Multiple Myeloma: Definition and Characteristics
Multiple myeloma is a malignant neoplasm characterized by the proliferation of clonal plasma cells in the bone marrow that produce monoclonal immunoglobulin, leading to bone destruction and marrow failure, with clinical manifestations including hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB criteria). 1
Disease Overview
- Multiple myeloma accounts for approximately 1.8% of all cancers and more than 15% of hematologic malignancies in the United States 1
- The median age at diagnosis is 69 years, with the disease most frequently diagnosed among people aged 65-74 years 1
- In 2020, an estimated 32,270 new cases of multiple myeloma were diagnosed in the United States, with approximately 12,830 deaths 1
Pathophysiology
- Multiple myeloma results from the neoplastic proliferation of plasma cell clones that accumulate in the bone marrow 1
- These malignant plasma cells produce monoclonal immunoglobulin (M-protein) that can be detected in serum and/or urine 1
- The interaction between myeloma cells and the bone marrow microenvironment activates various signaling pathways (PI3K/AKT/mTOR, RAS/MAPK, JAK/STAT, Wnt/β-catenin, and NF-κB) that contribute to disease progression 2
Diagnostic Criteria
The International Myeloma Working Group (IMWG) updated the definition of multiple myeloma to include:
Clonal bone marrow plasma cells ≥10% or biopsy-proven plasmacytoma 1, 3
Additional myeloma-defining biomarkers include 1:
- ≥60% clonal plasma cells in the bone marrow
- Involved/uninvolved free light chain ratio of ≥100
- More than one focal lesion on MRI (involving bone or bone marrow)
Clinical Manifestations
- Bone disease: Osteolytic lesions, pathologic fractures, and bone pain affecting 79% of patients at presentation 5
- Anemia: Present in approximately 73% of patients at diagnosis 5
- Renal dysfunction: Acute kidney injury occurs in about 19% of patients at presentation 5
- Hypercalcemia: Results from increased bone resorption 1, 6
- Recurrent infections: Due to suppression of uninvolved immunoglobulins 6
Diagnostic Workup
Initial diagnostic workup should include:
- Complete blood count with differential and platelet counts 1
- Blood chemistry including BUN, serum creatinine, calcium, albumin, LDH, and beta-2 microglobulin 1
- Serum and urine protein electrophoresis with immunofixation 3
- Serum free light chain assay with kappa/lambda ratio 3
- Bone marrow aspiration and biopsy with CD138 staining to determine plasma cell percentage 3
- Cytogenetic/FISH studies for risk stratification 3
- Full-body skeletal imaging (CT, PET, or MRI) 5
Disease Classification
Multiple myeloma can be classified into:
- Smoldering (asymptomatic) multiple myeloma: Serum monoclonal protein (IgG or IgA) ≥30 g/L and/or clonal bone marrow plasma cells 10-60% without end-organ damage 1, 3
- Symptomatic multiple myeloma: Presence of clonal plasma cells and evidence of end-organ damage (CRAB criteria) or myeloma-defining biomarkers 1, 4
- High-risk multiple myeloma: Characterized by specific cytogenetic abnormalities such as t(4;14), t(14;16), t(14;20), del(17p), or hypodiploidy 1, 6
Common Pitfalls in Diagnosis
- Failing to distinguish between monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma, and symptomatic multiple myeloma 3
- Not performing comprehensive cytogenetic testing, which is crucial for risk stratification and treatment planning 3
- Overlooking the need for skeletal imaging in all suspected cases, even when conventional radiography is negative 3
- Initiating treatment in patients with smoldering multiple myeloma without evidence of progression to symptomatic disease 3
Multiple myeloma remains incurable in the majority of patients despite significant advances in treatment options, including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, and stem cell transplantation 7, 8, 2.