What is multiple myeloma?

What is Multiple Myeloma

Multiple myeloma is a hematologic malignancy characterized by the neoplastic proliferation of clonal plasma cells that accumulate in the bone marrow, producing abnormal monoclonal immunoglobulin (M-protein) detectable in serum and/or urine, with potential for causing destructive bone lesions, kidney injury, anemia, and hypercalcemia. 1, 2

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
• The annual worldwide incidence is estimated to be 6-7 per 100,000 population 3

Pathophysiology

• The disease results from malignant transformation of normal plasma cells into clonal myeloma cells that accumulate in the bone marrow 1, 3
• These malignant plasma cells produce large quantities of monoclonal immunoglobulin (M-protein), which is an abnormal antibody that serves as a disease marker 1, 3
• The interaction between myeloma cells and the bone marrow microenvironment occurs through soluble cytokines and cell adhesion molecules, activating multiple signaling pathways including PI3K/AKT/mTOR, RAS/MAPK, JAK/STAT, Wnt/β-catenin, and NF-κB 4
• Aberrant activation of these pathways contributes to proliferation, survival, migration, and drug resistance of myeloma cells 4

Clinical Presentation and End-Organ Damage (CRAB Criteria)

At presentation, patients commonly exhibit the following manifestations:

• Bone disease: Lytic bone lesions, severe osteopenia, or pathologic fractures occur in approximately 79% of patients 1, 2
• Anemia: Hemoglobin <10 g/dL or ≥2 g/dL below lower limit of normal, present in approximately 73% of patients 1, 2
• Renal insufficiency: Serum creatinine >2 mg/dL or creatinine clearance <40 mL/min, with acute kidney injury occurring in 16-31% of patients at diagnosis 5, 6
• Hypercalcemia: Serum calcium >11.5 mg/dL 1, 5

Diagnostic Criteria

The International Myeloma Working Group requires clonal bone marrow plasma cells ≥10% or biopsy-proven plasmacytoma PLUS evidence of end-organ damage (CRAB criteria) or specific myeloma-defining biomarkers. 1, 5

Myeloma-Defining Biomarkers (in absence of CRAB criteria):

• ≥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

Disease Classification Spectrum

• MGUS (Monoclonal Gammopathy of Undetermined Significance): Serum monoclonal protein <3 g/dL, clonal bone marrow plasma cells <10%, and absence of end-organ damage; no immediate treatment required 5
• Smoldering Multiple Myeloma: Serum monoclonal protein ≥3 g/dL and/or clonal bone marrow plasma cells 10-60% without end-organ damage; 10% per year risk of progression for first 5 years; requires closer monitoring but no immediate treatment 1, 5
• Symptomatic Multiple Myeloma: Presence of clonal plasma cells with evidence of end-organ damage (CRAB criteria) or myeloma-defining biomarkers; requires immediate treatment 1, 5
• 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

Required Diagnostic Workup

• Complete blood count with differential and platelet counts 1
• Serum calcium, creatinine, β2-microglobulin, albumin, and lactate dehydrogenase 1, 2
• Serum and urine protein electrophoresis with immunofixation (24-hour urine collection, not random sample) 1, 5
• Nephelometric quantification of IgG, IgA, and IgM immunoglobulins 5
• Serum free light chain assay with kappa/lambda ratio 1, 5
• Bone marrow aspiration and biopsy with CD138 staining to accurately determine plasma cell percentage 1, 5
• Cytogenetic/FISH studies for risk stratification 1, 5
• Full-body skeletal imaging with computed tomography, positron emission tomography, or magnetic resonance imaging 2, 7

Prognosis and Staging

• The Revised International Staging System combines serum biomarkers (β2 microglobulin, albumin, lactate dehydrogenase) with genomic features from fluorescence in situ hybridization to assess estimated progression-free survival and overall survival 2
• At diagnosis, 28% of patients are classified as Revised International Staging stage I, with a median 5-year survival of 82% 2
• Despite significant treatment advances over the last two decades, multiple myeloma remains incurable but can be classified as a chronic disease with improved outcomes 8, 7