Monoclonal gammopathy of undetermined significance (MGUS) is a condition that may precede multiple myeloma.10 Patients with MGUS have monoclonal protein present without evidence of end organ damage (CRAB criteria [Calcium elevation, Renal dysfunction, Anemia, Bone disease]).3 Symptoms also include serum monoclonal protein <30 g/L and clonal marrow plasma cells <10%.3 The rate of progression from MGUS to multiple myeloma is 0.5% to 1% per year.3,10
Smoldering multiple myeloma (SMM) is the stage of the disease with no symptoms and no related organ or tissue impairment with both of the following criteria present3:
- Higher level of serum monoclonal protein than MGUS (≥30g/L) or urinary monoclonal protein ≥500 mg per 24 hours, and/or bone marrow monoclonal plasma cells 10% to 60%
- Absence of myeloma-defining events or amyloidosis
However, this high-risk cohort does not represent the majority of patients with SMM.3
Patients with higher-risk features in SMM have a 40% risk of progression to active myeloma.3 Transition from MGUS to multiple myeloma is characterized by increases in the number of multiple myeloma cells, angiogenesis, and osteolytic lesions.10
Active multiple myeloma is defined by the presence of clonal bone marrow cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma along with the presence of CRAB features or biomarkers of malignancy.3
In 2014, the International Myeloma Working Group made the following updates to the diagnostic criteria of multiple myeloma3:
- Added biomarkers of malignancy to the disease definition in addition to the existing criteria of end organ damage (CRAB features)
- Updated laboratory and radiographic results for the criteria of CRAB features
- Revised histological and monoclonal protein requirements for diagnosis
No single pathological or molecular feature can be used to differentiate patients with SMM with only clonal premalignant plasma cells versus patients with clonal malignant cells.3 There is a need for a group of biomarkers that could identify patients with SMM who are at risk of developing CRAB features of symptomatic MM.3
NAME |
DEFINITION2,3 |
Monoclonal Gammopathy of Undetermined Significance (MGUS)2 |
- Serum monoclonal protein present <30 g/L
- Absence of end organ damage (CRAB features)*
- Clonal bone marrow plasma cells <0%
|
Smoldering Multiple Myeloma (SMM)3 |
- Serum monoclonal protein ≥3 g/dL
Or
- Bence-Jones protein ≥500 mg/24 h
And/Or
- Clonal bone marrow plasma cells 10%–59%
And
- Absence of myeloma-defining events or amyloidosis3
- If skeletal survey is negative, assess for bone disease with whole-body MRI, FDG PET/CT, or low-dose CT scan
|
Multiple Myeloma3 |
Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma
And
Any one or more of the following myeloma-defining events:
- 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 >2 mg/dL) (>177 μmol/L) or creatinine clearance <40 mL/min
- Anemia (hemoglobin <10 g/dL or hemoglobin >2 g/dL below the lower limit of normal)
- One or more osteolytic bone lesions on skeletal radiography, CT, or FDG PET/CT
- Clonal bone marrow plasma cells ≥60%
- Involved: uninvolved serum FLC ratio ≥100 and involved FLC concentration 10 mg/dL or higher
- >1 focal lesion on MRI studies ≥5 mm3
|
* Organ damage classified as CRAB or any other significant clinical problem linked to myeloma progression such as recurrent infections or neuropathy unrelated to treatment
C – Calcium elevation >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 >2 mg/dL) (>177 μmol/L) or creatinine clearance <40 mL/min
A – Anemia (hemoglobin <10 g/dL or hemoglobin >2 g/dL below the lower limit of normal)
B – Bone disease (one or more osteolytic bone lesions on skeletal radiography, CT, or FDG PET/CT)
One or more CRAB features or other significant problem required for diagnosis of Symptomatic Myeloma
SLiM biomarkers of malignancy
S – Clonal bone marrow plasma cells ≥60%
Li – Abnormal serum FLC ratio ≥100 (involved kappa) or ≥0.01 (involved lambda)
M – >1 focal lesion on MRI studies ≥5 mm1
|
Concise review of the disease and treatment options: multiple myeloma cancer of the bone marrow. 2018 ed.
International Myeloma Foundation. Accessed May 29, 2019.2
Rajkumar SV, et al. Lancet Oncol. 2014;15(12):e538-e548.