About MRD

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 relapse^1,2
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 PR^3-6
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).

Abbreviations

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.

References

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.