What is multiple myeloma and its pathophysiology?

Multiple Myeloma: Cancer Type and Pathophysiology

Multiple myeloma is a hematologic malignancy characterized by the malignant proliferation of clonal plasma cells that accumulate in the bone marrow and produce monoclonal immunoglobulin (M-protein). 1

Cancer Classification

• Multiple myeloma accounts for approximately 1.8% of all cancers and more than 15% of hematologic malignancies in the United States 1
• It represents 10% of all hematological malignancies in Europe, with an incidence of 4.5–6.0 per 100,000 per year 2
• The median age at diagnosis is 69-72 years, most frequently diagnosed among people aged 65-74 years 2, 1
• This is a cancer of terminally differentiated plasma cells, classified as a plasma cell dyscrasia 3, 4

Pathophysiology

Cellular Origin and Clonal Proliferation

• Multiple myeloma results from neoplastic proliferation of plasma cell clones that are late B-cell lineage cells, which accumulate in the bone marrow 1, 4
• These malignant plasma cells produce monoclonal immunoglobulin (M-protein) that can be detected in serum and/or urine 1
• The pathognomonic laboratory finding is a monoclonal immunoglobulin or free light chain in the serum and/or urine in association with bone marrow infiltration by malignant plasma cells 5

Disease Progression Pathway

• Almost all patients with multiple myeloma evolve from an asymptomatic pre-malignant stage termed monoclonal gammopathy of undetermined significance (MGUS) 2
• MGUS progresses to multiple myeloma at a rate of 1% per year 2
• An intermediate asymptomatic stage called smoldering (indolent) multiple myeloma (SMM) can occur, which progresses to myeloma at 10% per year over the first 5 years, 3% per year over the following 5 years, and 1.5% per year thereafter 2

Genetic and Molecular Subtypes

• At the top hierarchical level, myeloma can be divided into hyperdiploid and non-hyperdiploid subtypes 2
• Non-hyperdiploid myeloma is mainly composed of cases harboring IgH translocations, generally 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
• Hyperdiploid myeloma is characterized by trisomies and a more indolent form of the disease 2
• Genetic progression factors include deletions of chromosomes 13 and 17, and abnormalities of chromosome 1 (1p deletion and 1q amplification) 2

Key Molecular Drivers

• Nuclear factor-κB-activating mutations serve as key drivers of cell survival and proliferation 2
• Deregulation factors for cyclin-dependent pathway regulators contribute to disease progression 2

End-Organ Damage Mechanisms

Bone Disease Pathophysiology

• Myeloma cells and bone marrow stromal cells produce multiple cytokines that stimulate osteoclast activity, including interleukin-1, interleukin-6, tumor necrosis factor, and receptor activator of nuclear factor kappa B-ligand (RANKL) 6
• Increased osteoclast activity leads to excessive bone resorption, releasing calcium from the bone matrix into the bloodstream, causing hypercalcemia 6
• Conventional radiographs reveal lytic lesions, osteoporosis, or fractures in 79% of patients at diagnosis 6

Clinical Manifestations at Presentation

• Approximately 73% of patients have anemia at presentation 7
• 79% have osteolytic bone disease 7
• 19% have acute kidney injury at the time of diagnosis 7

Common Pitfalls

• Do not confuse MGUS or smoldering multiple myeloma with active multiple myeloma—only active multiple myeloma with end-organ damage (CRAB criteria) or specific biomarkers requires immediate treatment 2, 4
• Recognize that genetic heterogeneity drives drug resistance—the emergence of genetically heterogeneous sub-clones is a major cause of the relapsed-refractory state 8
• Understand that cytogenetic abnormalities determine prognosis—high-risk cytogenetics including t(4;14), t(14;16), del(17p) predict more aggressive disease and should guide treatment intensity 9, 7