When should multiple myeloma be suspected in a patient?

When to Suspect Multiple Myeloma

Multiple myeloma should be suspected in patients presenting with unexplained hypercalcemia, renal insufficiency, anemia, or bone lesions (CRAB criteria), especially in individuals over 65 years of age with monoclonal protein in serum or urine. 1

Clinical Presentations That Should Trigger Suspicion

End-Organ Damage (CRAB Criteria)

• Hypercalcemia: Serum calcium >11.5 mg/dl or >2.75 mmol/L 1
• Renal insufficiency: Serum creatinine >1.73 μmol/l (or >2 mg/dl) or estimated creatinine clearance <40 ml/min 1
• Anemia: Normochromic, normocytic with hemoglobin value ≥2 g/dl below the lower limit of normal or hemoglobin <10 g/dl 1
• Bone lesions: Lytic lesions, severe osteopenia, or pathologic fractures detected on skeletal survey, CT, or MRI 1

Additional Clinical Presentations

• Recurrent bacterial infections attributable to plasma cell disorder 1
• Extramedullary plasmacytomas 1
• Unexplained back pain, especially in older adults 1
• Symptoms of hyperviscosity (visual disturbances, neurological symptoms) 2
• Peripheral neuropathy without other explanation 2

Laboratory and Imaging Findings That Should Raise Suspicion

Key Laboratory Abnormalities

• Presence of monoclonal protein (M-protein) ≥3 g/dL in serum 1
• Abnormal serum free light chain ratio (involved/uninvolved ratio ≥100, provided involved FLC is ≥100 mg/L) 3
• Bone marrow clonal plasma cells ≥10% 1
• Bence Jones proteinuria (monoclonal light chains in urine) 1
• Unexplained elevation in total protein with decreased albumin 1

Imaging Findings

• One or more focal lesions on MRI 3
• Lytic bone lesions on skeletal survey 1
• Pathologic fractures without adequate trauma 1

Distinguishing Between MGUS, Smoldering Myeloma, and Symptomatic Myeloma

Monoclonal Gammopathy of Undetermined Significance (MGUS)

• Serum monoclonal protein <3 g/dl 4
• Clonal bone marrow plasma cells <10% 4
• Absence of end-organ damage (CRAB criteria) 4
• Progresses to myeloma at a rate of approximately 1% per year 1

Smoldering Multiple Myeloma (SMM)

• Serum monoclonal protein (IgG or IgA) ≥3 g/dl and/or clonal bone marrow plasma cells ≥10% 1
• Absence of end-organ damage (CRAB criteria) 1
• Progresses to symptomatic myeloma at a rate of 10% per year over the first 5 years 1

Symptomatic Multiple Myeloma

• Clonal bone marrow plasma cells ≥10% or biopsy-proven plasmacytoma 1
• Evidence of end-organ damage (CRAB criteria) attributable to plasma cell disorder 1
• May also be diagnosed based on biomarkers of malignancy even without CRAB features:
  • Bone marrow clonal plasmacytosis ≥60% 3
  • Serum involved/uninvolved free light chain ratio ≥100 3

  • 1 focal lesion on MRI 3

Diagnostic Workup When Myeloma is Suspected

Essential Laboratory Tests

• Complete blood count to evaluate for anemia 1
• Serum calcium and creatinine to assess for hypercalcemia and renal dysfunction 1
• Serum protein electrophoresis and immunofixation to detect and characterize M-protein 1
• Quantification of immunoglobulins (IgG, IgA, IgM) 1
• Serum free light chain assay with kappa/lambda ratio 1
• 24-hour urine collection for protein electrophoresis and immunofixation 1
• Serum β2-microglobulin and lactate dehydrogenase for prognostic assessment 1

Bone Marrow Assessment

• Bone marrow aspirate and/or biopsy to evaluate plasma cell percentage and morphology 1
• Cytogenetics and FISH to detect high-risk features (del(17p), t(4;14), t(14;16)) 1

Imaging Studies

• Full skeletal survey including spine, pelvis, skull, humeri, and femurs 1
• MRI of spine and pelvis if symptomatic or if solitary plasmacytoma is suspected 1
• Low-dose whole-body CT or PET/CT if available 2

Common Pitfalls to Avoid

• Attributing anemia, renal dysfunction, or hypercalcemia to other common conditions without considering myeloma, especially in elderly patients 1
• Failing to investigate persistent back pain in older adults 1
• Missing the diagnosis by not performing immunofixation when SPEP is negative or equivocal 5
• Confusing diffuse osteoporosis with myeloma bone disease (sudden onset often indicates active disease, while long-standing progressive osteoporosis suggests another etiology) 1
• Failing to differentiate between MGUS, SMM, and symptomatic MM, which have different management approaches 4, 5
• Not recognizing that a single asymptomatic lytic bone lesion could be a benign bone cyst or angioma rather than myeloma (CT or MRI may help differentiate) 1

Special Considerations

• In patients with suspected myeloma but without typical CRAB features, consider primary systemic amyloidosis if there is substantial albuminuria, congestive heart failure, peripheral neuropathy, orthostatic hypotension, carpal tunnel syndrome, hepatomegaly, or malabsorption 1
• Elderly patients often have concomitant diseases that can mimic myeloma features; careful evaluation is needed to determine if abnormalities are attributable to plasma cell disorder 1
• Patients with unexplained monoclonal gammopathy should be monitored regularly as progression risk continues lifelong 5