MRD: ASH 2022 Ben Derman the MRD2STOP Guide
By Ben Derman, MD
How can the MRD2STOP guide help patients with MRD? So the study that we have conducted or we’re currently conducting is really a prospective trial. And what we’re trying to do is take patients who have shown to have a durable, deep response to treatment for their myeloma and who are on maintenance therapy and see if they are able to stop their treatment, and then what happens after that happens. And so we’re really relying on MRD (minimal residual disease) testing or MRD (minimal residual disease) technology. MRD (minimal residual disease) of course, stands for measurable, or some say minimal residual disease. And in myeloma, we know that’s strongly associated with an improved prognosis.
In myeloma specifically. But not just that, the deeper that you can assess a sample and the bone marrow the more prognostic it’s going to be. So what I mean by that is we have current technology that’s able to look for MRD (minimal residual disease) negativity, meaning the lack of detectable disease on the order of 10 to the minus sixth meaning 1 in a million cells that we can look at. And when you have MRD (minimal residual disease) negativity at that level, that really carries the most superior prognosis over less sensitive thresholds, like 10 to the minus fifth, one in a hundred thousand or 10 to the minus fourth one in 10,000. And the other thing that we know is that, with the current day and age, with all the therapies that we have in myeloma that are, advancing our outcomes for patients, more and more patients are reaching MRD (minimal residual disease) negativity, and then they are on maintenance therapy to help sustain that.
But the question is, When can people stop maintenance therapy? That’s the question that I get the most in clinic from patients. When can I stop? If, can I ever stop? And that’s what we try to assess to try to mitigate some of the side effects, toxicities, impact of quality of life as well as financial toxicity by seeing if we can stop therapy for some folks.
So in our study, we took patients who were in either in a sustained complete response over 2 years, or who had MRD (minimal residual disease) negativity with, at least a year prior, who also had a negative PET scan. And then they underwent what we call a multimodal MRD (minimal residual disease) analysis or assessment. That includes a PET scan to look for extra medullary disease, bone marrow aspirations to look for residual disease by both flow cytometry and next generation sequencing using the clonoSEQ assay, which is a 10 to the minus sixth threshold, meaning 1 in a million.
And we did some other exploratory analyses in the peripheral blood as well as the bone marrow to really try to understand if there might be some new methods that will be better able to tell us who is okay to stop and who is not. But for the trial purposes, patients had to be having undetectable disease by PET scan.
And by MRD (minimal residual disease) testing in the bone marrow, at least at the 10 of the minus sixth threshold in order to discontinue. And then we followed them, or we’re currently following them for 3 years every 3 months using blood work. And then every year using bone marrow aspiration as well as PET scans. So we’re doing MRD (minimal residual disease) surveillance essentially for 3 years.
The big exploratory analysis that we’re doing and that we shared in this abstract is actually trying to extend the current testing paradigm from 10 of the minus sixth to 10 of the minus seventh, which is 1 in 10 million. And there are a lot of challenges getting to this 10 of the minus seven threshold.
Primarily it’s because to get to 10 of the minus seventh of course, means you need at least 10 million cells. But not just that, you need to be able to actually analyze those cells, and that’s where currently we have an issue. We can draw enough cells from the bone marrow, but actually being able to analyze them is not currently validated by any assay.
So what we did is we tried to create a workaround. We took a bone marrow aspirate sample. Which has tens of millions of cells. But instead of trying to analyze that whole sample, we actually filtered out just the plasma cells, which are the cells of interest for us when we’re talking about MRD (minimal residual disease), cuz myeloma cells of course are plasma cells.
And then we run that sample, which is a much smaller fraction and that is in hopes to estimate what we get at 10 of the minus seventh to really approximate. What we shared in our presentation is that we had 38 patients who discontinued therapy. The majority, 95% of these patients were still in their first line of therapy.
And the majority of 95% were on Lenalidomide maintenance alone. When you look at the number of high-risk patients that we had on the study this comprised about 40% of the. And the, median time that patients were on some kind of additional therapy after a stem cell transplant or after just induction, if they did not receive a transplant, was about 42 months.
So think about 3 and a half years. And so far we have a follow-up time, median follow-up time of 15 months, and of the 38 patients who we enrolled in this discontinuation study, as of the data cutoff, we only had two patients who had disease progression or 5% and no deaths so far. And both patients who had disease progression were what we call biochemical progressions.
They did not have clinically symptomatic disease from that. Among the 38 patients in total, we had 5 patients who had what we call MRD (minimal residual disease) resurgence, meaning there was at least something detectable in the bone marrow where it wasn’t at their baseline. So 5 out of 38 had something detectable, but only 2 of those 5 patients actually had disease progression as I mentioned. But here’s where it gets really interesting, because not only are we finding out what happens to patients after they stop, but we can go back and look at their initial bone marrow and say, did this test that we did using this 10 to the minus seventh workaround, did that actually detect any disease that we could have, so we could have predicted that maybe these are the patients that were going to develop disease progression or disease recurrence, MRD (minimal residual disease) resurgence, and interestingly all 4 patients at baseline who had detectable disease using this 10 to the minus seventh assay later had MRD (minimal residual disease) resurgence or disease progression at 12 months.
And only 1 of the patients who was negative by all testing that we did, including 10 of the minus seventh, had converted to MRD (minimal residual disease) positivity at a later point as far as, at least at the data cutoff that we had. So when we look at things as a whole right now fast forwarding 12 months from when patients discontinue therapy, 21 of 25 or 84% have no evidence of disease using the 10 to the minus sixth threshold.
And if you were to increase that threshold, a 10 to the minus seventh, we actually have 20 out of 21 or 95% of patients who remained MRD (minimal residual disease) negative by every assay q So that’s, I think the real key thing here is that patients who are 10 to the minus seventh positive, meaning they have detectable disease using this modified assay, seem to certainly be at a higher risk of developing disease progression or MRD (minimal residual disease) resurgence.
If they were to stop, and maybe this is a sign that with further follow up, we might be able to say, hey, this is a test that you can use to decide whether someone should stop or not.
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What is MRD and next-generation sequencing (genomic sequencing)?
After finishing a course of treatment, “complete remission” is one of the most wonderful things a patient may hear. On the basis of scans and laboratory testing (clinical trials or clinical studies), there is no evidence of malignancy, indicating that the treatment was effective.
However, there is an additional word that can be somewhat confusing for patients: minimum residual disease (MRD). When treating individuals with blood cancers such as leukemia, lymphoma, and multiple myeloma, this term is widely employed.
We currently have substantially more sensitive assays for evaluating MRD (minimum residual disease) These may involve next-generation sequencing (genomic sequencing), which allows us to examine samples of bone marrow for genetic mutations. Even if no disease residuals are visible under a microscope, the presence of mutations suggests their presence.
Flow cytometry allows us to evaluate the same samples for abnormal proteins on the cell surface. By estimating the amount of cells expressing abnormal proteins, we can gain a more precise understanding of the number of remaining cancer cells. We routinely use these innovative assays to evaluate whether a patient has MRD (minimal residual disease) after getting standard treatment.
There is a great deal to gain. These malignancies can adapt to therapy, which implies that the cancer we have before treatment and the cancer we have after treatment are not identical. By evaluating the minimal residual disease (MRD), we can have a better understanding of what remains after treatment.
This expedites multiple tasks. First, it allows us to modify our treatment by adding medications that target specific vulnerabilities in the cancer cells, including those that are highly effective at eradicating even residual cells, or by performing a stem cell transplant, which is capable of eliminating remaining cells.
What are the most common questions for this research?
I think the most common question that we get is, how exactly are you doing this 10 to the minus seventh assay, and is it really 10 to the minus seventh? And I think the answer to that is that we’ve developed this workaround, right? And so we, when we actually take the bone marrow we actually looked at this in our study, so 60 out of the 62 bone marrow samples that we ran using our 10 to the minus seventh . Assay actually past quality control. So first of all, we know that the end result, which are CD138 selected cells that we’re analyzing is certainly feasible. And actually the total nucleated cell count that we get from the initial sample that we draw from the bone marrow was the median was 59 million.
And the interquartile range (IQR) range, so from the first of the third quartile was 40 to 102 million. So that tells you we’re getting a lot, of course we have to factor in pipetting efficiency and DNA extraction. So we’ve accounted for that in this (meta) analysis. And so even with that, our median nucleated cell count that we start with in the denominator is above 10 million, it was actually 13 million. So I think that’s an important piece. Another question that we get is, so we had 70 patients that were screened for this study and 38 patients who met eligibility and were able to discontinue therapy. And so some folks have asked us, why were there 32 out of the 70 patients who weren’t able to proceed with therapy?
And the important thing to remember is that a lot of the patients on this study have been on maintenance therapy for actually a long time. And so there are samples that they have of their initial disease, high burden disease specimen are from sometimes 10 years ago. And being able to get a clone identification or a clonotype that serves as the fingerprint for their myeloma to allow for MRD (minimal residual disease) analysis.
They’re not, those samples are just not available. Or they’re not analyzable anymore. So those are, that’s our one barrier. So there are definitely patients that probably would’ve been able to enroll if they had a sample that we could analyze. The other thing is we did find actually some patients with detectable disease during the screening process, and of course, we wouldn’t want to intervene and discontinue therapy for those folks. So that, that makes up a lot of of those patient.
Will this data affect clinician?
I’m really hoping that the data in the end when we’re done analyzing this study with the full 3 years of follow up, is going to influence clinician’s decision making. I think it’s a little too early right now to be able to make concrete conclusions with only a median of 15 months of follow up because what we’re learning at least so far is that, not much happens in the first year for most patients if they’re to discontinue therapy in this setting with no detectable disease. What we really wanna know though, is not just what happens in 1 year, but what happens in 2, in 3 years. Are we headed towards a situation where, patients may be able to take a treatment holiday in this situation, but knowing that they’re probably gonna have to restart treatment at a later point.
Or are there patients who really are cured, who have no detectable disease, they’re off of treatment and enough time has passed in order to be able to say, Hey, they don’t need to be on treatment ever again. And I think that’s what we’re hoping to be able to show is that there is a proportion of patients that meet that cure criteria. But I think it’s too early to be able to say just yet.
What is the next step for this research?
Next steps in terms of what we need to do on this study is, first of all, we need longer time of follow up. We really wanna see what happens in that full 3 years for patients to see, what is the MRD (minimal residual disease) resurgence rate and what is the progression rate that we see. And then we hope that those numbers are very low. We have the 1 year data for at least a good number of patients so far, but we really wanna see the full scope of things. We’re also collecting quality of life surveys in this study, and so as time goes on, we hope to be able to show pre and post discontinuation comparisons.
We’re also doing a formal cost savings analysis. Even with a median of 15 months of follow up. The back of the napkin calculation is that we may have saved upwards of $9 million dollars from stopping Lenalidomide alone with just 15 months of follow up. But, we have to factor in the costs of testing and reinitiating treatment among relapsed patients.
But even then, the cost savings can be immense, especially when they’re applied to a larger, on a larger scale. And then lastly, the holy grail, so to speak in myeloma diagnostics for MRD (minimal residual disease) is really around peripheral blood testing and whether there may be a peripheral blood test that can accurately determine whether patients are, have residual disease or not, and it may spare them a bone marrow biopsy or at least if something is detected, know that would spare them a bone marrow biopsy.
What are the key takeaways from this research and data?
To me, the key takeaways so far from our study is that MRD (minimal residual disease) negativity at the 10 of the minus sixth and even the 10 of the minus seventh level are sustained at a high rate, even after discontinuation of maintenance therapy in patients with multimodal MRD (minimal residual disease) negativity. I think the other key takeaway is that our MRD (minimal residual disease) analysis, using a CD138 selected NextGen sequencing assay using a 10 of the minus seventh in this case is not only feasible, but it may ultimately identify patients who are at a high risk for MRD (minimal residual disease) resurgence or clinical progression if treatment is discontinued.
And I think the other key takeaway away is that, MRD (minimal residual disease) guided discontinuation of maintenance therapy may actually carry significant cost savings if they’re applied more broadly.
There’s a lot of discussion right now about whether MRD (minimal residual disease) testing can be used or should be used to guide decision making in the clinic. And I’ll be the first to tell you even as someone who’s doing a lot of research in this, that we’re still not there yet to make blanket recommendations about that, but understanding the trends for where patient’s disease is, in terms of is there a deepening of response or are we losing response?
And MRD (minimal residual disease) is a great way to measure that, is certainly providing a lot of information, not only to patients, but to clinicians in terms of, whether deescalation of treatment or the thornier side is whether escalation of treatment is necessary. But I think as we get closer and closer towards those answers, understanding of patient’s trajectory is gonna be important and if you do have a good MRD (minimal residual disease) assay, I think it can be very helpful in terms of understanding what we’re gonna be doing for patients in the future.
Ben Derman, MD – About The Author, Credentials, and Affiliations
Dr. Ben Derman, a hematologist and oncologist, has spent his career focusing on multiple myeloma and related plasma cell diseases like monoclonal gammopathy, amyloidosis, plasmacytoma, and POEMS syndrome. To ensure his patients have the best chance of overall survival, he not only diagnoses and treats cancer but also uses innovative procedures like CAR T-cell therapy and stem cell transplantation.
Dr. Derman’s commitment to research through clinical trials has not wavered, despite his busy clinical schedule. He is currently researching potential treatments for multiple myeloma and is particularly interested in the use of minimal residual disease (MRD (minimal residual disease)) assays, which can assist in guiding treatment decisions by determining the absolute number of any remaining cancer cells in the body.
Dr. Derman is also looking at cutting-edge therapies that could have a positive impact on his patients’ well-being (Eg. clinical trials). So that he can better understand and care for people of different races who have multiple myeloma, he also wants to know what causes the different treatment outcomes for people of different races. There are a number of journals that have published his research, including the Journal of Immunotherapy of Cancer, Blood, Blood Advances, Blood Cancer Journal, Leukemia and Lymphoma, and the British Journal of Haematology.
Reference
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MD Anderson Cancer Center – What is minimal residual disease (MRD)? MD Anderson Cancer Center, July 15, 2020