What is multiple myeloma?

What is Multiple Myeloma

Multiple myeloma is a malignant neoplasm of plasma cells that accumulate in the bone marrow, producing monoclonal immunoglobulin (M-protein) and causing end-organ damage characterized by hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB criteria). 1, 2, 3

Epidemiology and Demographics

• Multiple myeloma accounts for approximately 1.8% of all cancers and more than 15% of hematologic malignancies in the United States, making it the second most common hematologic cancer 3, 4
• An estimated 34,920 new cases are diagnosed annually in the US, with approximately 588,161 cases worldwide 4
• The median age at diagnosis is 69 years, with the disease most frequently diagnosed among people aged 65-74 years 3, 5

Pathophysiology

• The disease results from neoplastic proliferation of a single clone of plasma cells that accumulate in the bone marrow and produce monoclonal protein detectable in serum and/or urine 3, 6
• Malignant plasma cells interact with the bone marrow microenvironment 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 7
• The disease is characterized by genomic instability with multiple genetic abnormalities affecting several oncogenic pathways 8

Clinical Presentation at Diagnosis

• Approximately 73% of patients present with anemia, 79% have osteolytic bone disease, and 19% have acute kidney injury 4
• The malignant proliferation produces skeletal destruction leading to bone pain and pathologic fractures 6
• M-protein can lead to renal failure, hyperviscosity syndrome, or through suppression of uninvolved immunoglobulins, recurrent infections 6
• Hypercalcemia is a common complication at presentation 6, 5

Diagnostic Criteria (CRAB + Biomarkers)

• The International Myeloma Working Group requires ≥10% clonal bone marrow plasma cells or biopsy-proven plasmacytoma PLUS evidence of end-organ damage (CRAB criteria) or specific myeloma-defining biomarkers 2, 3

CRAB Criteria for End-Organ Damage:

• C (Calcium): Serum calcium >11.5 mg/dL 1, 2
• R (Renal): Serum creatinine >2 mg/dL or creatinine clearance <40 mL/min 1, 2
• A (Anemia): Hemoglobin <10 g/dL or ≥2 g/dL below lower limit of normal 1, 2
• B (Bone): Lytic lesions, severe osteopenia, or pathologic fractures on skeletal survey 1, 2

Myeloma-Defining Biomarkers (Alternative to CRAB):

• ≥60% clonal plasma cells in the bone marrow 3
• Involved/uninvolved free light chain ratio of ≥100 3
• More than one focal lesion on MRI 3

Required Diagnostic Workup

• Complete blood count with differential and platelet counts 3
• Blood chemistry including serum calcium, creatinine, and β2-microglobulin 2, 3
• Serum protein electrophoresis with immunofixation to identify monoclonal protein 2, 3
• 24-hour urine collection for protein electrophoresis and immunofixation (not random sample) 2
• Nephelometric quantification of IgG, IgA, and IgM immunoglobulins 2
• Serum free light chain assay with kappa/lambda ratio 2, 3
• Bone marrow aspiration and biopsy with CD138 staining to accurately quantify plasma cell percentage 2, 3
• Cytogenetic/FISH studies for risk stratification 2, 3
• Full-body skeletal imaging with computed tomography, positron emission tomography, or magnetic resonance imaging 4

High-Risk Genetic Features

• High-risk disease is characterized by specific cytogenetic abnormalities including t(4;14), t(14;16), t(14;20), del(17p), or hypodiploidy 3, 6
• Commonly detected genetic aberrations include translocations involving immunoglobulin heavy chain (IgH) switch regions (chromosome 14q32) and oncogenes such as c-maf [t(14:16)], cyclin D1 [t(11:14)], and FGFR3/MMSET [t(4:14)] 8
• High-risk disease accounts for approximately 25% of patients with symptomatic multiple myeloma 6

Disease Spectrum and Critical Distinctions

• MGUS (Monoclonal Gammopathy of Undetermined Significance): Serum monoclonal protein <3 g/dL, clonal bone marrow plasma cells <10%, and no CRAB criteria or myeloma-defining biomarkers; progresses to MM at approximately 1% per year 2, 5
• Smoldering Multiple Myeloma (SMM): Serum monoclonal protein ≥3 g/dL and/or clonal bone marrow plasma cells 10-60% without end-organ damage; intermediate stage with 10% per year progression risk for first 5 years 2, 3, 5
• Symptomatic Multiple Myeloma: Presence of clonal plasma cells and evidence of end-organ damage (CRAB criteria) or myeloma-defining biomarkers; requires immediate treatment 2, 3

Prognosis

• The Revised International Staging System combines serum biomarkers (β2 microglobulin, albumin, lactate dehydrogenase) with genomic features [t(4;14), del(17p), t(14;16)] to assess prognosis 4
• Stage I patients (28% at diagnosis) have a median 5-year survival of 82% 4
• Despite significant treatment advances, multiple myeloma remains incurable in the majority of patients, with survival time range of 5-7 years for newly diagnosed patients 5, 7