Minimal residual disease (MRD) is being used more frequently in clinical trials and to identify the best treatment course for patients, but unknowns remain about the optimal use of MRD testing.
Achieving minimal residual disease (MRD) negativity is an independent prognostic factor for survival in multiple myeloma (MM); however there remain questions about the optimal use of MRD. In a review published in Pathology, the journal of the Royal College of Pathologists of Australasia, researchers outlined implementation challenges, standardization across laboratories and clinical trials, and the integration of MRD assessment into the management of MM.
While the majority of patients with MM respond to initial treatment and complete response (CR) rates exceed 70%, CR is a temporary state before patients relapse. “This indicates the presence of low-level persisting disease, which later emerges as clinical relapse in the absence of ongoing treatment,” the authors explained.
MRD status has been used to identify patients in CR with a deeper treatment who will have a superior survival, and more clinical trials are integrating MRD status as a secondary outcome. As a result, the International Myeloma Working Group (IMWG) introduced in 2016 a definition of MRD and recommendations for response assessment. MRD measurement methods and clinical integration continue to be refined, however.
Some of the questions that remain are whether MRD negativity can overcome negative prognostic factors; whether a multimodal, whole body approach to assessment can be used; and if the timing of when MRD negativity is reached matters.
For clinical decisions, such as who is likely to benefit from autologous stem cell transplant, the depth of MRD negativity is key and “assay sensitivity is critical,” the researchers wrote. Therefore, clinical trials should report assay sensitivity because studies “have demonstrated superior discrimination of PFS [progression-free survival] at the level of 10−6 compared with 10−4 or 10−5.”
Standardization between laboratories is becoming more important as MRD status is adopted as a primary end point in trials and even as an alternative to PFS for drug approvals.
“The need for comparison between sites also means that harmonised MRD assays should be widely accessible whether through a reference laboratory model or through on-site testing; a test available only in tertiary referral centres will be less useful for clinical translation,” the authors explained.
When to perform MRD testing is not clear, and the optimal time is likely dictated by tumor response to treatment. Although the IMWG recommends performing an MRD test once the patient achieves CR, patients receiving 4-drug regimens or chimeric antigen receptor T-cell therapy may achieve CR months after MRD negativity occurs. For those treatments, MRD testing might be better when the patient achieves a very good partial response.
Finally, cost of MRD testing remains an issue as it varies between countries and may mean testing is only preferred at certain centers.
“As shown by integration into active clinical trials, MRD assessment will only increase in relevance for MM in the upcoming years, as our ability to define its optimal use in clinical decision making continues to be refined,” the authors concluded.
Maclachlan KH, Came N, Diamond B, et al. Minimal residual disease in multiple myeloma: defining the role of next generation sequencing and flow cytometry in routine diagnostic use. Pathology. Published online March 3, 2021. doi:10.1016/j.pathol.2021.02.003