MRD as a New Paradigm in Myeloma Treatment

Rahul Banerjee, MD, FACP, assistant professor in the Division of Hematology and Oncology, at the University of Washington, discussed the use of minimal residual disease (MRD) assessment in multiple myeloma. Banerjee went on to explain how MRD can be applied to guide treatment decisions and monitor response to therapy.

He is speaking at the 21st annual International Myeloma Society conference, being held in Rio de Janeiro, Brazil, September 25-27. The event will feature leading experts discussing the basic, preclinical, and clinical aspects of myeloma. The American Journal of Managed Care^® spoke to him ahead of the IMS meeting.

This transcript has been lightly edited for clarity.

Transcript

How is MRD assessment being used to guide treatment decisions and monitor response in multiple myeloma? What are the implications of MRD negativity for long-term outcomes?

Banerjee: I would separate this question by clinical trials vs individual patients sitting in front of me. For clinical trials, we all were very excited earlier this year when the FDA approved, or at least gave its endorsement at an ODAC [Oncologic Drugs Advisory Committee] meeting to MRD being a primary end point for studies.¹ To familiarize the audience, the idea behind MRD is that it basically gives us the best tools in 2024 to look for any residual myeloma cells hiding behind, not [just] myeloma cells, even MGUS [monoclonal gammopathy of undetermined significance]–like cells, anything that's clonally abnormal, lurking underneath the scenes here.

One of the tests, the next-generation sequencing test [or] the clonality assay, can pick up 1 in a million cells, typically even more than that, if you have more than a million cells that are collected from the bone marrow, from the first pill aspirate. This is wonderful.

MRD negativity is amazing as an end point for trials because it reads out very quickly. With CAR [chimeric antigen receptor] T therapy, you're often able to see pretty quickly, within 28 days, that some patients who are going to do well are the ones who are MRD negative. A good example is the BENEFIT study that was presented at the American Society of Clinical Oncology [annual meeting] and recently published in Nature Medicine.² That was looking, for example, at Isa-VRd [isatuximab plus the triplet bortezomib, lenalidomide, and dexamethasone] vs Isa-Rd in newly diagnosed patients.

The primary end point there was MRD negativity at 18 months and it worked. Isa-VRd [isatuximab plus bortezomib, lenalidomide, and dexamethasone] beat Isa-Rd [isatuximab plus lenalidomide and dexamethasone]. It's worth noting that that was actually, I would argue, pretty practice changing for me because I had no doubt that Isa-VRd would beat VRd. Actually, the CEPHEUS study being presented at IMS will show that Dara-VRd was up from VRd in transplant-ineligible patients.³

The question would be for transplant-ineligible patients, we typically use the MAIA regimen,⁴ which is dara-Rd [daratumumab plus lenalidomide and dexamethasone] or a CD38 plus [lenalidomide] plus [dexamethasone], "does adding bortezomib once a week add on to that?" Here, they actually found a substantial 18-month benefit and MRD negativity. Interestingly, if you look even at 12 months, there was a significant difference between the curve. Even at the 12-month mark, you're able to see that we're using MRD negativity, that there's a difference between these 2 [regimens]. Isa-VRd is better than Isa-Rd and that's been changing my management. Right now, I'm considering quadruplets for maybe some more of my patients that might have been more borderline for transplant eligibility vs not.

If we had to wait for PFS [progression-free survival], that would have taken 4 to 5 years. The MAIA regimen, like Dara-Rd, or in this case, Isa-Rd, works very well. Medium PFS would have easily been 5 years, so MRD is great from that perspective, I'm so happy to see the FDA gave us blessing to [use] MRD as an end point here.

For the individual patient sitting in front of me, if they achieve MRD negativity, great, because that means that we can't even see 1 in a million cells left behind. Does that mean they're cured? Probably not, because even patients who achieve MRD negativity after CAR T, for example, I've had many who then go on to relapse years and years later.

The tricky part is if someone is MRD positive, it doesn't necessarily mean that the myeloma is about to come back. There are studies showing that, for example...25% of patients who have MRD resurgence, where their bone marrow goes from negative to positive low level MRD, never had a relapse, despite living for years and years thereafter.

I've had one patient who is now 9 years after transplant, still on maintenance, doing great, I checked MRD and she's still MRD positive. How is that possible? MRD will just tell you that the cells are abnormal, not that they're cancerous. There's this idea of an MGUS-like phenotype, MGUS is the pre-cancer condition, monoclonal gammopathy of undetermined significance, where you have the precancerous cells producing a protein. I can't say that these patients have MGUS, because MGUS is precancer and they're post-cancer, but it's MGUS-like. Just because these cells are there doesn't mean that they know how to cause kidney damage by cast nephropathy, doesn't mean that they know how to chew holes into the bones, etc.

MRD positivity is not a death sentence by any means. Unfortunately, in the field I feel we've hyped it a lot. There was a nice British study last year showing that they actually interviewed patients before and after their bone marrow biopsy, and the patients who were MRD positive were so disappointed. Honestly, that's on us as a field that we've hyped MRD negativity too much for individual patients.

I make it very clear for patients for MRD assessments that it's great to see if it's MRD negative, wonderful, if it's MRD positive, I'm not going to escalate your treatment, I'm not going to freak out, I'm not going to do anything differently. We don't know what to do differently for these patients. For MRD-positive patients, I would never escalate therapy or try to force them to become MRD negative, because we don't know that that will make them live better or live longer.

For patients who are MRD negative, if they have sustained MRD negativity on more than one check, they've been MRD negative twice, [if] MRI is negative, those are patients where I may talk about stopping maintenance therapy entirely in the frontline setting. To be clear, if someone's having toxicities from frontline maintenance, like from lenalidomide, or financial toxicity, you should address that earlier or change therapies or try something different. Don't wait for MRD negativity if someone's having toxicities but the absence of that, I do think it's reasonable, based on the data from the master study showing that in the absence of 2 or more higher cytogenetics, for the patients who had 0 or 0 to 1 high-risk cytogenetic features, discontinuation of all therapy if they achieve sustained MRD negativity at 10-5 worked for those patients is great to see.

The study alluded to earlier looking at daratumumab plus lenalidomide vs lenalidomide maintenance after transplant, had the second randomization, where of patients who achieve sustained MRD negativity after 2 years, do we continue all treatment, or do we stop all treatment?

That would be really interesting. That is the kind of data that I'm really looking for, randomized data, not of MRD as an end point, but of MRD as a middle point of basically helping us decide what to do. Should we continue therapy or stop there for some MRD negative? That I think will be really interesting to see.

References

1. Seymour C. FDA’s ODAC recognizes MRD as an accepted end point for accelerated approval in multiple myeloma. OncLive. April 12, 2024. Accessed October 15, 2024. https://www.onclive.com/view/fda-s-odac-recognizes-mrd-as-an-accepted-end-point-for-accelerated-approval-in-multiple-myeloma
2. Leleu X, Hulin C, Lambert J, et al Isatuximab, lenalidomide, dexamethasone and bortezomib in transplant-ineligible multiple myeloma: the randomized phase 3 BENEFIT trial. Nat Med. 2024;30(8):2235-2241. doi: 10.1038/s41591-024-03050-2.
3. Usmani S. Daratumumab + bortezomib/lenalidomide/dexamethasone in patients with transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: Results of the phase 3 CEPHEUS study. Presented at: International Myeloma Society 21st Annual Meeting & Exposition; Rio de Janiero, Brazil; September 25-28, 2024. Abstract OA – 63.
4. Facon T, Kumar S, Plesner T, Orlowski R, et al. for the MAIA trial investigators. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380(22):2104-2115. DOI: 10.1056/NEJMoa1817249