A Review of Methods Being Investigated to Monitor MRD in MM

There are a range of techniques being investigated for the blood-based monitoring of minimal residual disease (MRD) in patients with multiple myeloma (MM) that may overcome the limitations of bone marrow (BM) analysis. Although, blood-based methods are unlikely to achieve the same level of sensitivity, they may help reduce the number of BM samples required from a patient, according to a study published in Clinical Lymphoma, Myeloma, & Leukemia.

“In most patients, the cause of the relapse is residual drug-resistant MM cells,” the authors explained. “Despite multiple options available, most patients eventually become refractory to all available drug classes, so it is critical to monitor patients' remission for signs of disease relapse.”

Clinical trials are using MRD as a surrogate end point to predict patient survival. In addition, there are ongoing investigations into the role of MRD to monitor the duration of maintenance therapy.

Currently, clinical laboratories monitor MRD in MM using BM samples, but there are challenges:

• False negatives are not uncommon, since MM infiltration in BM is patchy
• BM sample quality can be affected by hemodilution
• As disease progresses, plasma cells proliferate outside of the BM
• BM aspiration is traumatic for patients

“Peripheral blood sampling is much less invasive for the patient, potentially leading to earlier detection of relapse due to more frequent sampling and MRD monitoring,” the authors wrote.

Although polymerase chain reaction (PCR) is highly sensitive, it requires patient-specific primers be designed, which “makes it unappealing for use in a clinical laboratory.” In addition, it only applies to approximately 75% of patients, which limits its use for the purposes of MRD monitoring.

Next-generation sequencing (NGS) can sequence entire genomes or targeted regions and is the technique currently being used to detect MRD in the BM of patients with MM. One benefit of NGS is that samples can be stored for batch analysis. However, NGS requires a pretreatment sample, which makes it unsuitable for patients in remission. In addition, it’s one of the more expensive methods.

Matrix-assisted laser desorption ionization time-of-flight mass spectrometry is relatively low cost, can process a lot of samples quickly, and can detect monoclonal free light chains. It does not rival methods that can detect circulating MM cells (CMMCs) as part of MRD monitoring. The method detects M-protein, but since M-protein has a long half-life in serum, there may be a period where malignant plasma cells have been destroyed in the BM, but M-proteins linger.

Finally, next-generation flow cytometry (NGF) is a widely used method to assess MRD and a promising technique to monitor CMMCs. A benefit of NGF is that it does not need a diagnostic sample and is applicable to all patients. One downside is that it needs a fresh sample and data suggest the sensitivity is lower than PCR and NGS.

“Further research is still required to identify ways to improve the sensitivity of blood-based methods for MRD detection in MM and assess their clinical utility,” the authors concluded.

Reference

O’Brien A, O’Halloran F, Mykytiv V. Minimal residual disease in multiple myeloma: potential for blood-based methods to monitor disease. Clin Lymphoma Myeloma Leuk. Published August 2, 2021. doi:10.1016/j.clml.2021.07.032