Transplant-Eligible NDMM: Assessing Response to Therapy and Role of MRD Negativity


Comprehensive discussion on the assessment of response to frontline therapy for transplant-eligible multiple myeloma and the role of MRD negativity in assessing response.

Ajai Chari, MD:
Let’s move to Omar. You heard about MASTER alluding to this as MRD [minimal residual disease] negativity. How do you change your treatment? What’s your end point? How do you make decisions about this induction?

Omar Nadeem, MD: It’s great that we have so many choices and combinations. The good news is that most patients are having amazing responses to induction therapy, and in the triplet and quadruplet [therapy] era. That’s only getting better as time goes on. In our practice, we’re using mostly quadruplets for transplant-eligible patients, and most patients respond and tend to get deeper responses. The challenging part is making treatment decisions based on MRD. If they haven’t achieved MRD negativity at a certain point, that doesn’t mean they won’t eventually become MRD negative. If they’re following a good path, they’re achieving the benchmarks, getting to a PR [partial response], then a VGPR [very good partial response], then heading to transplant, I don’t feel the need to modify therapy because they haven’t gotten to a particular response at that given time. So many patients convert to MRD negativity well into maintenance if they’re following that path. As long as they’re responding and deepening the response, I don’t usually modify therapy just because they haven’t reached a certain benchmark at that point.

Ajai Chari, MD: So your duration of induction is 4 to 6?

Omar Nadeem, MD: Yes, 4 to 6 months.

Ajai Chari, MD: You don’t use MRD to make a decision about transplant?

Omar Nadeem, MD: I don’t.

Ajai Chari, MD: After transplant, are you using it to make consolidation decisions?

Omar Nadeem, MD: I don’t.

Ajai Chari, MD: You’re consistent throughout the whole thing.

Omar Nadeem, MD: Right now we’re seeing from the MASTER trial some MRD adaptive therapy designs. As Cristina mentioned, high-risk patients still had early relapses. We know that’s not enough despite having repeated cycles of consolidation and probably the most intensive frontline therapy they can get. However, from DETERMINATION we see amazing results: 67 months of PFS [progression-free survival] when assigned triplet and single-agent maintenance. We’re starting to see durable responses in that area. With getting the quad [quadruplet therapy] and having multiagent maintenance, we’re seeing benefits in numerous trials. The story isn’t just in that initial short window, in my opinion.

Ajai Chari, MD: I want to come back to that because that’s an interesting study that we heard about, but MRD is an amazing Pandora’s box that we’ve got to open. How are you using MRD in clinic?

Rafael Fonseca, MD: I’m a little different from Omar. I actually base my post-transplant therapy on MRD.

Cristina Gasparetto, MD: Me too.

Rafael Fonseca, MD: The reason for that is we’ve seen that attainment of MRD as very important. We have 3 meta-analyses that show that it correlates with OS [overall survival] and PFS. We know that better treatments result in higher percentages of MRD negativity, and we know that attainment of MRD negativity can overcome the prognostic effect of the genetic markers. When I see a patient post-transplant, if they have standard risk and are MRD positive, then I acknowledge that some of them will convert to MRD negative with maintenance alone, but I discuss and offer consolidation with the daratumumab-based combination. If they’re high risk, I insist on additional treatment. I don’t want to leave cells behind. I know all this needs to be tested empirically, and we’re going through clinical trials, but if I was a patient in that spot, I’d want to get more treatment.

Cristina Gasparetto, MD: Absolutely, I totally agree. I think that way with high-risk patients. I’m not joking. Some of the data on the quadruplet therapy rate of MRD after 4 cycles of consolidation was phenomenal, at 50%. With the daratumumab–RVd [lenalidomide, bortezomib, dexamethasone], it’s at the same level after transplant, after consolidation, so with the high-risk patient, I’m more aggressive. I want to achieve that because I don’t want that clone to proliferate when I’m thinking about and going to clone evolution, so I push it. With the standard risk, sometimes I balance because it takes a little longer to achieve MRD negativity, so sometimes I push the envelope. It depends on the frailty and the age, but I’m chasing MRD. I do sequential MRD. Do you know why? Because if I had myeloma, I’d like that to be done for me. I’d want the MRD negativity, the sustainability.

Ajai Chari, MD: You gave a beautiful presentation about the love equation.

Cristina Gasparetto, MD: The love equation.

Ajai Chari, MD: It’s better to have loved and lost or to never have at all, right?

Cristina Gasparetto, MD: Yeah.

Ajai Chari, MD: Your point is important. Having MRD at 1 point in time but not sustaining it isn’t good enough, right?

Cristina Gasparetto, MD: Not good enough.

Ajai Chari, MD: But especially for community folks, it’s important we clarify how MRD is being done in these studies. It’s SPEP [serum protein electrophoresis] negative, IFE [serum immunofixation electrophoresis] negative, UPEP [urine protein electrophoresis] negative, urine immunofixation negative, and imaging negative. That’s when we’re looking at MRD for most of these studies. Sometimes in some hematologic malignancies, you use blood-based PCR [polymerase chain reaction] assays to do your MRD. This is very different. We have to keep in mind that the sampling of the marrow is indeed that, and it may not be representative. Krina, what about you? How are you using MRD?

Krina Patel MD: I’m more like Omar. My high-risk patients, MRD negative or not, get consolidation and doublet or triplet maintenance for a few years. For my standard-risk patients, I use MRD for those who are worried about going to transplant. I have a lot of patients who just don’t want to do it. Sometimes it helps me show them that maybe this is still the right thing to do. Very few of my patients are MRD negative before transplant. We use it in that sense. I try not to use it to say whether we’re going to transplant. But I use any tool that can help them look at it.

For maintenance, we have a couple of trials. If you’re MRD positive, you can go on the SWOG trial…. I try to put them on those trials to get the answer if that’s the right thing to do for standard risk. But with a lot of my patients, especially during COVID-19, we were trying to get them off therapy to give their immune systems time to come back. I’m still on the fence a little about treating some patients.

Rafael Fonseca, MD: Ajai, it’s important for the audience to know there’s significant subjectivity. The DETERMINATION trial, which was in the Plenary Series [at ASCO], is the sister trial of IFM 2009, which is in France. It was started in 2009, so as we learn, we have to decide what we do for today’s patients. I wouldn’t say what we’re saying is in any way written in stone. There’s maybe a preponderance of evidence, but it’s not beyond a reasonable doubt that you can put patients on maintenance.

Cristina Gasparetto, MD: Absolutely. That trial, of course, doesn’t have the antibody, the daratumumab. I’m always pro transplant, and I’ve always been pro transplant. However, I’m amazed by the data of the MAIA, the long-term follow-up. I’m trying to reconsider and say the addition of the antibody may push us in a different direction.

Transcript edited for clarity.

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