Evaluation of first-line treatment strategies in NDMM: the DETERMINATION trial

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Ajai Chari, MD: Hello and welcome to this Live® Peer exchange® entitled “A New Wave of Advances in the Treatment of Multiple Myeloma: Translating Evidence into Clinical Practice”. My name is Ajai Chari. I am Professor of Medicine and Director of Clinical Research at the Icahn School of Medicine at Mount Sinai in New York [New York]. It is a pleasure for me to have a group of eminent experts in the field of multiple myeloma. I’ll let them introduce themselves.

Dr Krina Patel: Hi, I’m Krina Patel. I am 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 am a professor of medicine at Duke University [School of Medicine in Durham, North Carolina].

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

Ajai Chari, MD: Welcome everyone. Thanks for joining me. Let’s start with our first topic. If we’re true to ourselves, there’s this joke that if you ask 5 myeloma doctors, you’ll get 6 opinions. Let’s see what we offer. We will start with the newly diagnosed context, the evolving therapeutic landscape of newly diagnosed myeloma. Let’s set the stage with what we’re talking about: the choices of treatment regimens for this transplant-eligible population. Historically, we have done VRd [bortezomib, lenalidomide, dexamethasone] in the USA. Some made KRd [carfilzomib, lenalidomide, dexamethasone]. In Europe, we see VTd [bortezomib, thalidomide, dexamethasone], and there is a question of whether to transplant sooner or later. The most recent questions are quads [quadruplet therapy]: can you add a CD38 to the front with VRd [bortezomib, lenalidomide, dexamethasone] or KRd [carfilzomib, lenalidomide, dexamethasone]?

We’ll go through some of these diets together, but let me start with this year’s exciting ASH update. [American Society of Hematology Annual Meeting], which was long overdue…. This is the DETERMINATION study. It’s the American answer, and things are taking longer here due to a slower build-up of clinical trials. But there is also an important difference in French design. The IFM study, published in the New England Journal of Medicinewas VRd [bortezomib, lenalidomide, dexamethasone] followed by transplant or continuation of VRd [bortezomib, lenalidomide, dexamethasone] then maintenance lenalidomide for 1 year. The American difference is that lenalidomide was given until progression. Many people felt that the criticism of the French study was that you’re stacking the odds in favor of the transplant because the control arm doesn’t get treatment beyond a year. What did it show? We see it with the randomized study of about 360 patients, and the follow-up is quite impressive, at 76 months. We see that the main endpoint, which is important because people will often talk about other endpoints, was the SSP [progression-free survival].

After a median follow-up of 76 months, the PFS of the control group was 46.2 months and the transplant was 67.6 months. That in itself was very impressive. This translated into a hazard ratio of 1.53, which was statistically significant. There were deeper answers and more MRDs [minimal residual disease] negativity. Overall survival at this follow-up was not statistically significantly different. I’m curious to hear people’s opinions on this.

Security is the other issue. There was more hematological toxicity. The quality of life, which is going to be increasingly important when you have so many choices, temporarily decreased after the transplant. But other than that, it was comparable. We are still concerned about secondary malignancy, especially with post-transplant lenalidomide, but there was no difference in all PMS [second primary malignancies]. However, there was an increase in hematological malignancies: with AML [acute myeloid leukemia] and MDS [myelodysplastic syndrome], 0 patients in the non-graft. It was statistically significant. We await additional data on whole genome sequencing, improved quality of life and correlative analyses. I’m curious to know what you think about it. Is this practice changing for you? Are you surprised? Krina, do you want to start?

Dr Krina Patel: The question is always transplant or not. My patients ask about this, but it actually showed us that the 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 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 that 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 are impressed with the PFS advantage. We all see this, but does anyone have a different take on this? For lack of overall survival [OS], does this change your practice? Does this deter you from having a transplant?

Rafael Fonseca, MD: I do not think so. There are many questions that are still there. Lack of overall survival should always be taken with a grain of salt because, as I always say, lack of evidence is not proof of absence. We have to wait 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 will happen with the quads. It is important. The benefit of the transplant seems to be there. In fact, I have it in my disclosure slides. I’m totally pro-transplant and scratching my head because I could change that, especially if we start measuring things like MRD before transplant. There is a lot to unpack about the study.

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

Ajai Chari, MD: Does anyone want to comment further on the primary vs secondary endpoint? This is a very important distinction. Go ahead, Christina.

Cristina Gasparetto, MD: First, I agree with the importance of PFS and longer follow-up for some of these patients. Projected survival is the same, but how do we keep them alive with continued therapy? I was surprised by the MRD of the patients after the transplant. When you showed the slides—that whether you get MRD after a transplant or with continued treatment, there was a similarity—it surprised me. I always thought that the MRD that we can achieve after high dose chemotherapy, after transplant, was deeper. My concern is when I recommend a transplant rather than continuing treatment. In a clinical trial, we are able to get a patient to stay on treatment, especially on this regimen. We have Velcade [bortezomib] twice weekly with cumulative toxicity and peripheral neuropathy. In the real world we are not [capable], so patients tend to stop treatment too soon. We don’t hit the target with the MRD, and then we get stuck with the patient progressing very quickly, so we have to be very careful. The transplant allows us to control the disease faster, allows the patient to stop treatment and go without treatment for an extended period. Also, each time we start a new therapy, there is a countdown. If we start 5 or 6 years later, it’s probably better. We have new therapies available versus continuing therapy.

Ajai Chari, MD: You raise some important points regarding MRD negativity and how that translates. But here we have the MRD negativity, which already translates to PFS. The key thing I want people to pay attention to is, statistically, why a main endpoint – what is it? Therein lies all your power. Once people progress, you lose statistical control. The ability of PFS to translate into SG is based not only on the efficacy and toxicity of the randomized intervention, but also on what happens during progression. We know that 22% of patients obtained a transplant. Based on the global variations and the practice patterns here—this is an American study—you don’t control all of these downstream events, and you have relatively limited tracking. Maybe MRD negativity with transplant will translate differently than non-transplant, but not with current follow-up.

Cristina Gasparetto, MD: Exactly.

Transcript edited for clarity.

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