Measuring Sustained MRD Provides Path to Tailoring Myeloma Therapy

The introduction of several efficacious therapies for newly diagnosed multiple myeloma has led to quadruplet combinations being given as induction therapy. At this stage, physicians are deciding how to use these agents on a case-by-case basis and looking toward the potential of minimal residual disease (MRD) to guide therapeutic approaches after induction. In a recent virtual Case-Based Roundtable meeting, Hans Lee, MD, director of Myeloma Research at the Sarah Cannon Research Institute in Nashville, Tennessee, moderated a discussion on the future of the field of frontline myeloma treatment. Although research into MRD-guided treatment is still ongoing, Lee suggested MRD testing patients now provides valuable insights into how their treatment could be personalized in the future.

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This article is part 2 of a 2-part series from a Case-Based Roundtable event.

DISCUSSION QUESTION

• Where is the field headed in terms of quadruplet primary therapy? ​

Hans Lee, MD: What are your thoughts in terms of where the field is headed terms of quadruplet primary therapy, for instance, using Dara-VRd [daratumumab (Darzalex), bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone] or Isa-KRd [isatuximab (Sarclisa), carfilzomib (Kyprolis), lenalidomide, and dexamethasone]? Is there any situation where that you would vary the quadruplet that's used, whether it’s bortezomib vs carfilzomib or daratumumab vs isatuximab?

Andrew Jallouk, MD: I use Dara-VRd. I don't know a situation where I prefer isatuximab to daratumumab. I view isatuximab as second to market, and they're essentially equivalent. They are trying to do studies to find a niche for it.

Jigar Shah, MD: I use Dara-VRd in my practice primarily. If, for some reason, there are insurance issues or financial issues from a patient standpoint or insurance requirement, then I would lean towards the alternative. The MRD data that are coming out may alter the future way of doing things after the induction regimen.¹

Jeremy Pantin, MD: We do have an approval for Isa-VRd in the transplant-ineligible [setting], and we would be able to get insurance approval for a quadruplet in a scenario like that, especially if we think that they're fit enough to go through that.² From a real-world setting, when you have approval barriers for using a quadruplet, that's where I think it could find a niche.

Brian Hemphill, MD: What are your thoughts on carfilzomib vs bortezomib?

Lee: In the majority of patients, there are more data on Dara-VRd vs KRd, but I think there are some nice data on high-risk myeloma with carfilzomib, and you don't really see neuropathy with carfilzomib over bortezomib.³ Sometimes with my younger patients who have high-risk myeloma or ultra–high-risk myeloma, I may favor carfilzomib over bortezomib in that context. Also, if a patient has preexisting peripheral neuropathy for whatever reason, I probably favor carfilzomib over bortezomib. Those are a couple of scenarios where I'd consider carfilzomib, although by and large, I use bortezomib.

DISCUSSION QUESTION

• How will MRD testing change practice in the future?

Gary Tian, MD: How often do you [test] MRD, and at what different time points do you [test] MRD?

Lee: I use quite a bit of MRD testing. I typically do it after induction. There's going to be a smaller fraction of patients who are MRD negative after 4 or 6 cycles of induction. But nevertheless, I think it's informative, particularly in the patients with standard-risk myeloma. If a third of them are MRD negative at that point, you can inform the transplant discussion. I also do it post-transplant as well, and I do it serially while on maintenance therapy, because I believe there will be more robust data coming on when to discontinue maintenance lenalidomide based on sustained MRD negativity.

I want to have the data for the patients [so that] when those data come out, [if] they’ve had 2 or 3 MRD negative bone marrow [biopsies indicating] sustained MRD negativity, I can tell them the data just came out and we can discontinue [maintenance]. Whereas, if I never generate those data, I would be saying that the data just came out, but I don't know what to do, because I haven't obtained any MRD testing on them. I probably do it a little bit more frequently because of following where the field could lead. But there are lots of variation to this. There's no standard approach.

Tian: If they are MRD negative after transplant, do you [test] every 6 months?

Lee: I probably do a bone marrow [biopsy] for MRD testing every 1 to 2 years. Some people do it annually, but I don't do it that frequently. Again, [I do it] just to track the sustained MRD negativity status. If a patient, for instance, has MRD-negative disease at 18 months post-transplant and at 3 years post-transplant, then we have 3 MRD negative points. That's considered sustained MRD negativity. Of course, you don't want to do it too frequently. I think patients find it uncomfortable to do repetitive bone marrow [biopsies], but what I try to aim for is enough data to conclusively tell the patient they have sustained MRD negativity.

David Chism, MD: How do you determine MRD [sensitivity of] 10^-5 vs 10^-6? Is there a big difference when you're looking for it?

Lee: So, 10^-5 is a sensitivity that can be assessed with flow cytometry. Usually that setting, 2 billion cells are gated by the flow cytometer, and you can detect 1 abnormal myeloma cell in 100,000 normal cells. 10^-5 would be considered the standard definition of MRD negativity, per the International Myeloma Working Group criteria. You could attain higher sensitivity with the next-generation sequencing ClonoSeq assay, which is a send-out test by Adaptive Biotechnologies that has the ability to detect 1 in 1 million abnormal cells at a sensitivity of 10^-6. So, it depends on the technique of the MRD assay that you use.

Chism: Have you had any barriers to reimbursement for MRD testing?

Lee: Overall, it has been reimbursed; even the ClonoSeq assay is an FDA-approved test at this point that is covered by third-party payers. I have probably had 1 or 2 circumstances where it wasn't covered, and I had to do an appeal. But, at least with the ClonoSeq assay, I haven't had issues with reimbursement.

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DISCLOSURES: Lee previously reported consulting or advisory roles with Takeda, GlaxoSmithKline, Sanofi, Bristol Myers Squibb, Genentech, Allogene Therapeutics, AbbVie, Janssen Research & Development, Regeneron; research funding from Takeda, Amgen, Janssen, GlaxoSmithKline, Regeneron, Bristol Myers Squibb/Celgene. Jallouk previously reported consulting for Kite/Gilead. Pantin previously reported speaker’s bureau work for Sanofi, Bristol Myers Squibb and Omeros Corporation and honoraria and consultancy from Legend Biotech and Novartis Pharmaceuticals.

REFERENCES:

1. Broijl A, Roeloffzen W, Dimopoulos MA, et al. Analysis of sustained MRD negativity in patients with newly diagnosed multiple myeloma treated with carfilzomib-lenalidomide-dexamethasone with or without isatuximab (phase III IsKia trial). Presented at: European Hematology Association 2025 Congress; June 12-15, 2025; Milan, Italy. Abstract S208.

2. FDA approves isatuximab-irfc with bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma. News release. FDA. September 20, 2024. Accessed August 4, 2025. https://tinyurl.com/pph8yf6c

3. Costa LJ, Chhabra S, Medvedova E, et al. Daratumumab, carfilzomib, lenalidomide, and dexamethasone with minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma. J Clin Oncol. 2022;40(25):2901-2912. doi:10.1200/JCO.21.01935