Multiple myeloma diagnostic criteria

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Serge Korjian M.D.

Overview

The International Myeloma Working Group (IMWG) proposed updated criteria for the diagnosis of multiple myeloma in November 2014. The diagnosis requires >10% clonal plasma cell proliferation in the bone marrow, or biopsy-proven plasmacytosis at an extramedullary site plus one of more of the multiple myeloma-defining CRAB features (hypercalcemia, renal failure, anaemia, and bone lesions) or one or more of the newly added biomarkers of malignancy (clonal bone marrow plasma cell percentage ≥60%, involved:uninvolved serum free light chain ratio ≥100, and >1 focal lesions on MRI studies).

Table 1

International Myeloma Working Group Diagnostic Criteria for Multiple Myeloma and Related Plasma Cell Disorders

Disorder	Disease Definition
Non-IgM monoclonal gammopathy of undetermined significance (MGUS)	All 3 criteria must be met: Serum monoclonal protein (non-IgM type) <3gm/dL Clonal bone marrow plasma cells <10%* Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB) that can be attributed to the plasma cell proliferative disorder
Smoldering multiple myeloma	Both criteria must be met: Serum monoclonal protein (IgG or IgA) ≥3gm/dL, or urinary monoclonal protein ≥500 mg per 24h and/or clonal bone marrow plasma cells 10–60% Absence of myeloma defining events or amyloidosis
Multiple Myeloma	Both criteria must be met: Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma Any one or more of the following myeloma defining events: ○ Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: ▪ 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) ▪ Renal insufficiency: creatinine clearance <40 mL per minute or serum creatinine >177 μmol/L (>2 mg/dL) ▪ Anemia: hemoglobin value of >2 g/dL below the lower limit of normal, or a hemoglobin value <10 g/dL ▪ Bone lesions: one or more osteolytic lesions on skeletal radiography, computed tomography (CT), or positron emission tomography-CT (PET-CT) ○ Clonal bone marrow plasma cell percentage ≥60%) ○ Involved: uninvolved serum free light chain (FLC) ratio ≥100 (involved free light chain level must be ≥100 mg/L)) ○ >1 focal lesions on magnetic resonance imaging (MRI) studies (at least 5mm in size)
IgM Monoclonal gammopathy of undetermined significance (IgM MGUS)	All 3 criteria must be met: Serum IgM monoclonal protein <3gm/dL Bone marrow lymphoplasmacytic infiltration <10% No evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder.
Light Chain MGUS	All criteria must be met: Abnormal FLC ratio (<0.26 or >1.65) Increased level of the appropriate involved light chain (increased kappa FLC in patients with ratio > 1.65 and increased lambda FLC in patients with ratio < 0.26) No immunoglobulin heavy chain expression on immunofixation Absence of end-organ damage that can be attributed to the plasma cell proliferative disorder Clonal bone marrow plasma cells <10% Urinary monoclonal protein <500 mg/24h
Solitary Plasmacytoma	All 4 criteria must be met Biopsy proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells Normal bone marrow with no evidence of clonal plasma cells Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion) Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, or bone lesions (CRAB) that can be attributed to a lympho-plasma cell proliferative disorder
Solitary Plasmacytoma with minimal marrow involvement**	All 4 criteria must be met Biopsy proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells Clonal bone marrow plasma cells <10% Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion) Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, or bone lesions (CRAB) that can be attributed to a lympho-plasma cell proliferative disorder

From Lancet Oncol.¹

^*A bone marrow can be deferred in patients with low risk MGUS (IgG type, M protein <15 gm/L, normal free light chain ratio) in whom there are no clinical features concerning for myeloma

^**Solitary plasmacytoma with 10% or more clonal plasma cells is considered as multiple myeloma

Diagnostic Criteria

In November 2014, the International Myeloma Working Group (IMWG) updated the criteria for the diagnosis of multiple myeloma to include novel validated biomarkers that are associated with the development of CRAB features (hypercalcaemia, renal failure, anaemia, and bone lesions). The update also clarified the underlying laboratory and radiographic findings of CRAB features, as well as the histological and monoclonal protein requirements for the disease diagnosis.

Criteria for the Diagnosis of Monoclonal Gammopathy of Undetermined Significance (MGUS)

All three criteria must be met:

• Presence of serum monoclonal protein (IgG or IgA) <3 g/dL
• Presence of bone marrow clonal plasma cells <10%
• Absence of multiple myeloma-defining events or amyloidosis

===Criteria for the Diagnosis of Smoldering Multiple Myeloma Both criteria must be met:

• Serum monoclonal protein (IgG or IgA) ≥3 g/dL or urinary monoclonal protein ≥500 mg per 24 h and/or clonal bone marrow plasma cells 10–60%
• Absence of multiple myeloma-defining events or amyloidosis

===Revised Criteria for the Diagnosis of Multiple Myeloma

• Both criteria must be met:

≥10% clonal expansion of bone marrow plasma cells or biopsy-proven bony or extramedullary plasmacytoma and one or more of the following features:

• Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder:

• 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)
• Renal insufficiency: creatinine clearance <40 mL per min or serum creatinine >177 μmol/L (>2 mg/dL)
• Anemia: hemoglobin value of >2 g/dL below the lower limit of normal, or a hemoglobin value <10 g/dL
• Bone lesion: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT

• Any one or more of the following biomarkers of malignancy:

• Clonal bone marrow plasma cell percentage ≥60%
• Involved:uninvolved serum free light chain ratio ≥100
• >1 focal lesions on MRI studies

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References

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