Multiple Myeloma Differential Diagnoses

Updated: Sep 13, 2023
  • Author: Dhaval Shah, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Diagnostic Considerations

The most widely accepted schema for the diagnosis of multiple myeloma (MM) uses particular combinations of laboratory, imaging, and procedure findings as diagnostic criteria. (See Workup.) The findings are as follows:

  • I = Plasmacytoma on tissue biopsy
  • II = Bone marrow with greater than 30% plasma cells
  • III = Monoclonal globulin spike on serum protein electrophoresis, with an immunoglobulin (Ig) G peak of greater than 3.5 g/dL or an IgA peak of greater than 2 g/dL, or urine protein electrophoresis (in the presence of amyloidosis) result of greater than 1 g/24 h
  • a = Bone marrow with 10-30% plasma cells
  • b = Monoclonal globulin spike present but less than category III
  • c = Lytic bone lesions
  • d = Residual IgM level less than 50 mg/dL, IgA level less than 100 mg/dL, or IgG level less than 600 mg/dL

The following combinations of findings are used to make the diagnosis of MM:

  • I plus b, c, or d
  • II plus b, c, or d
  • III plus a, c, or d
  • a plus b plus c
  • a plus b plus d

Active multiple myeloma

Criteria for the diagnosis of active (symptomatic) MM are as follows [2] :

  • Clonal bone marrow plasma cells ≥10% or
  • Biopsy-proven bony or extramedullary plasmacytoma and
  • One or more myeloma-defining events

Myeloma-defining events include the following [2] :

  • Serum calcium level >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 PET-CT
  • Clonal bone marrow plasma cells ≥60%
  • Abnormal serum free light chain (FLC) ratio ≥100 (involved kappa) or < 0.01 (involved lambda)
  • One or more focal >5 mm lesions on MRI scans

Active disease may also be indicated by repeated infections, amyloidosis, or hyperviscosity.

Indolent and smoldering multiple myeloma

Indolent MM is a subset of MM with the following features:

  • Bone disease absent (or very limited)
  • Performance status greater than 70%
  • Hemoglobin level greater than 10 g/dL
  • Serum calcium level within the reference range
  • Creatinine level < 2 mg/dL
  • No infections
  • Low M protein levels (ie, < 7 g/dL for IgG, < 5 g/dL for IgA)

Smoldering (asymptomatic) MM is similar to indolent MM. Diagnostic criteria for smoldering MM are as follows [2] :

  • Serum monoclonal protein: IgG or IgA ≥3 g/dL, or
  • Bence-Jones protein ≥500 mg/24 h and/or
  • Clonal bone marrow plasma cells 10%–60% and
  • Absence of myeloma-defining events or amyloidosis

The National Comprehensive Cancer Network recommends whole-body or skeletal magnetic resonance imaging (MRI), with contrast, or whole-body positron emission tomography/computed tomography (PET/CT) to differentiate active from smoldering MM. [2]

Other problems to be considered

Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare syndrome consisting of polyneuropathy, organomegaly, endocrinopathy, M protein deviations, and skin changes.

Amyloidosis is often secondary to MM, but it may develop without MM. Patients with amyloidosis typically lack sufficient numbers of plasma cells in the bone marrow or sufficiently high levels of M protein to meet the diagnostic criteria for MM.

Differential Diagnoses