What are the CRAB criteria (hypercalcemia, renal insufficiency, anemia, bone disease) that define symptomatic multiple myeloma and indicate the need for treatment?

CRAB Criteria for Multiple Myeloma

The CRAB criteria define end-organ damage in symptomatic multiple myeloma and consist of: hypercalcemia (serum calcium >11.5 mg/dL), renal insufficiency (serum 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, 2

Diagnostic Framework

The diagnosis of symptomatic multiple myeloma requires both of the following components 1, 2:

• ≥10% clonal plasma cells on bone marrow examination or biopsy-proven plasmacytoma 1, 3
• Evidence of end-organ damage attributable to the plasma cell disorder, specifically meeting at least one CRAB criterion 1, 2

Detailed CRAB Definitions

C - Hypercalcemia

• Serum calcium >11.5 mg/dL 1, 2
• Results from osteolytic bone destruction and increased bone resorption 1

R - Renal Insufficiency

• Serum creatinine >2 mg/dL (>173 μmol/L) 1, 2
• OR estimated creatinine clearance <40 mL/min 1, 2
• Light chain cast nephropathy is the most common cause, occurring when monoclonal free light chains obstruct renal tubules 4

A - Anemia

• Hemoglobin <10 g/dL 1, 2
• OR hemoglobin value ≥2 g/dL below the lower limit of normal 1, 2
• Must be normochromic and normocytic 1

B - Bone Disease

• Lytic lesions on skeletal survey 1, 2
• Severe osteopenia 1, 2
• Pathologic fractures 1, 2
• Bone disease occurs in approximately 79% of multiple myeloma patients 4

Critical Diagnostic Distinctions

MGUS (Monoclonal Gammopathy of Undetermined Significance)

• Serum monoclonal protein <3 g/dL 1, 2
• Clonal bone marrow plasma cells <10% 1, 2
• Absence of CRAB criteria 1, 2
• Progresses to myeloma at approximately 1% per year 2, 5

Smoldering Multiple Myeloma (SMM)

• Serum monoclonal protein ≥3 g/dL and/or clonal bone marrow plasma cells ≥10% 1, 2
• Absence of CRAB criteria or myeloma-defining biomarkers 1, 2
• Progresses to symptomatic myeloma at approximately 10% per year during the first 5 years 2
• No immediate treatment recommended; close monitoring required 1, 3

Symptomatic Multiple Myeloma

• Meets plasma cell threshold AND has CRAB criteria 1, 2
• Treatment must be initiated immediately in all patients meeting CRAB criteria 1, 3

Updated 2014 Myeloma-Defining Biomarkers

Beyond CRAB criteria, the International Myeloma Working Group added biomarkers that indicate near-inevitable progression 2, 6:

• ≥60% clonal plasma cells in bone marrow 2, 6
• Serum free light chain ratio >100 (involved:uninvolved) 2, 6
• >1 focal lesion on MRI, each ≥5 mm 2, 6

Presence of any biomarker permits myeloma diagnosis even without CRAB findings 2

Essential Diagnostic Workup

Laboratory Tests Required

• Serum and urine protein electrophoresis with immunofixation 1, 2
• 24-hour urine collection for protein electrophoresis (not random sample) 2
• Nephelometric quantification of IgG, IgA, and IgM 1, 2
• Serum free light chain assay with kappa/lambda ratio 1, 2
• Complete blood count with differential 1, 2
• Serum creatinine and creatinine clearance 1, 2
• Serum calcium 1, 2
• β2-microglobulin, albumin, and LDH for prognostic stratification 2

Bone Marrow Evaluation

• Bone marrow aspiration and biopsy mandatory 1, 2
• CD138 staining must be performed to accurately quantify plasma cell percentage 1, 2
• Cytogenetic/FISH studies required for risk stratification, specifically probing for del(17p), t(4;14), t(14;16), and del(13q) 2

Imaging Studies

• Skeletal survey (spine, pelvis, skull, humeri, femora) or whole-body low-dose CT 2
• MRI of thoracolumbar spine and pelvis if skeletal survey negative but clinical suspicion remains 2
• PET/CT can detect active myeloma and is more sensitive than plain radiographs 2

Treatment Initiation Criteria

Treatment should be initiated immediately in all patients with active myeloma fulfilling CRAB criteria 1, 3, 2:

• Hypercalcemia >11.0 mg/dL 1
• Creatinine >2.0 mg/dL 1
• Hemoglobin <10 g/dL 1
• Active bone lesions 1

Common Pitfalls to Avoid

• Do not delay treatment while awaiting additional testing if CRAB criteria are clearly met; delaying treatment increases morbidity and mortality 3, 4
• CRAB criteria are not pathognomonic of multiple myeloma—lymphoma can rarely present with identical features 7
• Distinguish SMM from symptomatic myeloma carefully; SMM does not require immediate treatment despite elevated M-protein or plasma cells 1, 3
• Avoid NSAIDs in patients with renal impairment as they worsen kidney function 3, 4
• Do not use contrast media without ensuring adequate hydration in patients with renal insufficiency 3
• Bone marrow examination is not routinely needed for IgG MGUS if serum M-protein ≤15 g/L without end-organ damage 2

Prognostic Implications

Among CRAB features in the novel agent era 8:

• Hypercalcemia and bone disease confer significantly worse prognosis 8
• Anemia and renal failure show no significant difference in survival with modern therapies 8
• Bone disease is the most common CRAB feature and may have the strongest prognostic value 8