MRD Testing With Next-Generation Sequencing Can Guide Treatment of Multiple Myeloma

Gayathri Ravi, MD

Quadruplet induction/consolidation therapy, autologous stem cell transplantation (ASCT), and minimal residual disease (MRD)-informed treatment modification was proven to be feasible and led to similar responses to what has previously been observed in clinical trials, in patients with multiple myeloma.

In patients with newly diagnosed multiple myeloma, MRD is a strong predictor of progression-free survival (PFS) and overall survival (OS). This is especially true in patients who have received ASCT.

According to a presentation at the 64th Annual ASH Meeting, in a clinical academic-community pathway, investigators evaluated the optimal treatment and MRD-based monitoring of patients with NDMM who were eligible for ASCT.

Within research published in Blood, patients with relapsed/refractory multiple myeloma were assessed with the institutional standard for induction therapy with subcutaneous daratumumab 1,800 mg, bortezomib 1.3 mg/m2 days 1,8,15, lenalidomide 25 mg twice a day on days 1-21, and dexamethasone 40 mg twice a day on days 1,8,15,22 of each 28-day cycle.

Among the 69 patients included in this analysis, 59 have reached post-ASCT response assessment. Findings reported at ASH showed the median follow-up was 15.5 months (range, 3.7-27.6) and that MRD testing by NGS was trackable for 61 (88%) patients.

Additionally, 16 of the 42 patients (38%) with trackable MRD and >12 months post initiation of therapy achieved 2 consecutive MRD-negative results 10-5. This ultimately led to subsequent treatment discontinuation and entry into the MRD surveillance phase of the study.

In an interview with Targeted Oncology^TM, Gayathri Ravi, MD, assistant professor at University of Alabama, Birmingham, further discussed these findings, and the role of MRD testing in multiple myeloma.

Targeted Oncology: Can you discuss the study you presented at ASH 2022?

Ravi: Our main objective of the study looked at the reproducibility of the quadruplet induction in the real-world setting. We know the data from clinical trials like GRIFFIN [NCT02874742], but we don't know if that's reproducible in the real-world. That was 1 of the objectives, and the other one was MRD. It's becoming more and more relevant in today's practice of myeloma, so we tried to see how we could apply MRD-adapted treatment management in real-world practice, as well as to see what the feasibility of that is, not just in an academic center, but also involving our community partners.

What were the findings of this research?

The response rates are similar to what was seen in clinical trial setting in terms of response rates, post-induction, post-transplant, and post-consolidation. For MRD, it was similar to what came out of GRIFFIN, ours was 21%. Our primary objective was to look at the MRD data or the feasibility of obtaining it in the real-world setting. We were able to get MRD results in 88% of our study population, which was impressive considering 60% of them were induced in the community. The MRD negativity data were also like the clinical trial setting, which was encouraging as it's applicable in real-world practice.

What role does MRD play in decision making and treating patients with cancer?

MRD is a strong prognostic factor. We do know that people who are not able to achieve MRD negativity have early-risk of progression and relapse. At this time, most of the trials have been conducted during treatment time points to measure MRD to look at post-induction therapy, post-transplant, post-consolidation, and periodically during maintenance therapy, mostly in the trial setting and not outside in the real practice.

What we do not know is if MRD alone is sufficient to decide on discontinuation of therapy, or should we monitor additional parameters in addition to the regular myeloma labs that we measure? If so, how frequently should we measure that, especially when we decide of taking patients off treatment? We do not have data on that, so that is something that is critical, especially if we are looking at MRD-based therapies where we talk about monitoring patients off treatment. Then, we need to know when we need to measure them, how frequently we need to measure them, and what else we need to measure.

What are the next steps for research in this space? What do you expect to see in the future?

The main thing is to find a balance between using an MRD-adapted treatment in the real-world setting. In our study, we offered patients a chance to stop treatment, which has not been done outside of a large-scale clinical trial setting, to look at monitoring MRD. We stopped treatment of patients who achieved MRD negativey 10-5, at 2 different timelines during their treatment scheme. If we were able to achieve that, then we offered the option of cessation of treatment. If they did not achieve that, they would go with standard of care, consolidation, maintenance, down the path that's been in practice.

What we noted was that monitoring MRD was very helpful in the sense that there was an MRD resurgence in only 1 of the patients in whom we stopped treatment for. There was no clear evidence of clinical progression of the disease at that time. We were able to capture the possibility of a relapse sooner, even before it became clinically measurable with the regular myeloma labs monitoring. Every patient wants to be able to come off treatment at some point, which I think in the current myeloma landscape, it's not done yet, or not figured out yet in a complete way. I think the chance that this could offer our patients the possibility of cessation of treatment is what I'm excited about. Again, there's still a lot of fine details that need to be figured out in terms of once we stopped treatment, how we monitor them, how frequently we monitor them, what kind of imaging and what kind of labs in addition to MRD are needed. We don't have answers to that yet.

What are the key takeaways?

The main thing is that it’s possible to engage our community partners because in real-world practice, a majority of our patients get their treatment in the community and come to an academic center for transplant or for a second opinion if multiple lines of treatment have been through. It's important to engage our community partners earlier in the treatment course so that we can reproduce what we can in the clinical trial setting, outside of a trial setting, and in the real-world practice.

What we also found in the study that was useful was engaging the patients in their care. A majority of them do not know what MRD is. Unless we educate on how there is a test like this, it is irrelevant. It can potentially offer you a chance to stop treatment at some point. We don't know if you're going to get there, but there is a possibility of that. Then patients get very involved. In fact, I've had patients come back and ask me, what was my number that you told me was a deeper layer of testing? As a physician, we have to own up and take responsibility for engaging with our patients and our community partners. It's important for us to engage our community partners and patients in their care, so that we can adapt to a rapidly emerging treatment landscape and provide our patients the best of care.

REFERENCE:

Gayathri Ravi, Smith Giri, Susan Bal, Kelly N. Godby, Vishnu V.B. Reddy, Donna Salzman, Omar Alkharabsheh, Scott A. McDaniel, Melissa Sentell, Luciano J. Costa; Induction quadruplet therapy and minimal/measurable residual disease (MRD)-informed treatment adaptation in newly diagnosed multiple myeloma (NDMM): results from an academic-community pathway. Blood 2022;140 (Suppl 1):8048–8049. doi:10.1182/blood-2022-170099