminished transiently after transplant. But other than that, it was comparable. We’re always concerned about secondary malignancy, especially with lenalidomide post-transplant, but there was no difference in all SPMs [second primary malignancies]. There was an increase in hematologic malignancies, however: with AML [acute myeloid leukemia] and MDS [myelodysplastic syndrome], 0 patients in the nontransplant. That was statistically significant. We’re waiting on additional data about whole-genome sequencing, more quality of life, and correlative analyses. I’m curious about your thoughts are on this. Is this practice changing for you? Are you surprised? Krina, do you want to start?

Krina Patel MD: The question is always transplant or not. My patients are asking about it, but this actually showed us that transplant still gives you a 21-month PFS benefit. It hasn’t changed my practice in that sense because I recommend transplant for the majority of my patients. But I do have serious discussions with them about secondary malignancies and things like that. Some of my patients don’t necessarily want to go because of that, but we try to explain the myeloma is what we’re trying to treat. That’s what this trial has proven: that you’ll have a better response with better myeloma control for longer, which is always what we’re looking for.

Ajai Chari, MD: So you’re impressed by the PFS benefit. We all see that, but does anybody have a different take from that? For the lack of overall survival [OS], does that change your practice? Does that dissuade you from doing a transplant?

Rafael Fonseca, MD: I don’t think so. There are a lot of questions that are still out there. The lack of overall survival always has to be taken with a grain of salt because, as I always say, the absence of evidence is not evidence of absence. We have to wait for a long time with these clinical trials, and there are exceptions. We get it, but for the most part, PFS anticipates what’s going to happen later, and for the most part, adaptive response anticipates what we’re going to see with PFS.

The interesting question is what’s going to happen with the quads. That’s important. The benefit of transplant seems to be there. In fact, I have it in my disclosure slides. I’m biased totally toward transplant, and I’m scratching my head because I might be changing that, particularly if we start measuring things like MRD before transplant. There’s a lot to unpack on the study.

One thing that should be said, though, is what you mentioned with the secondary malignancies. There was nothing in the transplant arm, so the contribution of the lenalidomide to the myeloid secondary malignancies is questioned because we’ve assumed it was the lenalidomide. There’s good biology behind this—there’s ALL [acute lymphoblastic leukemia], which we can talk about—but not a lot on the myeloid side. This trial in many ways opens more questions than it ends up closing.

Ajai Chari, MD: Does anybody want to comment further on the primary vs secondary end point? That’s a really important distinction. Go ahead, Cristina.

Cristina Gasparetto, MD: First, I agree with the importance of PFS and the longer follow-up for some of these patients. The projected survival is the same, but how can we keep them alive with the continuation of therapy? I was surprised by the MRD of patients after transplant. When you showed the slides—that if you achieve MRD after transplant or with the continuation of therapy, there was a similarity—that surprised me. I always thought that the MRD we can achieve after high-dose chemotherapy, after transplant, was deeper. My concern is when I recommend transplant vs continuation of therapy. In a clinical trial, we’re capable of pushing a patient to remain on therapy, particularly in this regimen. We have Velcade [bortezomib] twice a week with cumulative toxicity and peripheral neuropathy. In the real world, we’re not [capable], so patients tend to discontinue therapy too prematurely. We’re not achieving the goal with MRD, and then we’re stuck with the patient progressing very rapidly, so we have to be very careful. The transplant allows us to control the disease faster, allows the patient to go off therapy and remain off therapy for a prolonged period of time. Also, every time we start a new therapy, there’s a clock ticking. If we start 5 or 6 years later, probably better. We have new therapies available vs continuation of therapy.

Ajai Chari, MD: You bring up some important points regarding MRD negativity and how that translates. But here we have MRD negativity, which translates into PFS already. The key thing I want people to pay attention to is, from a statistical point of view, why is a primary end point- what it is? That’s where all your power is. Once people progress, you lose all statistical control. The ability of PFS to translate into OS is based on not only the efficacy and toxicity of the randomized intervention but also what happens at progression. We know that 22% of patients got transplants. Based on global variations and practice patterns here—this is a US study—you’re not controlling for all those downstream events, and you have relatively limited follow-up. Maybe MRD negativity with a transplant will translate differently relative to nontransplant, but not with current follow up.

Cristina Gasparetto, MD: Exactly.

Transcript edited for clarity.

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