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.53 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.17,54


Hypothetical curves of depth of response and relapse

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 cell-surface markers expression and genomic architecture.54

2006 2011 2016
The 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.55 Immunophenotypic 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 10-556 In 2006, consensus criteria for response and MRD assessment in MM were published.55


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.
*Requires a CR, which is defined as negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow aspirates.

ASO-PCR, allele-specific oligonucleotide polymerase chain reaction; BM, bone marrow; FC, flow cytometry; IF, immunofluorescence; IHC, immunohistochemistry; MM, multiple myeloma; NGF, next-generation flow; NGS, next-generation sequencing; PC, plasma cells