Multiple myeloma (MM) diagnosis relies on a combination of clinical findings, laboratory tests, imaging, and procedural results. Accurate diagnosis is crucial, but it’s equally important to consider the differential diagnosis to distinguish MM from other conditions with similar presentations. This article provides an in-depth look at the diagnostic criteria for multiple myeloma and explores key considerations in its differential diagnosis, aiming to enhance diagnostic precision and patient care.
Diagnostic Criteria for Multiple Myeloma
The diagnosis of multiple myeloma involves specific combinations of findings across several categories. These include:
- I – Plasmacytoma on tissue biopsy: Confirmed presence of plasma cell tumor in tissue.
- II – Bone marrow plasma cells: Bone marrow analysis showing more than 30% plasma cells.
- III – Monoclonal globulin spike: Evident on serum protein electrophoresis (SPEP), with IgG peak > 3.5 g/dL or IgA peak > 2 g/dL, or urine protein electrophoresis (UPEP) > 1 g/24 h in amyloidosis cases.
- a – Bone marrow plasma cells (intermediate): Bone marrow analysis showing 10-30% plasma cells.
- b – Monoclonal globulin spike (lower level): Present but not meeting category III criteria.
- c – Lytic bone lesions: Presence of bone damage due to myeloma.
- d – Immunoglobulin level suppression: Residual IgM < 50 mg/dL, IgA < 100 mg/dL, or IgG < 600 mg/dL.
Multiple myeloma is diagnosed when specific combinations of these findings are present, such as:
- 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
Active, or symptomatic, multiple myeloma is characterized by the following criteria:
- Clonal bone marrow plasma cells ≥10% or
- Biopsy-proven bony or extramedullary plasmacytoma and
- One or more myeloma-defining events.
Historically, myeloma-defining events were recognized by the CRAB acronym:
- Calcemia (hypercalcemia)
- Renal failure
- Anemia
- Bone lesions (lytic)
This CRAB criteria helped differentiate active MM from conditions like monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM). The criteria have since expanded to incorporate newer biomarkers and a more nuanced understanding of the disease.
Current myeloma-defining events include:
- Hypercalcemia: Serum calcium level > 0.25 mmol/L (> 1 mg/dL) above 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 per minute.
- Anemia: Hemoglobin < 10 g/dL or > 2 g/dL below the lower limit of normal.
- Bone Lesions: One or more osteolytic bone lesions on skeletal radiography, CT, or PET-CT.
- Clonal Bone Marrow Plasma Cells ≥60%.
- Serum Free Light Chain (FLC) Ratio ≥100: Involved/uninvolved serum FLC ratio ≥100 (provided involved FLC is ≥100 mg/L).
- Focal Lesions on MRI: One or more focal > 5 mm lesions on MRI scans.
Recurrent infections, amyloidosis, or hyperviscosity can also indicate active disease.
Indolent and Smoldering Multiple Myeloma
Indolent MM represents a less aggressive form of the disease with features such as:
- Absent or very limited bone disease.
- Good performance status (> 70%).
- Hemoglobin level > 10 g/dL.
- Normal serum calcium and creatinine levels.
- No infections.
- Low M protein levels.
Smoldering multiple myeloma (SMM) shares similarities with indolent MM but is defined by specific diagnostic criteria:
- 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.
To differentiate between active and smoldering MM, advanced imaging such as whole-body or skeletal MRI with contrast, or whole-body PET/CT are recommended. These imaging techniques help to identify early signs of active disease that might not be evident through standard blood tests and bone marrow analysis alone.
Differential Diagnoses of Multiple Myeloma
When considering a diagnosis of multiple myeloma, it’s essential to differentiate it from other conditions that may present with similar symptoms or laboratory findings. Key differential diagnoses include:
POEMS Syndrome
POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, Skin changes) is a rare paraneoplastic syndrome linked to a clonal plasma cell neoplasm. While it involves plasma cells and monoclonal gammopathy, similar to MM, POEMS syndrome has distinct features. The dominant features include neuropathy, endocrine dysfunction, fluid overload, elevated VEGF, and sclerotic bone lesions, unlike the lytic lesions typically seen in MM. Differentiating POEMS syndrome from MM is critical as treatment strategies differ significantly, with radiation therapy being a primary approach for POEMS.
Diagnostic criteria for POEMS syndrome include two mandatory major criteria:
- Polyneuropathy (typically demyelinating)
- Monoclonal plasma cell proliferative disorder (usually lambda light chain)
And one of three other major criteria:
- Castleman disease
- Sclerotic bone lesions
- Elevated vascular endothelial growth factor (VEGF)
Along with at least one minor criterion such as:
- Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy)
- Extravascular volume overload (edema, pleural effusion, or ascites)
- Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic)
- Skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, plethora, acrocyanosis, flushing, white nails)
- Papilledema
- Thrombocytosis/polycythemia
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Amyloidosis
Amyloidosis, particularly AL amyloidosis, can be secondary to multiple myeloma, but it can also occur independently. Patients with amyloidosis may not always meet the criteria for MM, particularly regarding bone marrow plasma cell percentage or M-protein levels. While both conditions involve plasma cell dyscrasias, the clinical presentation and the predominant organ involvement can differ. Amyloidosis often involves organ damage due to amyloid fibril deposition, which may not be the primary feature in early MM.
Solitary Plasmacytoma
Solitary plasmacytoma can manifest as a localized tumor of plasma cells in bone (osseous plasmacytoma) or soft tissue (extraosseous plasmacytoma). Osseous plasmacytomas are most common in the vertebrae. Crucially, solitary plasmacytomas, by definition, lack evidence of plasma cell myeloma or widespread marrow plasmacytosis. This localized nature and absence of systemic myeloma features distinguishes it from multiple myeloma, although solitary plasmacytoma can sometimes progress to MM.
Conclusion
Accurate differential diagnosis is paramount in managing patients suspected of having multiple myeloma. Understanding the nuances of diagnostic criteria for active, smoldering, and indolent MM, as well as recognizing conditions like POEMS syndrome, amyloidosis, and solitary plasmacytoma, ensures appropriate diagnostic pathways and targeted treatment strategies. A comprehensive evaluation integrating clinical, laboratory, and imaging findings is essential for distinguishing multiple myeloma from its mimics and providing optimal patient care.
