Improving Patient Outcomes

As treatments lead to deeper and more sustained responses, new markers for measuring and predicting treatment response that are more sensitive than current endpoints are required.[1]

This page will explore minimal residual disease (MRD), which is currently being investigated as a potential surrogate endpoint for survival outcomes in clinical studies.[2]

MRD – the unseen burden after treatment

Despite achieving a complete response (CR) following induction therapy, some patients with multiple myeloma (MM) subsequently go on to relapse with poor outcomes – suggesting that some residual disease remains. This minimal residual disease is known as MRD.[3]

New, sensitive methods for detecting MRD at a very low level are needed.[2]

Clinical relevance of MRD

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Current recommendations for MRD assessment

The MRD-negativity threshold defines undetectable disease. In the updated International Myeloma Working Group response criteria for MM, MRD negativity is defined as the absence of clonal plasma cells in bone marrow aspirates at a minimum sensitivity of 1 in 100,000 (105) nucleated cells or higher, in patients who have achieved a CR.[4]

The MRD-negativity threshold is considerably more sensitive than the criteria for CR, which requires negative immunofixation in the urine and serum, disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow aspirates.[4]

MRD negativity

Imaging negative criteria provide a measure of disease outside of the bone marrow – requiring the disappearance of positive lesions seen on baseline or previous positron emission tomography/computed tomography (PET/CT) scans.[4]

If MRD negativity can be shown both inside, using next-generation sequencing (NGS) or next-generation flow (NGF), and outside (using imaging) of the bone marrow, and can be confirmed by assessments at least one year apart, it is considered to be sustained.[4]

MRD testing over time may provide the best assessment of a sustained response; however, the optimal timing and frequency of MRD evaluation is still under investigation.[4]

Sensitivity and specificity

To detect MRD at levels of one cell in 10⁵–10⁶, tests with high sensitivity and specificity are required.[4]

NGS or NGF are recommended for the assessment of MRD in bone marrow aspirates at the minimum threshold of 1 in 105 cells. Flow cytometry is another commonly used technique for evaluating MRD in bone marrow samples.[4]

Sensitivity graph

Adapted from Kumar et al. 2016[4] and Paiva et al. 2015[5]

Current MRD assessment techniques

Current MRD assessment techniques, such as NGS or NGF, analyse cells collected from bone marrow biopsy or aspirate.[4] The procedures to obtain bone marrow biopsies and aspirations are painful for the patient and, as they are taken from a single site, may not reflect the heterogeneous nature of MM and result in false-negative results. Mass spectrometry analysis of M-protein as a way to measure MRD is being considered using peripheral blood samples, and in some cases bone marrow samples.[6]

MRD negativity is associated with improved survival

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MRD negativity supersedes CR

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MRD in the future

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Find out more

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CP-275046 - May 2022