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Disease definitions for the monoclonal gammopathies: MGUS and related disorders

Disease definitions for the monoclonal gammopathies: MGUS and related disorders
Type of monoclonal gammopathy Premalignancy with low risk of progression (1 to 2% per year) Premalignancy with high risk of progression (10% per year) Malignancy
IgG or IgA (non-IgM)*

Non-IgM MGUS

All criteria must be met:
  1. Serum monoclonal protein <3 g/dL
  2. Clonal BM plasma cells <10%
  3. Absence of end-organ damage that can be attributed to the PCPD and absence of myeloma defining biomarkers (CRAB SLiM criteria)

Smoldering MM

Both criteria must be met:
  1. Serum monoclonal protein (IgG or IgA) ≥3 g/dL and/or clonal BM plasma cells ≥10%
  2. Absence of end-organ damage that can be attributed to a PCPD and absence of myeloma defining biomarkers (CRAB SLiM criteria)

MM

  1. Clonal BM plasma cells ≥10%

Plus one of the following:

  1. Evidence of end-organ damage that can be attributed to the underlying PCPD, specifically one or more of the following (CRAB criteria):
    • Hypercalcemia: serum calcium ≥11.5 mg/dL
    • Kidney impairment: serum creatinine >2 mg/dL or estimated creatinine clearance <40 mL/min
    • Anemia: normochromic, normocytic with hemoglobin >2 g/dL below lower limit of normal or hemoglobin <10 g/dL
    • Bone lesions: lytic lesions ≥5 mm attributed to a PCPD on skeletal radiography, MRI, CT, or PET/CT
  2. Presence of one of the following myeloma-defining biomarkers (SLiM criteria):
    • ≥60% clonal plasma cells in bone marrow
    • Involved/uninvolved FLC ratio ≥100
    • MRI with >1 focal bone lesion
IgM

IgM MGUSΔ

All criteria must be met:
  1. Serum monoclonal protein <3 g/dL
  2. Clonal BM lymphoplasmacytic cells <10%
  3. Absence of end-organ damage such as anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder

Smoldering WM

Both criteria must be met:
  1. Serum IgM monoclonal protein ≥3 g/dL and/or BM lymphoplasmacytic infiltration ≥10%
  2. No evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder

WM

All criteria must be met:
  1. IgM monoclonal gammopathy (regardless of size of M protein)
  2. ≥10% BM lymphoplasmacytic infiltration (usual intertrabecular) by small lymphocytes that exhibit plasmacytoid or plasma cell differentiation and a typical immunophenotype (eg, surface IgM+, CD5±, CD10–, CD19+, CD20+, CD23–) that satisfactorily excludes other lymphoproliferative disorders including chronic lymphocytic leukemia and mantle cell lymphoma
  3. Evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder

IgM myeloma

All criteria must be met:
  1. Symptomatic monoclonal PCPD characterized by a serum IgM monoclonal protein regardless of size
  2. Presence of ≥10% plasma cells on BM biopsy
  3. Presence of lytic bone lesions related to the underlying plasma cell disorder and/or translocation t(11:14) on FISH
Light chain

Light chain MGUS

All criteria must be met:
  1. Abnormal FLC ratio◊ with increased level of the involved light chain (increased κ FLC in patients with increased ratio and increased λ FLC in patients with decreased ratio)
  2. No immunoglobulin heavy chain expression on immunofixation
  3. Clonal BM plasma cells <10%
  4. Absence of end-organ damage that can be attributed to the PCPD and absence of myeloma defining biomarkers (CRAB SLiM criteria)

Light chain smoldering MM

All criteria must be met:
  1. Abnormal FLC ratio◊ with increased level of the involved light chain (increased κ FLC in patients with increased ratio and increased λ FLC in patients with decreased ratio)
  1. or
  2. Urinary monoclonal protein on urine protein electrophoresis ≥500 mg/24 h
  1. Clonal BM plasma cells ≥10%
  2. No immunoglobulin heavy chain expression on immunofixation
  3. Absence of end-organ damage that can be attributed to the PCPD and absence of myeloma defining biomarkers (CRAB SLiM criteria)

Light chain MMΔ

All three of the following:
  1. Abnormal FLC ratio◊ with increased level of the involved light chain (increased κ FLC in patients with increased ratio and increased λ FLC in patients with decreased ratio)
  1. or
  2. Urinary monoclonal protein on urine protein electrophoresis ≥500 mg/24 h
  1. Clonal BM plasma cells ≥10%
  2. No immunoglobulin heavy chain expression on immunofixation

Plus one of the following:

  1. Evidence of end-organ damage that can be attributed to the underlying PCPD, specifically one or more of the following (CRAB criteria):
    • Hypercalcemia: serum calcium ≥11.5 mg/dL
    • Kidney impairment: serum creatinine >2 mg/dL or estimated creatinine clearance <40 mL/min
    • Anemia: normochromic, normocytic with hemoglobin >2 g/dL below lower limit of normal or hemoglobin <10 g/dL
    • Bone lesions: lytic lesions ≥5 mm attributed to a PCPD on skeletal radiography, MRI, CT, or PET/CT
  2. Presence of one of the following myeloma-defining biomarkers (SLiM criteria):
    • ≥60% clonal plasma cells in bone marrow
    • Involved/uninvolved FLC ratio ≥100
    • MRI with >1 focal bone lesion

BM: bone marrow; CRAB: hypercalcemia, renal insufficiency, anemia, and bone lesions; FISH: fluorescent in situ hybridization; FLC: free light chain; MGUS: monoclonal gammopathy of undetermined significance; MM: multiple myeloma; PCPD: plasma cell proliferative disorder; WM: Waldenström macroglobulinemia.

* Occasionally, patients with IgD and IgE monoclonal gammopathies have been described and will be considered part of this category as well.

¶ These acronyms represent the following markers of MM-related organ/tissue impairment (CRAB) and biomarkers associated with near inevitable progression to end-organ damage (SLiM):

  • C – Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL)
  • R – Renal insufficiency: creatinine clearance <40 mL per min or serum creatinine >177 micromol/L (>2 mg/dL)
  • A – Anemia: hemoglobin value of >20 g/L below the lower limit of normal, or a hemoglobin value <100 g/L
  • B – Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET/CT
  • S – ≥60% clonal plasma cells in the bone marrow
  • Li – Involved/uninvolved serum free light chain ratio ≥100
  • M – MRI with >1 focal lesion involving bone or bone marrow

Δ Note that conventionally IgM MGUS is considered a subtype of MGUS, and similarly light chain MM is considered a subtype of MM. Unless specifically distinguished, when the terms MGUS and MM are used in general, they include IgM MGUS and light chain MM, respectively.

◊ When interpreting the FLC assay in clinical practice, clinicians should refer to the normal reference range specified by the laboratory reporting the result. Reference ranges differ between assays from different manufacturers and are dependent upon the instrument used for measurement. Reference ranges may also be adjusted for the patient's estimated glomerular filtration rate[1]; For the serum FLC assay developed by The Binding Site:
  • eGFR ≥60 mL/min/1.73 m2
    • FLC ratio 0.26 to 1.65
    • Serum free kappa 3.3 to 19.4 mg/L
    • Serum free lambda 5.7 to 26.3 mg/L
  • eGFR 45 to 59 mL/min/1.73 m2
    • FLC 0.46 to 2.62
    • Serum free kappa 7.8 to 83.6 mg/L
    • Serum free lambda 7.3 to 65.1 mg/L
  • eGFR 30 to 44 mL/min/1.73 m2
    • FLC 0.48 to 3.38
    • Serum free kappa 8.8 to 103.3 mg/L
    • Serum free lambda 8.2 to 73.2 mg/L
  • eGFR <30 mL/min/1.73 m2
    • FLC 0.54 to 3.30
    • Serum free kappa 11.7 to 265 mg/L
    • Serum free lambda 12.6 to 150.9 mg/L

Adapted from: Rajkumar SV, Kyle RA, Buadi FK. Advances in the diagnosis, classification, risk stratification, and management of monoclonal gammopathy of undetermined significance: implications for recategorizing disease entities in the presence of evolving scientific evidence. Mayo Clin Proc 2010; 85:945.

With additional data from:
  1. Long TE, Indridason OS, Palsson R, et al. Defining new reference intervals for serum free light chains in individuals with chronic kidney disease: Results of the iStopMM study. Blood Cancer J 2022; 12:133.
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