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Minimal residual disease definition
Minimal residual disease (MRD) refers to the small number of malignant cells below the limit of
detection available with conventional morphologic assessment.68 In multiple myeloma, MRD refers to
myeloma cells that are present in the bone marrow after a clinical response has been measured and the
patient is in remission. These residual myeloma cells are clinically relevant, as they may lead to
disease progression and relapse.20,69
Response criteria in multiple myeloma
The response criteria have evolved over time due to therapeutic advances in multiple myeloma. In 1998,
a conventional complete response (CR) required bone marrow aspirates with less than 5% plasma cells,
irrespective of their clonal nature. Current technology allows for further identification of myeloma
cells by expression of cell-surface markers and genomic architecture.69
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2006The CR rate was refined and expanded to include stringent CR
(sCR), defined as CR plus normal free light chain ratio, and absence of clonal PCs by IHC or IF
method.70
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2011Immunophenotypic and molecular CR were introduced:
Immunophenotypic CR: defined as sCR plus absence of clonal BM PCs with minimum 1 million BM cells
analyzed by multiparametric FC (≥ 4 colors). Molecular CR: CR plus negative ASO-PCR, with a
sensitivity of 10-5.71
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2016In 2016, consensus criteria for response and MRD assessment
in MM were published.69
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International Myeloma Working Group (IMWG) MRD criteria69
| MRD Definition |
IMWG MRD Criteria* |
| Sustained MRD negative |
MRD negativity in the marrow (NGF or NGS, or both) and by imaging as
defined below, confirmed minimum of 1 year apart. Subsequent evaluations can be used to further
specify the duration of negativity (eg, MRD-negative at 5 years). |
| Flow MRD negative |
Absence of phenotypically aberrant clonal plasma cells by NGF on bone
marrow aspirates using the EuroFlow standard operation procedure for MRD detection in multiple
myeloma (or validated equivalent method) with a minimum sensitivity of 1 in 105
nucleated cells or higher. |
| Sequencing MRD negative |
Absence of clonal plasma cells by NGS on bone marrow aspirate in which
presence of a clone is defined as less than 2 identical sequencing reads obtained after DNA
sequencing of bone marrow aspirates using the LymphoSIGHT platform (or validated equivalent
method) with a minimum sensitivity of 1 in 105 nucleated cells or higher. |
| Imaging-positive MRD negative |
MRD negativity as defined by NGF or NGS plus disappearance of every area of
increased tracer uptake found at baseline or a preceding PET/CT or decrease to less mediastinal
blood pool standard uptake value or decrease to less than that of surrounding normal tissue. |
Hypothetical curves of depth of response and relapse15
