What Is MRD?

Minimal residual disease (MRD), sometimes called measurable residual disease, refers to a measurement of myeloma cells that remain after treatment. MRD testing allows researchers to more quickly assess treatment effectiveness, which has led to accelerated drug development. MRD is now an endpoint for progression-free survival in many clinical trials.¹

Why Is MRD Assessment Important?

Dr. Jens Hillengass (Roswell Park Comprehensive Cancer Center, Buffalo, NY) delivered a presentation titled “MRD Negativity, Going with the Flow, NGS, Mass Spec, or PET” at ASCO 2021. This presentation was especially compelling in that it included the latest thoughts on this important tool, particularly in regard to comparing the various testing methods and potentially using MRD to guide clinical decision-making.

Dr. Hillengass began by stressing the prognostic importance of MRD testing. MRD-negative patients have the best outcomes, and the higher the sensitivity of the assessment tool, the better the prognosis. MRD can be assessed through bone marrow biopsies, imaging tests, and more recently, a serum (blood) test. As Dr. Hillengass pointed out, different technologies provide different information, and each has advantages and disadvantages.

Methods of Testing MRD

• Bone Marrow Tests

Methods of measuring MRD in bone marrow include next-generation sequencing (NGS) and next-generation flow (NGF). Although both methods are highly sensitive, they require bone marrow biopsies, which are invasive and which most patients dread. Another disadvantage relates to the sample itself. The infiltration of plasma cells in the marrow can be “patchy,” meaning that biopsies taken from different areas could yield different plasma cell percentages.

In 2020, Dr. Alejandro Medina and colleagues compared results obtained using NGS and NGF in 106 patients and found a high correlation between the two methods.² However, there are differences between the two. Although NGS tests do not require fresh bone marrow samples, a diagnostic baseline sample is needed to identify clones for comparison with subsequent samples. NGF testing does not require a baseline sample, but it does require a fresh sample for testing. NGF has a shorter turnaround time than NGS.³

• Imaging: MRI vs. PET

“Use of newer imaging techniques is changing the whole landscape, from diagnosis to treatment to supportive care to survivorship…”

—Dr. Jens Hillengass

In 2019, Dr. Hillengass led the International Myeloma Working Group in developing a new set of guidelines for imaging techniques. These guidelines are helping to improve disease detection, which leads to earlier treatment. Furthermore, the guidelines are important in meeting the need for sensitive imaging techniques that accurately assess treatment response.⁴

Bone marrow biopsies are nearly always done in the iliac crest, but myeloma can be found in other areas of the body. Imaging helps identify those areas. Unlike bone marrow biopsies, imaging is not invasive. Imaging shows the whole body, which means that heterogeneity, or patchiness, is not a concern as it is for NGF and NGS.

PET scans require an intravenous injection of a tracer that includes glucose and a small amount of a radioactive drug. Because cancer cells are metabolically more active and take up more glucose than normal cells, the scan helps identify active areas of myeloma. PET is often combined with computed tomography (CT) for attenuation correction, which removes soft tissue artifacts, providing better image quality. PET-CT is currently the most frequently used imaging method for evaluating focal lesions and assessing response to treatment.

MRI has a high sensitivity for bone marrow infiltration, especially when combined with a special technology called diffusion-weighted imaging (DWI). Diffuse infiltration of plasma cells correlates well with plasma cell percentage in the bone marrow. However, MRI mostly shows cellularity, which can include healthy bone marrow cells as well as myeloma cells. (Cellularity refers to the ratio of cells to fat; a normal ratio varies with age.) In comparing the two types of imaging, Dr. Hillengass showed that MRI and PET are nearly equal in sensitivity for nodular infiltration patterns, but that MRI is more sensitive for diffuse infiltration.  In myeloma, diffuse infiltration is more prognostically significant. At this time, DWI is used primarily in research but is expected to enter clinical practice in the near future.

Although imaging is not as sensitive as bone marrow tests, it is important in detecting areas of disease outside the bone marrow.

• Mass Spectrometry

Perhaps the most exciting news in MRD testing relates to mass spectrometry. Monoclonal plasma cells produce monoclonal proteins, which can be measured in the blood or urine. Mass spectrometry is a highly sensitive blood-based test that measures the molecular mass of specific molecules in a blood sample.

There are several advantages to mass spectrometry. It is less invasive than bone marrow-based NGS and NGF tests, requiring only a blood draw. It is easily repeated, which allows for more frequent monitoring, and it is highly sensitive. Moreover, mass spectrometry overcomes the disadvantage of the patchy bone marrow because it shows the distribution of the monoclonal protein in the peripheral blood.

Despite these advantages, bone marrow tests will likely remain standard, at least for the next few years. Mass spectrometry is not readily available in most centers. Additionally, depending on how it is used, bone marrow may provide details that are not possible with other tests. For example, when questioned about the value of bone marrow testing, Dr. Hillengass replied that researchers are beginning to look into cells of the immune system, which are crucial to keeping low levels of myeloma cells under control, and for now, those seem to be better assessed in the bone marrow.

Results from a recent study at Memorial Sloan-Kettering suggest that mass spectrometry is currently most useful as a partner for bone marrow-based MRD testing and as a tool for detecting early relapse.⁵

Implementing MRD Into Clinical Decision Making

“The use of MRD in decision making is by far the most controversial aspect of MRD in MM.”

          —Dr. Ben Derman, University of Chicago Medical Center

 

As Dr. Hillengass pointed out in his presentation, MRD negativity is not a cure. But can it be used as a guideline to avoid over-treatment and unnecessary toxicity? Dr. Hillengass spoke of a recent study by Dr. Ben Derman and colleagues that investigated the impact of adding Elotuzumab, a monoclonal antibody, to a triplet induction regimen. The quadruplet combination resulted in deep responses, and treatments were de-escalated earlier for patients who reached MRD negativity. This MRD-guided treatment design demonstrated the feasibility of using MRD testing for decision-making in de-escalating therapy for patients who achieve deep responses.⁶

Another question pertains to MRD-negative patients who become MRD-positive. Rasmussen and colleagues explored the question of how to respond when MRD reappears. The investigators mention two small studies indicating that MRD reappearance precedes biochemical relapse by four months and clinical relapse by nine months. Further research is needed to determine if early intervention prevents the development of treatment-resistant clones and an increase in tumor burden.⁷

Members of the Spanish Myeloma Group explored the concept of implementing MRD into clinical decisions, concluding that it may currently be safer to make decisions based on persistent MRD than on undetectable MRD. However, examples were cited from numerous MRD-guided clinical trials that illustrate the potential for using MRD in making decisions regarding transplant, intensity and duration of treatment, and the use of newer drugs, such as monoclonal antibodies and second- or third-generation proteasome inhibitors.⁸

What about the many patients who do well despite being MRD-positive? Some patients have benign clones or unique immune features that allow them to do well in spite of persistent MRD positivity.⁸ Patients in this category are often assured by their specialists that there is no advantage in increasing the toxicity of treatment by pushing toward MRD negativity.

Most clinicians are not yet ready to use MRD testing as a tool for making treatment decisions. Concerns include timing, cost, depth of testing, MRD as a surrogate endpoint, and unknown utility.⁹ Can MRD identify patients who might not need transplants? Should treatment be intensified for a patient who is MRD-positive or decreased for an MRD-negative patient? Is it safe to stop treatment for a patient with sustained MRD negativity? These questions are being explored in clinical trials, and it is hoped that the answers will lead to more personalized treatment, better outcomes, and potentially, a cure.

Summary

“MRD has now arrived in multiple myeloma.”  

                                     —Dr. C. Ola Landgren

MRD is probably the most important prognostic factor in multiple myeloma, but questions remain on how it can best be used in clinical practice. Research has clearly shown that MRD has more prognostic value than complete response. It is relevant for both standard- and high-risk patients, and it is reproducible, meaning that results are consistent across centers regardless of whether NGF or NGS is used.

Considerations in assessing MRD include, as Dr. Hillengass points out, sensitivity, invasiveness, and reproducibility. In addition, a sustained response is important. MRD is accepted as an endpoint for clinical trials, but further work is needed to more clearly demonstrate its use as a decision-making tool in clinical practice.

REFERENCES

1. Avet-Loiseau H, Corre J, Lauwers-Cances V, et al. Evaluation of minimal residual disease (MRD) by next-generation sequencing (NGS) is highly predictive of progression-free survival in the IFM/DFCI 2009 trial. Blood. 2015;126(23):191. doi:10.1182/blood.V126.23.191.191

2. Medina A, Puig N, Flores-Montero J, et al. Comparison of next-generation sequencing (NGS) and next-generation flow (NGF) for minimal residual disease (MRD) assessment in multiple myeloma. Blood Cancer J. 2020;10(10):108. doi:10.1038/s41408-020-00377-0

3. Chng WJ. Next-generation sequencing vs. flow in MRD testing. Which is better? Myeloma360. https://myeloma360.com/next-generation-sequencing-vs-flow-in-mrd-testing-which-is-better/. Published June 26, 2018. Accessed June 13, 2021.

4. Hillengass J, Usmani S, Rajkumar SV, et al. International myeloma working group consensus recommendations on imaging in monoclonal plasma cell disorders [published correction appears in Lancet Oncol. 2019 Jul;20(7):e346]. Lancet Oncol. 2019;20(6):e302-e312. doi:10.1016/S1470-2045(19)30309-2

5. Eveillard M, Rustad E, Roshal M, et al. Comparison of MALDI-TOF mass spectrometry analysis of peripheral blood and bone marrow-based flow cytometry for tracking the measurable residual disease in patients with multiple myeloma. Br J Haematol. 2020;189(5):904-907. doi:10.1111/bjh.16443

6. Derman BA, Zonder JA, Kansagra AJ, et al. Interim analysis of phase 2 minimal residual disease (MRD)-adaptive trial of elotuzumab, carfilzomib, lenalidomide, and dexamethasone (Elo-KRd) for newly diagnosed multiple myeloma (MM). J Clin Oncol. 2021;39(15_suppl):8011. doi:10.1200/JCO.2021.39.15_suppl.8011

7. Rasmussen AM, Askeland FB, Schjesvold F. The next step for MRD in myeloma? Treating MRD relapse after first-line treatment in the REMNANT study. Hemato. 2020; 1(2):36-48. doi:10.3390/hemato1020008

8. Burgos L, Puig N, Cedena MT, et al. Measurable residual disease in multiple myeloma: ready for clinical practice?. J Hematol Oncol. 2020;13(1):82. doi:10.1186/s13045-020-00911-4

9. Derman BA, Jasielec JK, Jakubowiak AJ. Clinician attitudes and practices toward measurable residual disease in multiple myeloma. Br J Haematol. 2020;190(3):470-472. doi:10.1111/bjh.16805