International Myeloma Working Group response criteria

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The International Myeloma Working Group response criteria are consensus definitions used to assess response to treatment of multiple myeloma. With the latest version published in 2016, the criteria have been widely adopted for classifying responses in clinical trials and in routine practice . Imaging assessment of bone lesions and extramedullary plasmacytomas are an optional component of the response criteria, except FDG PET is required for reporting imaging minimal residual disease (MRD)-negative status.

Classification

Baseline disease

Measurable disease is a requirement for some of the response categories. Measurable disease is defined by any of the following:

  • serum M-protein ≥1 g/dL
  • urine M-protein ≥200 mg/24 h
  • involved serum free light chain (FLC) ≥10 mg/dL if the free kappa/lambda ratio is abnormal

Using these disease parameters to document response or progression requires a repeat measurement (or two discrete samples from the same day) to confirm.

On FDG PET, baseline positive bone lesions can be defined by various criteria :

  • SUVmax ≥2.5 within osteolytic area >1 cm
  • SUVmax ≥1.5 within osteolytic area ≤1 cm
  • focal increased uptake within bones present on at least two consecutive slices, regardless of whether an underlying lesion is visible on CT

For response assessment purposes other than minimal residual disease evaluation, imaging studies are not required but various modalities (CT, MRI, or PET) can be used to detect and assess response in bone lesions and soft tissue plasmacytomas.

Standard response criteria
  • progressive disease is defined by any of the following:
    • any of the following imaging findings:
      • new lesion
      • ≥50% increase in the longest diameter of a lesion that previously measured >1 cm in short axis
      • ≥50% increase from the nadir in the sum of products of the two longest perpendicular diameters (SPD) of more than one lesion
    • ≥25% increase from the nadir in any of the following:
      • serum M-protein (with ≥0.5 g/dL absolute increase)
      • urine M-protein (with ≥200 mg/24 h absolute increase)
      • difference between involved and uninvolved serum free light chain (FLC) levels (with >10 mg/dL absolute increase) if serum and urine M-protein unmeasurable
      • bone marrow plasma cell percentage (with ≥10% absolute increase) if serum and urine M-protein unmeasurable and involved free light chain unmeasurable
    • ≥1 g/dL absolute increase in serum M-protein if the nadir was ≥5 g/dL
    • ≥50% increase in circulating plasma cells (with minimum of 200 cells/μL) if this is the only measure of disease
  • stable disease is a category of exclusion, i.e., the patient does not meet criteria for progressive disease, minimal response, partial response, very good partial response, or complete response
  • minimal response requires all of the following:
    • ≥50% decrease in the sum of products of two longest perpendicular diameters (SPD) of soft tissue plasmacytoma(s) if present at baseline
    • 25-49% decrease in serum M-protein
    • 50-89% decrease in urine M-protein
  • partial response requires all of the following:
    • ≥50% decrease in the sum of products of two longest perpendicular diameters (SPD) of soft tissue plasmacytoma(s) if present at baseline
    • ​≥50% decrease in serum M-protein
    • ≥90% decrease in urine M-protein or to <200 mg/24 h
    • ​≥50% decrease in the difference between involved and uninvolved serum free light chain (FLC) levels if serum and urine M-protein unmeasurable
    • ≥50% decrease in bone marrow plasma cells (if the percentage was ≥30% at baseline) if serum and urine M-protein unmeasurable and involved free light chain unmeasurable
  • very good partial response requires any of the following:
    • ​serum and urine M-protein detected by immunofixation but not electrophoresis
    • both of the following:
      • ≥90% decrease in serum M-protein
      • urine M-protein <100 mg/24 h
    • ​≥90% decrease in the difference between involved and uninvolved serum free light chain (FLC) levels if serum and urine M-protein unmeasurable
  • complete response requires all of the following:
    • ​disappearance of any soft tissue plasmacytomas
    • serum and urine M-protein not detected by immunofixation
    • normal free light chain (FLC) ratio (0.26-1.65) if serum and urine M-protein unmeasurable
    • bone marrow plasma cell percentage <5%
  • stringent complete response requires complete response as above plus the following:
    • ​normal free light chain (FLC) ratio (0.26-1.65)
    • bone marrow plasma cell immunohistochemistry kappa:lambda ratio without evidence of clonal cells (≤4:1 if kappa patient or ≥1:2 if lambda patient)
Minimal residual disease criteria

Minimal residual disease (MRD)-negative refers to a deeper level of response than the above standard categories. These response categories require having achieved complete response and additional criteria:

  • flow or sequencing minimal residual disease (MRD)-negative requires absence of phenotypically abnormal clonal plasma cells from bone marrow aspirates using either a validated next-generation flow method (e.g. EuroFlow) or next-generation DNA sequencing method (e.g. LymphoSIGHT) that can detect 1 in 10 thousand nucleated cells or better
  • imaging plus minimal residual disease (MRD)-negative refers to flow or sequencing MRD-negative in addition to disappearance of all areas of increased FDG uptake found at prior PET to an SUVmax below that of surrounding normal tissue or below that of mediastinal blood pool (Deauville 1 or 2) 
  • sustained minimal residual disease (MRD)-negative refers to imaging plus MRD-negative confirmed at least one year apart
Relapse criteria

Relapse refers to recurrent disease manifestations after a prior response.

  • clinical relapse requires any of the following manifestations of myeloma (CRAB features):
    • new soft tissue plasmacytomas or bone lesions (not including osteoporotic fractures)
    • ​definite (≥50% and ​≥1 cm) increase in the size (sum of products of two longest perpendicular diameters (SPD)) of measurable existing soft tissue plasmacytomas or bone lesions
    • hypercalcemia >11 mg/dL
    • ≥2 g/dL decrease in hemoglobin not attributed to therapy or conditions other than myeloma
    • ≥2 mg/dL increase in serum creatinine attributed to myeloma compted to the initiation of therapy
    • hyperviscosity attributed to paraproteinemia
  • relapse from complete response requires reappearance/development of any of the following:
    • ​serum or urine M-protein by immunofixation or electrophoresis
    • ≥5% plasma cells in the bone marrow
    • any of the above signs of clinical relapse
  • relapse from minimal residual disease (MRD)-negative occurs with loss of MRD-negative status (clonal plasma cells on sequencing or flow of bone marrow, or positive lesions on FDG PET) or any of the above signs of relapse from complete response