What is Minimal Residual Disease?

MRD is currently defined as the presence of small amounts of myeloma cells left in the body following the achievement of a complete response (CR) after treatment. MRD testing helps to measure the effectiveness of treatment and can help to predict risks of relapse. MRD status is an important prognostic marker and its potential as surrogate endpoint for progression-free survival currently studied. Several clinical trials are investigating the added clinical value of MRD-guided therapy decisions. Since current MRD testing require invasive procedure (bone marrow aspirates), there is a huge unmet need to monitor MRD on blood.

Why measuring MRD is so important?

A powerful tool for prognosis

MRD negativity is associated with better clinical outcomes. Recent studies have shown a strong correlation between MRD negativity, especially sustained MRD negativity, in patients with CR and prolonged progression free survival (PFS) and overall survival.

Treatment response evaluation

Thanks to recent therapy improvements, high number of patients reach a complete response (CR). However, achieving CR does not necessarily mean that all myeloma cells are gone and the majority of patients face periods of remission followed by relapse. Therefore, major efforts have been made to measure MRD for response evaluation beyond CR.
IMWG (Kumar, 2016) defined consensus criteria to identify responses beyond CR that allows uniform reporting on MRD-status.

Guide for treatment decisions

Several prospective trials are currently looking at the added clinical value of MRD for response-driven treatment decisions.
Since MRD-guided therapy would rely on periodic MRD-monitoring, there is an urgent clinical need for ultra-sensitive techniques such as mass spectrometry (MS) that allow MRD evaluation on blood as a less invasive alternative of MRD-bone marrow evaluation.

MRD testing

The International Myeloma Working Group defines MRD negativity as no myeloma cells being detected in 100,000 cells using Flow cytometry (Next Generation Flow, NGF) or Next Generation Sequencing (NGS).
These techniques require patients to undergo a bone marrow (BM) aspiration or bone marrow biopsy to collect a bone marrow sample. This can be combined with imaging techniques to detect malignant cells outside the bone marrow. BM-MRD testing estimate the myeloma tumor burden by the quantification of cell-based parameters, such as the expression of specific cell surface markers (NGF) or Ig gene rearrangements (NGS).

The result of MRD assessment is either positive, meaning that myeloma cells are detected, or negative, meaning that myeloma cells are not detected. MRD negativity indicates a very deep response to treatment. If this deep response is maintained over time, with repeat MRD testing, patients will on average, have longer periods of remission and overall survival. MRD testing may require repeat bone-marrow aspiration and/or biopsy which can negatively impact a patient’s quality of life. It can also result in false negative results due to hemodilution or extramedullary disease. MRD timepoints are therefore limited and sometimes are missing.

Next Generation Sequencing

Next Generation Sequencing is a bone marrow -based MRD testing.
Each B- or T-cell receptor is coded by unique DNA sequences made of 3 segments—Variable, Diversity, and Joining (VDJ)—that serve as DNA “barcodes” that can be used to track malignant cells.
NGS identifies and quantifies unique B- and T-cell receptors associated with the malignant clone.
The IMWG defines MRD-negative as the absence of clonal plasma cells in the bone marrow aspirate, measured with techniques that have a minimal sensitivity to detect 1 myeloma cell in 100 000 nucleated cells.

Next Generation Flow cytometry

Next Generation Flow cytometry is a bone marrow -based MRD testing.
NGF use distinctive cell surface and cytoplasmic markers for clonal plasma cell detection. These methods allow fast examination of millions of cells (or the corresponding amount of DNA) and provide a quantitative assessment of residual myeloma cells in the bone marrow.
The IMWG defines MRD-negative as the absence of clonal plasma cells in the bone marrow aspirate, measured with techniques that have a minimal sensitivity to detect 1 myeloma cell in 100 000 nucleated cells.

Magnetic Resonance Imaging

Since MM is often a patchy disease and myeloma cells may also grow outside the bone marrow, there is a risk of false negative bone marrow-based MRD test results due to sampling bias. Therefore, the IMWG incorporated imaging in addition to bone marrow evaluation. Magnetic Resonance Imaging is a sensitive, non-invasive imaging technique to detect bone involvement, provide information on soft tissue disease and the pattern of myeloma growth in the bone marrow. Positron emission tomography (PET) imaging is used to assess metabolic activity of tumor cells.
The limitations of PET/CT (computed tomography) are the radiation exposure, the risk of false negative and the lack of standardized criteria for evaluation of disease activity.

IMWG MRD criteria

The International Myeloma Working Group has defined new response categories of minimal residual disease negativity, with or without imaging-based absence of extramedullary disease, to allow uniform reporting within and outside clinical trials.