What is multiple myeloma?

What is Multiple Myeloma

Multiple myeloma is a malignant cancer characterized by the clonal proliferation of plasma cells in the bone marrow that produce abnormal monoclonal immunoglobulin (M-protein), leading to bone destruction, renal failure, anemia, and hypercalcemia. 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
• The median age at diagnosis is 69 years, with most cases diagnosed between ages 65-74 years 1
• In 2020, approximately 32,270 new cases were diagnosed in the United States, with 12,830 deaths 1
• The disease is twice as common in males compared to females and more prevalent in Black individuals than White individuals, with the lowest incidence in Asian populations 2

Pathophysiology

• The disease originates from neoplastic B-lymphocytes from the follicular germinal center of lymph nodes that migrate to the bone marrow 2
• These malignant plasma cells directly interact with stromal cells and extracellular matrix, producing monoclonal immunoglobulin detectable in serum and/or urine 1
• Interleukin-6 is the most crucial cytokine driving MM growth, exerting both proliferative and anti-apoptotic effects 2
• The malignant cells activate osteoclastogenesis while inhibiting osteoblasts, leading to bone loss and osteolytic lesions 2
• Neoplastic plasma cells stimulate bone marrow angiogenesis through production of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) 2
• Advanced disease is characterized by increased angiogenesis with focal lesions, while end-stage disease features highly proliferative plasmablasts that can cause extramedullary dissemination or plasma cell leukemia 2

Genetic Classification

Multiple myeloma can be stratified into two major genetic subtypes based on recurring genomic aberrations 2:

Hyperdiploid Myeloma (40-60% of patients)

• Characterized by multiple trisomies with 47-75 chromosomes total 2
• Generally associated with more indolent disease and better prognosis 2
• Rare or absent IgH translocations 2

Non-Hyperdiploid Myeloma

• Characterized by IgH translocations, typically associated with more aggressive clinical features and shorter survival 2
• The three main IgH translocations are t(11;14)(q13;q32), t(4;14)(p16;q32), and t(14;16)(q32;q23) 2

Genetic Progression Factors

• Deletions of chromosomes 13 and 17 2
• Chromosome 1 abnormalities (1p deletion and 1q amplification) 2
• Nuclear factor-κB-activating mutations and deregulation of cyclin-dependent pathway regulators 2

Diagnostic Criteria

The International Myeloma Working Group defines multiple myeloma by the presence of 1:

Required Findings

• Clonal bone marrow plasma cells ≥10% OR biopsy-proven plasmacytoma 1

PLUS Evidence of End-Organ Damage (CRAB Criteria)

• Calcium elevation: Serum calcium >11.0 mg/dL 3
• Renal insufficiency: Serum creatinine >2.0 mg/dL 3
• Anemia: Hemoglobin <10 g/dL or 2 g/dL below lower limit of normal 3
• Bone lesions: Lytic lesions, severe osteopenia, or pathologic fractures 3

OR Myeloma-Defining Biomarkers (Without CRAB Features)

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

Disease Classification

Smoldering (Asymptomatic) Multiple Myeloma

• Serum monoclonal protein (IgG or IgA) ≥30 g/L and/or clonal bone marrow plasma cells 10-60% 1
• No evidence of end-organ damage or myeloma-defining biomarkers 1
• Observation without immediate treatment is recommended, with monitoring at 3-6 month intervals 3

Symptomatic Multiple Myeloma

• Presence of clonal plasma cells with evidence of end-organ damage (CRAB criteria) or myeloma-defining biomarkers 1
• Requires immediate treatment 4

High-Risk Multiple Myeloma

• Defined by specific cytogenetic abnormalities: t(4;14), t(14;16), t(14;20), del(17p), gain 1q, or p53 mutation 4
• Associated with poor prognosis and requires more aggressive treatment approaches 4

Clinical Presentation

• Extramedullary disease can occur in advanced cases 3
• Risk factors include occupational exposure to pesticides, petroleum, ionizing radiation, and presence of monoclonal gammopathy of undetermined significance (MGUS) 2
• The disease is preceded by MGUS, which progresses to MM at approximately 1% per year 5
• Some patients experience an intermediate phase called smoldering multiple myeloma (SMM), with most cases progressing to MM over 15 years 5