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25.3.5. Consensus criteria for response and minimal residual disease assessment in multiple myeloma (2016)

Chapter 25
Section Contents

Consensus criteria for response and minimal residual disease (MRD) were published in 2016 [905], a decade after IMWG recommendations for the uniform reporting of clinical trials were first published [584][115][21]. These new criteria, summarised in Table 25.4, define new minimal residual disease response categories (for patients who have achieved a complete response), that are based on flow cytometry, gene sequencing or imaging techniques. It is proposed that all future clinical trials in MM should follow these guidelines when reporting results.

Required baseline and follow-up tests for response assessment using IMWG consensus criteria

The κ/λ sFLC ratio is required for all patients to define a stringent CR. It should also be performed for all patients at suspected CR as well as at suspected clinical or biochemical progression. In addition, normalisation of sFLCs should also be performed at every time point (every cycle) for patients in whom the only measurable disease is by sFLC levels (Table 25.4).

The guidelines also discuss a potential role for Hevylite in the definition of MRD. Once patients are classified as IMWG MRD negative (by cell-based assays and imaging), normalisation of the Hevylite ratio may provide further evidence of tumour eradication and immune system recovery. Further study of Hevylite as a marker of MRD is encouraged.


Response subcategory
Response criteria
Sustained MRD-negative*
  • MRD negativity in the marrow by next-generation sequencing (NGS) or next-generation flow (NGF), or both, and MRD negativity by imaging, as defined below, confirmed minimum of 1 year apart
Flow MRD-negative**
  • Absence of phenotypically aberrant plasma cells by NGF on bone marrow aspirates with a minimum sensitivity of 1 in 105 nucleated cells
Sequencing MRD-negative***
  • Absence of clonal plasma cells by NGS on bone marrow aspirate with a minimum sensitivity of 1 in 105 nucleated cells
Imaging-positive MRD-negative
  • MRD negativity as defined by NGF or NGS, and
  • Disappearance of every area of increased tracer uptake found at baseline or a preceding PET/CT or decrease to less mediastinal blood pool standardised uptake values or decrease to less than that of surrounding normal tissue
Stringent complete response (sCR)CR as defined below, and
  • Normal FLC ratio, and
  • Absence of clonal plasma cells by immunohistochemistry
Complete response (CR)
  • Negative IFE of serum and urine, and
  • Disappearance of any soft tissue plasmacytomas, and
  • <5% plasma cells in bone marrow aspirates
  • In patients in whom the only measurable disease is by sFLC levels, CR is defined as a normal FLC ratio (0.26-1.65) in addition to the CR criteria listed above
Very good partial response (VGPR)
  • Serum and urine M-protein detectable by IFE but not on electrophoresis, or
  • ≥90% reduction in serum M-protein plus urine M-protein <100 mg per 24 hours
  • In patients in whom the only measurable disease is by sFLC levels, VGPR is defined as a >90% decrease in the difference between involved and uninvolved sFLC levels
Partial response (PR)
  • ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg per 24 hours
  • In patients in whom the only measurable disease is by sFLC levels, PR is defined as a ≥50% decrease in the difference between involved and uninvolved sFLC levels
  • If serum and urine M-protein are unmeasurable, and sFLCs are also unmeasurable, ≥50% reduction in bone marrow plasma cells is required in place of M-protein, provided baseline percentage was ≥30%
  • In addition to the above criteria, if present at baseline, ≥50% reduction in the size of soft tissue plasmacytomas is also required
Minimal Response
  • ≥25% but ≤49% reduction of serum M-protein, and
  • Reduction in 24-h urine M-protein by 50-89%, and
  • If present at baseline, a ≥50% reduction in the size of soft tissue plasmacytomas
Stable disease (SD)Not meeting criteria for CR, VGPR, PR or progressive disease
Progressive disease (PD)Any one or more of the following:
  • Increase of 25% from lowest confirmed response value in any one or more of the following:
    • Serum M-protein (absolute increase must be ≥5 g/L) and/or
    • Urine M-protein (absolute increase must be ≥200 mg/24 hours) and/or
    • In patients in whom the only measurable disease is by sFLC levels, the difference between involved and uninvolved sFLC levels (absolute increase must be >100 mg/L)
    • If serum and urine M-protein are unmeasurable, and sFLCs are also unmeasurable, bone marrow plasma cell percentage (absolute % must be ≥10%)
  • Appearance of new lesions, ≥50% increase from nadir in SPD of >1 lesion, or a ≥50% increase in the longest diameter of a previous lesion >1 cm in short axis
  • ≥50% increase in circulating plasma cells (minimum of 200 cells per µL) if this is the only measure of disease
*Subsequent evaluations can be used to further specify the duration of negativity (e.g. MRD-negative at 5 years)
**Using EuroFlow standard operation procedure for MRD detection in MM, or validated equivalent method
***Presence of a clone defined as less than two identical sequencing reads obtained after DNA sequencing of bone marrow aspirates using the LymphoSIGHT platform or validated equivalent method
Note that all response categories require two consecutive assessments made at any time before the institution of any new therapy; for MRD there is no need for two consecutive assessments, but information on MRD after each treatment stage is recommended. All categories of response and MRD require no known evidence of progressive or new bone lesions if radiographic studies were performed. Radiographic studies are not required to satisfy these response requirements. Bone marrow assessments need not be confirmed. For PD, serum M-protein increases of ≥10 g/L are sufficient to define relapse if baseline M-protein is ≥50 g/L.

Table 25.4. IMWG criteria for response and MRD assessment in MM [905].

In patients with measurable disease by SPE or UPE (defined as serum monoclonal protein ≥10 g/L; urine monoclonal protein ≥200 mg/24 hours), or both, will be assessed for response based only on these two tests, and not by FLC assays. In these patients, FLC assays are only required for assessment of stringent complete response.

In patients in whom the only measurable disease is by sFLC levels (defined as involved FLC ≥100 mg/L, provided that the FLC ratio is abnormal), the definition of partial or very good partial sFLC response requires subtraction of the tumour ("involved") FLC from the non-tumour ("uninvolved") FLC. This difference calculation provides an interpretable result even when the non-tumour FLC is below the detection limit or fluctuating widely (thereby making the sFLC ratio unreliable). It is also helpful when interpreting high concentrations of the alternate FLC, as observed in patients with impaired renal function (Chapter 27).