ASCO20 Virtual Scientific Program
Multiple Myeloma Session Roundup: Minimal Residual Disease Assessment and Implications
Several abstracts and posters on minimal residual disease (MRD) in multiple myeloma were presented at the ASCO20 Virtual Scientific Program, in the “Hematologic Malignancies—Plasma Cell Dyscrasia” track. On-demand poster discussion sessions became available at 8 AM ET on Friday, May 29.
Following the presentation, our featured experts, Robert Z. Orlowski, MD, PhD, S. Vincent Rajkumar, MD, and Paul G. Richardson, MD, were interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Their clinical perspectives on this session are presented here.
Clinical Program Leader and Director of Clinical Research
“There is a complexity to MRD that remains to be understood. There is MRD negativity by virtue of disease detection, but there is also what I call MRD negativity of the host. This relates to the immune milieu generated by the patient against their disease.”
With increasingly effective therapies, there has been a considerable focus on the emerging generation tools for MRD assessment. MRD is a critical tool in clinical trials, and it is appropriately gaining prominence as an important secondary end point in research. We would love to see the use of MRD as a primary end point, but we also recognize that there are regulatory challenges to that approach and that the dialogue is very much ongoing. From the patient care perspective, developing MRD technology to be as user-friendly as possible (ie, a blood-based test) would be a huge advantage. Several abstracts and posters on MRD in this session were very favorable and pointed in a positive direction in terms of the technology of MRD assessment.
The caution that I have relates to how MRD influences choices of therapy, recognizing that it is a dynamic measurement that needs to be assessed over time, and not just at one time point. Additionally, our treatments clearly have impact, and maintenance therapy has been shown to increase the rate of negative MRD results, so this is an impact that really matters over time. There is also a complexity to MRD that remains to be understood. There is MRD negativity by virtue of disease detection, but there is also what I call MRD negativity of the host. This relates to the immune milieu generated by the patient against their disease. Nevertheless, MRD assessment is a very exciting, new, and informative clinical tool at the present time, albeit primarily focused in the research space at the moment.
Edward W. and Betty Knight Scripps Professor of Medicine
“The appropriate threshold for MRD in prognostic applications might be different from the threshold that should be used to guide treatment. How to use MRD to take action, and at what threshold, remain to be determined.”
In abstract 8513, MRD assessments in the peripheral blood using mass spectrometry were compared with next-generation sequencing (NGS) in the bone marrow. The authors reported a high degree of concordance between the 2 techniques. This was a small study of only 36 patients; however, it was exciting in that, if developed further, this technology could be quite valuable, since assessing MRD in the bone marrow has the associated challenges of bone marrow biopsy. These assays measure protein products, and something to keep in mind is that the protein may linger long after the myeloma cell that produced it is gone. So, negativity in the peripheral blood may lag behind negativity in the bone marrow.
Another comparative study was presented in abstract 8533, where MRD data for both multiparameter flow cytometry and NGS were analyzed for different therapeutic arms in the FORTE trial. The authors reported good concordance between multiparameter flow cytometry and NGS, but, for me, one of the most significant questions spurred by this study relates to the impact of the MRD sensitivity threshold. Consider the KRd–autologous stem cell transplantation arm. At a sensitivity of 10−5, approximately 70% to 80% of patients were MRD negative, but that percentage fell to approximately 35% at 10−6 with NGS based on evaluable patients.
So, if at 10−6, one finds that roughly 70% of patients are still MRD positive after KRd induction and autologous stem cell transplantation, then what does one do with that information? In other words, MRD is still a research tool, for now. Further, the appropriate threshold for MRD in prognostic applications might be different from the threshold that should be used to guide treatment. How to use MRD to take action, and at what threshold, remain to be determined. The International Myeloma Working Group definition of MRD negativity should be used (ie, where a complete response is required, and, subsequently, MRD negativity in the bone marrow is demonstrated) because comparisons cannot be made if everyone uses their own definition.
Director of Myeloma Section
“The suggestion that a blood-based MRD test will be possible is exciting. I do share the concerns raised regarding use of the MRD data and how to incorporate these data into our clinical practice."
With its mass spectrometry–based MRD assessments in the peripheral blood, abstract 8513 was, to me, the most exciting in this group because it suggests that a blood-based MRD test will be possible. This will certainly be a lot easier for the patient than what we currently do, which is a bone marrow evaluation and then either flow cytometry or NGS. Studies have examined the use of peripheral blood with NGS; however, the sensitivity with this approach is much lower than with NGS of the marrow.
I do share the concerns raised regarding use of the MRD data and how to incorporate these data into our clinical practice. One concern relates to “mission creep.” That is, when a new test becomes available for use in 1 setting, with good indication, that test may also be used elsewhere. Because mass spectrometry is so sensitive, many more patients with monoclonal gammopathy of undetermined significance (MGUS) may be identified. Increased sensitivity may sound like a trivial problem; however, say there are 5 times the current number of patients with MGUS being identified, and these patients presumably have an even lower disease burden than those with conventionally detected MGUS. Further, the symptom burden among patients with MGUS may be substantially higher than one would expect, even though MGUS is considered an asymptomatic condition. Patients with MGUS often have a high level of concern about what their future holds and whether they will progress. I would hate for many more patients to be in this situation, especially as these are the patients who would likely have a much lower chance of progressing compared with those with MGUS who have been diagnosed using the current methods.
Derman BA, Stefka AT, McIver A, et al. Measurable residual disease (MRD) assessed by mass spectrometry (MS) in peripheral blood versus next generation sequencing (NGS) in bone marrow in multiple myeloma treated on phase II trial of KRd+ASCT [abstract 8513]. J Clin Oncol. 2020;38(15 suppl):8513. Accessed May 29, 2020. https://meetinglibrary.asco.org/record/186146/abstract
Gambella M, Omedé P, Spada S, et al. Minimal residual disease by flow cytometry and allelic-specific oligonucleotide real-time quantitative polymerase chain reaction in patients with myeloma receiving lenalidomide maintenance: a pooled analysis. Cancer. 2019;125(5):750‐760.
Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328‐e346.
Kunacheewa C, Lee HC, Patel K, et al. Minimal residual disease negativity does not overcome poor prognosis in high-risk multiple myeloma: a single-center retrospective study. Clin Lymphoma Myeloma Leuk. 2020;20(5):e221‐e238.
Murray D, Kumar SK, Kyle RA, et al. Detection and prevalence of monoclonal gammopathy of undetermined significance: a study utilizing mass spectrometry–based monoclonal immunoglobulin rapid accurate mass measurement. Blood Cancer J. 2019;9(12):102.
Oliva S, Genuardi E, Belotti A, et al. Multiparameter flow cytometry (MFC) and next generation sequencing (NGS) for minimal residual disease (MRD) evaluation: results of the FORTE trial in newly diagnosed multiple myeloma (MM) [abstract 8533]. J Clin Oncol. 2020;38(15 suppl):8533. Accessed May 29, 2020. https://meetinglibrary.asco.org/record/186188/abstract
Patel DA, Gopalakrishnan R, Engelhardt BG, et al. Minimal residual disease negativity and lenalidomide maintenance therapy are associated with superior survival outcomes in multiple myeloma. Bone Marrow Transplant. 2020 Jan 28. doi: 10.1038/s41409-020-0791-y
Perrot A, Lauwers-Cances V, Corre J, et al. Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma. Blood. 2018;132(23):2456‐2464.
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