CRAB Criteria for Multiple Myeloma
Definition of CRAB Criteria
The CRAB criteria define end-organ damage in multiple myeloma and consist of four specific parameters: hypercalcemia (Calcium >11.5 mg/dL), renal insufficiency (cReatinine >2 mg/dL or creatinine clearance <40 mL/min), anemia (hemoglobin <10 g/dL or ≥2 g/dL below lower limit of normal), and bone lesions (lytic lesions, severe osteopenia, or pathologic fractures). 1
Individual CRAB Components
C - Calcium Elevation (Hypercalcemia)
- Serum calcium >11.5 mg/dL 1, 2
- This threshold is consistently defined across international guidelines 1
R - Renal Failure
- Serum creatinine >2 mg/dL OR creatinine clearance <40 mL/min 1, 2
- Creatinine clearance should be measured using validated equations such as MDRD or CKD-EPI 3
A - Anemia
- Hemoglobin <10 g/dL OR ≥2 g/dL below the lower limit of normal 1, 2
- The dual threshold accounts for patients with baseline variations in normal hemoglobin ranges 1
B - Bone Lesions
- Lytic lesions, severe osteopenia, or pathologic fractures identified on skeletal survey 1, 2
- Imaging should include skeletal survey and MRI of thoracic-lumbar spine and pelvis, especially if conventional imaging is negative 1
Role in Multiple Myeloma Diagnosis
Multiple myeloma requires ≥10% clonal bone marrow plasma cells (or biopsy-proven plasmacytoma) PLUS at least one CRAB criterion OR specific myeloma-defining biomarkers. 1, 4, 5
The updated 2014 International Myeloma Working Group criteria expanded beyond CRAB to include three additional biomarkers that can establish diagnosis even without CRAB features: 6, 7
- ≥60% clonal plasma cells in bone marrow 1, 4
- Involved/uninvolved serum free light chain ratio ≥100 (provided involved FLC ≥100 mg/L) 1, 4
Critical Diagnostic Distinctions
MGUS (Monoclonal Gammopathy of Undetermined Significance)
- Serum monoclonal protein <3 g/dL 1
- Clonal bone marrow plasma cells <10% 1
- Absence of any CRAB criteria 1
- No treatment required, but lifelong monitoring needed 1
Smoldering Multiple Myeloma (SMM)
- Serum monoclonal protein ≥3 g/dL and/or clonal bone marrow plasma cells ≥10% 1
- No CRAB criteria present 1
- No immediate treatment, but closer monitoring than MGUS (10% per year progression risk for first 5 years) 1
Treatment Implications When CRAB Criteria Are Met
Immediate treatment must be initiated in all patients meeting CRAB criteria, as delaying therapy increases morbidity and mortality. 2
Treatment Algorithm Based on Transplant Eligibility
Transplant-eligible patients:
- Bortezomib, lenalidomide, dexamethasone (VRd) for 3-4 cycles followed by autologous stem cell transplantation 5
- High-risk patients: Consider daratumumab, bortezomib, lenalidomide, dexamethasone (Dara-VRd) 5
Transplant-ineligible patients (≥65 years or medically unfit):
- VRd for approximately 8-12 cycles followed by lenalidomide maintenance 5
- Alternative: Bortezomib, melphalan, prednisone (VMP) for 8-12 cycles 2
- Alternative: Melphalan, prednisone, thalidomide (MPT) 2
Specific Management by CRAB Component
Hypercalcemia:
Renal impairment:
- Bortezomib-based regimens are preferred as they can be safely administered without dose adjustment 2
- Avoid NSAIDs and maintain adequate hydration 2
Bone disease:
- Bisphosphonates (zoledronic acid or pamidronate) to reduce skeletal-related events 2
Common Pitfalls to Avoid
CRAB criteria are not pathognomonic for multiple myeloma - lymphoma and other malignancies can occasionally present with similar features, requiring confirmation with bone marrow examination and monoclonal protein studies. 8
Do not perform unnecessary bone marrow biopsies in low-risk MGUS patients (IgG MGUS with serum M-protein ≤15 g/L without end-organ damage), but bone marrow examination is recommended for all IgA and IgM M-proteins. 1
Distinguish between evolving and non-evolving SMM patterns, as they have dramatically different progression timelines (evolving: ~1.5 years; non-evolving: ~4 years). 1