MRD: Lingering Posttreatment Malignant Cells That May Eventually Cause Relapse
- MRD describes the low level of malignant cells that persist in the bone marrow after treatment but cannot be detected with conventional outcome measures and which eventually lead to relapse1,2
- A patient who is MRD negative has achieved clinical remission with the absence of aberrant clonal cells by NGF or NGS per at least 100,000 nucleated cells2
- Even patients in CR may remain MRD+, if residual malignant cells are detected on a test sample. Studies have shown that patients in CR with persistent MRD have outcomes on par with patients in PR3-6
- Current IMWG criteria for MRD- defines the threshold as a minimum sensitivity of 10-5, although as testing has improved it has become increasingly common to establish MRD- at a threshold of 10-6 2,7
Defining MRD per IMWG response criteria2
HIGHEST Detectable tumour burden in blood and bone marrow LOWEST
SD: Stable disease/no change
Not meeting criteria for CR, VGPR, PR, minimal response, or progressive disease
PR: Partial Response
- A ≥ 50% reduction of serum M-protein and reduction in 24h urinary M-protein by ≥ 90% or to <200 mg/24 h
- If serum and urine M-protein are unmeasurable, a ≥ 50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria
- If serum and urine M-protein and serum-free light assay are unmeasurable, a ≥ 50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥ %30
- In addition to the above listed criteria, if present at baseline, a ≥ 50% reduction in the size of soft tissue plasmacytomas is also required
VGPR: Very Good Partial Response
Serum and urine M-protein detectable by immunoflixation but not on electrophoresis or ≥ 90% reduction in serum M-protein plus urine M-protein level < 100 mg/24 h
CR: Complete Response
Negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas, and < 5% plasma cells in bone marrow aspirates
sCR: Stringent Complete Response
CR plus normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry
MRD-a: Minimal Residual Disease Negativity
- 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 <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 plus 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 SUV or decrease to less than that of surrounding normal tissue
Sustained MRD-b: Sustained Minimal Residual Disease Negativity
MRD negativity in the marrow (NGF or NGS, of both) and by imaging as defined on the previous slide, confirmed minimum of 1 year apart. Subsequent evaluations can be used to further specify the duration of negativity (eg, MRD-negative at 5 years)
aRequires a CR.
bSustained MRD negativity when reported should also annotate the method used (eg, sustained flow MRD-negative, sustained sequencing MRD-negative).
CR=complete response; FLC=free light chain; IMWG=International Myeloma Working Group; M-protein=myeloma protein; MRD=minimal residual disease; MRD-=minimal residual disease negativity; MRD+=minimal residual disease positivity; NGF=next-generation flow; NGS=next-generation sequencing; PET/CT=positron emission tomography–computed tomography; PR=partial response; sCR=stringent complete response; SD=stable disease; SUV=standardised uptake value; VGPR=very good partial response.
- Kostopoulos IV, Ntanasis-Stathopoulos I, Gavriatopoulou M, Tsitsilonis OE, Terpos E. Minimal residual disease in multiple myeloma: current landscape and future applications with immunotherapeutic approaches. Front Oncol. 2020;10:860.
- Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328-e346.
- Burgos L, Puig N, Cedena M-T, et al. Measurable residual disease in multiple myeloma: ready for clinical practice? J Hematol Oncol. 2020;13(1):82.
- Munshi NC, Avet-Loiseau H, Rawstron AC, et al. Association of minimal residual disease with superior survival outcomes in patients with multiple myeloma: a meta-analysis. JAMA Oncol. 2017;3(1):28-35.
- Lahuerta J-J, Paiva B, Vidriales M-B, et al. Depth of response in multiple myeloma: a pooled analysis of three PETHEMA/GEM clinical trials. J Clin Oncol. 2017;35(25):2900-2910.
- Martinez-Lopez J, Wong SW, Shah N, et al. Clinical value of measurable residual disease testing for assessing depth, duration, and direction of response in multiple myeloma. Blood Adv. 2020;4(14):3295-3301.
- Dimopoulos MA, Moreau P, Terpos E, et al. Multiple myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32(3):309-322.
Importance of MRD
See why MRD negativity may be the most powerful indicator of long-term outcomes1-6
The Future of MRD
Is MRD negativity the new standard for measuring depth of response?1,2,7