MRD Testing in Multiple Myeloma

Multiple myeloma is a cancer of the plasma cells that affects about 160,000 people in the United States per year.¹ Traditionally, the established way to measure treatment response in multiple myeloma has been via the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma. More recently, measurable residual disease (MRD) has gained traction as a compelling marker for disease status across various hematologic malignancies, including multiple myeloma. MRD indicates the amount of detectable cancer cells within a particular number of total bone marrow cells. For instance, if a sample is deemed MRD-negative by an assay with a sensitivity of 10^-6, this means that no cancer cells were identified in a sample with at least 1,000,000 bone marrow cells.²

In multiple myeloma, MRD-negativity after treatment is associated with significantly longer progression-free and overall survival compared to MRD-positivity. Even in patients who achieve a complete response to treatment by traditional IMWG criteria, MRD status can further discern differences in survival. Since the goal of multiple myeloma treatment is to induce the deepest response, MRD is uniquely suited to help evaluate the depth of that response. For these reasons and more, experts note that MRD is the most reliable marker of treatment response in patients with multiple myeloma.

Moreover, patients have reported that it is important to them to know their MRD status; being MRD negative can provide a great sense of relief for a patient. A convenient way to measure MRD is by using the clonoSEQ^® assay, an FDA-approved test in lymphoid malignancies that uses next-generation sequencing technology. clonoSEQ is readily available throughout the U.S. and covered by many payers.³

In clinical practice, MRD can be used alongside other response assessments to help inform clinical decision-making in patients with multiple myeloma. For example, if a patient who has been in long-term complete response presents with fatigue, diarrhea, or other side effects of treatment and has sustained MRD-negativity, the oncologist may be more reassured to stop therapy, in comparison to if the patient were MRD-positive. This is one strategy in which MRD testing can be effectively used in the community setting.

Another strategy is to monitor MRD during routine follow-up for disease status after transplantation at an academic center. In this way, community cancer programs have essential roles in care coordination and long-term follow-up in the journey of a patient with multiple myeloma. For instance, one oncologist discusses stopping maintenance therapy in a standard-risk patient with an MRD-negative status and poor tolerability to treatment.⁴ During routine follow-up two years later, the patient’s MRD status showed a low level of residual disease, but the patient was otherwise in complete response.⁴ Subsequent MRD testing frequency was increased to every six months, and clinical relapse was ultimately noted six months after the initial MRD-positive result.⁴ Routine MRD testing in this patient allowed for faster detection of relapsed disease.⁴

A question that remains is what duration of negativity supports treatment discontinuation. Some oncologists believe that three years of sustained negativity is a good standard to consider treatment de-escalation and potential cure.⁵ Many trials addressing discontinuation of therapy are ongoing with some beginning to show encouraging results. Furthermore, additional research is needed to determine the ideal sensitivity threshold that counts as MRD-negative status.⁶ Important factors to consider regarding the implementation of MRD testing for multiple myeloma include when testing should be performed and if there is a potential treatment change based on the MRD result. Now is the time to focus on operationalizing MRD testing across all avenues of care as its utility continues to grow.

Learn more about MRD testing in multiple myeloma on this CANCER BUZZ podcast. The podcast and this blog are part of the MRD Testing Implementation Roadmaps education project funded by Adaptive Biotechnologies.

References

1. National Cancer Institute: Surveillance, Epidemiology, and End Results Program. Cancer stat facts: myeloma. Accessed June 2, 2022. seer.cancer.gov/statfacts/html/mulmy.html

2. Bal S. Assessment of measurable residual disease (MRD) in multiple myeloma: a review of the data. Clin Adv Hem Oncol. 2020;supp 1(1):3-10. https://pubmed.ncbi.nlm.nih.gov/33843860/

3. Adaptive Biotechnologies. ClonoSEQ by Adaptive. Accessed May 30, 2022. clonoseq.com 

4. ClonoSEQ. Multiple myeloma: adult patient. Published 2021. Accessed June 3, 2022. clonoseq.com/wp-content/uploads/2021/11/PM-US-cSEQ-0075-2_clonoSEQ_Branded_MyelomaCase_ClinicalRelapse6mo_WEB.pdf

5. Davies F, Usmani SZ. Is MRD testing worthwhile in myeloma? Published July 2017. Accessed June 3, 2022. ashpublications.org/ashclinicalnews/news/3223/Is-MRD-Testing-Worthwhile-in-Myeloma

6. Multiple Myeloma Research Foundation. Advances in MRD testing in myeloma 2019: meeting summary. Published October 30, 2019. Accessed June 3, 2022. themmrf.org/2019/10/30/advances-in-mrd-testing-in-myeloma-2019-meeting-summary/