Using MRD Negativity to Discontinue Maintenance Treatment in Multiple Myeloma

Ben Derman, MD

Discontinuation of maintenance therapy and multimodal minimal residual disease (MRD) negativity led to a high rate of sustained MRD-negativity and lack of disease progression in patients with multiple myeloma, according to the prospective MRD2STOP study (NCT04108624).

In the study, patients who had received at least 1 year of maintenance therapy, were in a complete response with MRD negativity by PET/CT, and by either flow cytometry or next-generation sequencing (NGS) at a sensitivity of at least 10^-5 in the bone marrow were enrolled.

Patients underwent peripheral blood testing every 3 months, and bone marrow MRD testing and PET/CT assessments yearly for 3 years. MRD by NGS was assessed using the clonoSEQ Assay. A total of 38 patients met protocol eligibility criteria and discontinued maintenance therapy.

The median follow-up among those enrolled was 14 months and of the 38 patients, 34 (89%) remained on study while 2 experienced disease progression and another 2 withdrew from the study due to relocation and lack of insurance. Five of the patients had MRD resurgence at the 10^-6 threshold, and the rate of sustained MRD-negativity at 12 months was 21/25 (84%).

Of the patients who had baseline MRD assessments that were negative by the standard 10^-6 assay and who had a paired CD138-enriched sample analyzed, only 4 patients had the CD138-enriched assay detected disease. Four of the 5 patients had MRD resurgence at the 10^-6 threshold using the standard assay, including 2 patients who experienced disease progression.

To date, these results show that MRD that is assessed using the clonoSEQ assay with CD138-enrichment may be helpful when identifying patients who can discontinue therapy.

In an interview with Targeted Oncology^TM, Ben Derman, MD, assistant professor of medicine at the University of Chicago Medical Center, discussed data from an ongoing clinical trial evaluating MRD-guided discontinuation of maintenance therapy in patients with multiple myeloma.

Targeted Oncology: Can you discuss your trial regarding MRD negativity in myeloma?

Derman: We call this a prospective trial using multimodal MRD negativity to guide discontinuation of maintenance therapy in myeloma. The idea is based on the fact that MRD is measurable, and we know it has strongly been associated with improved prognosis in myeloma. More importantly, MRD negativity at a depth of what we call 10^-6 or detecting 1 clonal myeloma cell within a million cells in the bone marrow, we know that that carries superior prognosis over less-sensitive thresholds. So, we've arrived at a good problem in myeloma. We have lots of therapies that can induce and sustain MRD negativity, including maintenance therapy, which involves a single agent, drug, usually lenalidomide, and lenalidomide can convert patients who haven't reached MRD negativity to get there or can sustain that.

The problem is, we don't know when to stop lenalidomide, if ever. The standard of care in the United States is generally to continue indefinitely. This impacts quality of life, it can lead to second cancers, which is a major concern for our patients, long term, and it carries significant financial toxicity. The question for this trial came from patients because they were constantly asking us how we can, or can we stop treatment at some point? What we set out to answer is, can this multimodal sustained MRD negativity guide discontinuation of maintenance therapy in myeloma. When I say multimodal, what I mean is using the different tools at our disposal that are available in the clinic right now as part of a standard of care approach to guide discontinuation.

Can you explain the design of the trial? What actions were performed?

We took patients who were in complete response, we took patients who had already known to be negative, no detectable disease by a PET scan, and who had been on maintenance for at least 1 year. What we did is we performed MRD testing in the bone marrow. We did imaging with a PET scan. The MRD testing in the bone marrow specifically focused on using clonoSEQ or the next generation sequencing to tell us if a patient had detectable disease at that 10^-6 threshold. Patients who were negative or undetectable for disease at that threshold, and who had no detectable disease by PET scan, were permitted to undergo discontinuation of their maintenance therapy on protocol. Then they were followed every 3 months with bloodwork and clinical visits, and then every year with MRD surveillance for 3 years by a bone marrow biopsy and aspiration testing. We do those same tests throughout the study.

We've added some exploratory evaluations called MRD at 10^-7, which at present, is not feasible. It's not because we can't get enough cells from the bone marrow as we can get upwards of 10 or 20 million cells from the bone marrow. The problem is, we don't know how to analyze that. Part of what we did in this study that I think is novel is we took the same clonoSEQ assay, but instead of trying to fit more than 10 million cells in there, we filtered out and we selected just the CD138-positive cells. These are the plasma cells in the sample typically. We created the CD138-positive enrichment sample from a much larger sample from the bone marrow aspirant with the hopes that it would be able to better detect disease compared to the 10^-6 assay.

What were some of the eligibility criteria for the trial and who was enrolled?

We have 38 patients who met eligibility and discontinued therapy. Looking at the demographics of our patients, I think it is representative of a myeloma population. Their median age was 66, we had 18% Black, 11% Hispanic enrollment, and 39% had a high-risk disease by some fashion in some manner. Most patients, 95%, were what we considered to be in their first-line of therapy, meaning they had never had disease progression at any point in their disease. About 2/3 had a prior transplant, stem cell transplant, and the majority, about 79%, had multiple drugs before going into maintenance. We call it multi-drug consolidation. The majority of patients, 95%, were on lenalidomide maintenance. When you factor in the amount of time spent on consolidation and maintenance therapy, the median was about 42 months for patients, so 3 and a half years, for the most part, after a transplant or induction while they were on treatment.

What were some of the findings from the trial?

We only have 15 months of follow-up so far on the study, but of the 38 patients who enrolled, we had 2 who had disease progression, 1 at 12 months, 1 in 18 months, and both were what we call biochemical progression. They didn't have bone disease, they didn't have new fractures, and these were patients that just had lab parameters showing progression. Fortunately, we've had 0 deaths. Of those 38 patients, we had 5 patients who had MRD resurgence at 10^-6, meaning they went from MRD-negative to MRD-positive at some point in this study. Only 2 of those 5 patients had disease progression.

What's interesting about this is the fact that 4 out of those 5 patients who had MRD resurgence were found to have detectable disease using our 10^-7 assay. That suggests that this 10^-7 assay is not only feasible, but may be able to tell us who should not discontinue, because if you have a detectable disease on that assay, it might be telling us that something is not right here. There's still some small amount of disease that we wouldn't have been able to detect using the 10^-6 assay.

Thinking about it another way, if you take those 38 patients who were all MRD-negative at 10^-6 from the start, 4 of those patients were 10^-7 positive and all of those patients converted to MRD positivity or had disease progression at 12 months, which I think is telling. Even when you look at the number of patients who've reached the 12 month mark, we had 25 patients who either reached the 12 month mark or had progression. Basically, 21 out of 25 remained MRD-negative at 10^-6, and when you look at the 10⁷ threshold, we had 20 out of 21 or 95%, who were MRD-negative still at the 10^-7 threshold. What we're seeing still are high rates of sustained MRD negativity 12 months after discontinuation.

What are the next steps based on the implication of these findings?

What's going to be important is to see what happens beyond a year, what happens at 24 months, what's going to happen at 36 months, and try to see, is 10-6 negativity going to be able to tell us who can actually come off of therapy safely without worrying about their disease coming back? That may help us define patients who may be cured of their myeloma, which is a controversial concept. I think what's encouraging is the fact that when you think about $18,000 a month for lenalidomide in the United States and you multiply that by 507 months of observation that we had just in this short follow-up on the study, we saved about $9 million dollars from stopping lenalidomide alone. Now, you have to factor in the cost of testing and reinitiating treatment and patients who relapse, but that's still going to lead to significant cost savings on the order of millions of dollars.

What we're looking for is longer follow-up. We are collecting quality-of-life surveys that we hope to be able to share soon, do a formal cost savings analysis, and try to incorporate some peripheral blood tests that might be able to help circumvent the need for bone marrow biopsies in the future.

What are your key takeaways from this research?

The key thing that I'm taking away from the study even at an early point is that MRD negativity at both 10^-6 and 10^-7 can be sustained at a high rate, even after discontinuation of maintenance therapy in patients who have this multimodal MRD negativity. From the experimental side, we're learning that this MRD analysis using a CD138 selected approach, what we call 10^-7 with the NGS assay through clonoSEQ, is not only feasible, but helped to identify patients who are at a high-risk for MRD resurgence or clinical progression, if the treatment was going to be discontinued.

What unmet needs still exist in this space?

In my own clinical practice, I'm a bit of an iconoclast in the sense that I've already started to use MRD to guide decision making which in myeloma, has not been proven yet. What we're hoping to show with this study is that you can do that. Primarily, the way I'm using it is in de-escalation. Here I've shown what you do if somebody is on single-agent maintenance therapy and they want to try to figure out a pathway to get off of therapy. The similar situation is a patient who is on multiple drugs as maintenance therapy, which happens sometimes in myeloma, especially patients who are considered to have high-risk disease. They might have reached the same level of MRD negativity as some of these other patients just on a single-agent.

The question is, do they have to be on both of these drugs forever? I've been starting to use MRD negativity to help guide that decision with patients by having a nuanced discussion with patients about whether it's advisable, safe, and worthwhile to start dropping certain drugs over time, and using it as a way to help guide our conversation. I'm clear with the fact that we don't know how this is going to work or if there is evidence to support this. We know that there's no evidence to support this yet, but I'm hoping that as time goes on, we're going to be able to accumulate that.

On the other side of the same coin, are we at a point where MRD positivity does not go away or that's persistent, is that the new biochemical progression? Should we be considering that as a way to escalate treatment in some patients? That has significant implications, cost implications, because you're going to be spending more money on treatment. It has implications for the patient's quality-of-life, because you're going to be adding more drugs. That is not a place where we have any data to guide us yet either. It's not something that I'm doing yet in clinical practice, but I think it is right for answering in a clinical trial setting to see if patients who have sustained MRD positivity may actually benefit from escalation of therapy.

REFERENCES:

Derman B, Major A, Major S, et al. Prospective trial using multimodal measurable residual disease negativity to guide discontinuation of maintenance therapy in multiple myeloma (MRD2STOP). Presented at: 2022 ASH Annual Meeting; December 10-13, 2022; New Orleans, LA. Abstract 870