What is multiple myeloma?

What is Multiple Myeloma?

Multiple myeloma is a malignant blood cancer characterized by the neoplastic proliferation of plasma cell clones that accumulate in the bone marrow, producing abnormal monoclonal immunoglobulin (M-protein) and causing end-organ damage through hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB criteria). 1

Epidemiology and Demographics

• Multiple myeloma accounts for approximately 1.8% of all cancers and more than 15% of hematologic malignancies in the United States 1
• In 2020, an estimated 32,270 new cases were diagnosed in the United States, with approximately 12,830 deaths 1
• The median age at diagnosis is 69 years, with the disease most frequently diagnosed among people aged 65-74 years 1
• It represents the second most common hematological malignancy and accounts for 10%-15% of all hematologic malignancies 2

Pathophysiology and Disease Mechanism

• The disease results from 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 pathogenesis involves interaction between myeloma cells and the bone marrow microenvironment through soluble cytokines and cell adhesion molecules 3
• Multiple signaling pathways become aberrantly activated, including PI3K/AKT/mTOR, RAS/MAPK, JAK/STAT, Wnt/β-catenin, and NF-κB pathways, contributing to proliferation, survival, migration, and drug resistance 3

Diagnostic Criteria (IMWG Definition)

The diagnosis requires two essential components:

• Clonal bone marrow plasma cells ≥10% or biopsy-proven plasmacytoma 1, 4
• Evidence of end-organ damage (CRAB criteria) OR specific myeloma-defining biomarkers 1, 4

CRAB Criteria for End-Organ Damage

• Hypercalcemia: Serum calcium >11.5 mg/dL 4
• Renal insufficiency: Serum creatinine >2 mg/dL or creatinine clearance <40 mL/min 4
• Anemia: Hemoglobin <10 g/dL or ≥2 g/dL below lower limit of normal 4
• Bone lesions: Lytic lesions, severe osteopenia, or pathologic fractures 4

Myeloma-Defining Biomarkers (Without CRAB)

• ≥60% clonal plasma cells in the bone marrow 1
• Involved/uninvolved free light chain ratio of ≥100 1
• More than one focal lesion on MRI 1

Required Diagnostic Workup

Laboratory testing must include: 1, 4

• Complete blood count with differential and platelet counts
• Blood chemistry including serum calcium, creatinine, and β2-microglobulin
• Serum protein electrophoresis with immunofixation
• 24-hour urine collection for protein electrophoresis (not random sample)
• Nephelometric quantification of IgG, IgA, and IgM immunoglobulins
• Serum free light chain assay with kappa/lambda ratio
• Bone marrow aspiration and biopsy with CD138 staining
• Cytogenetic/FISH studies for risk stratification

Imaging studies required: 1

• Skeletal survey and/or MRI of thoracic-lumbar spine and pelvis
• Consider PET or CT for comprehensive bone disease assessment

Disease Classification and Risk Stratification

Clinical Stages

• MGUS (Monoclonal Gammopathy of Undetermined Significance): Serum monoclonal protein <3 g/dL, clonal bone marrow plasma cells <10%, and absence of CRAB criteria 4
• Smoldering Multiple Myeloma: Serum monoclonal protein ≥3 g/dL and/or clonal bone marrow plasma cells 10-60% without end-organ damage 1, 4
• Symptomatic Multiple Myeloma: Presence of clonal plasma cells and evidence of CRAB criteria or myeloma-defining biomarkers 1

Risk Stratification

High-risk multiple myeloma is defined by specific cytogenetic abnormalities: 1

• t(4;14), t(14;16), t(14;20) translocations
• del(17p)
• Hypodiploidy or deletion of chromosome 13 with conventional cytogenetics
• High-risk disease accounts for approximately 25% of patients with symptomatic multiple myeloma 5

Clinical Manifestations

Common presenting features include: 5, 2, 6

• Anemia (present in approximately 73% at diagnosis)
• Osteolytic bone disease (present in approximately 79% at diagnosis)
• Bone pain and pathologic fractures from skeletal destruction
• Acute kidney injury (present in approximately 19% at diagnosis)
• Hypercalcemia
• Recurrent infections due to suppression of uninvolved immunoglobulins
• Hyperviscosity syndrome (less common)

Critical Distinctions to Avoid Misdiagnosis

• MGUS requires no immediate treatment, only lifelong monitoring 4
• Smoldering multiple myeloma requires closer monitoring than MGUS (10% per year progression risk for first 5 years) but immediate treatment is not currently recommended 4
• Symptomatic multiple myeloma meeting CRAB criteria requires immediate treatment initiation, as delaying treatment increases morbidity and mortality 7
• The presence of monoclonal protein alone without plasma cell infiltration or end-organ damage does not constitute multiple myeloma 4