Pathogenesis and molecular mechanisms
The disease is based on the clonal expansion of a single plasma cell clone synthesizing identical heavy and light chains of immunoglobulins—the so-called M-component. Tumor cell proliferation is actively supported by the cytokine IL-6, which is produced by bone marrow stromal fibroblasts and macrophages.
At the genetic level, frequent alterations include chromosomal translocations in the IgG locus region on chromosome 14, as well as aberrations of chromosome 4 with a mutation in the fibroblast growth factor receptor gene (FGFR3). The tumor grows from the bone marrow cavities toward the cortical layer, and the secretion of specific factors activates osteoclasts, causing massive bone tissue resorption.
Clinical and morphological manifestations
Skeletal involvement primarily affects the spine, ribs, and flat bones of the skull. Radiologically, destruction foci appear as “punched-out” holes, which carries a risk of pathological fractures and vertebral collapse.
Blood tests show a high ESR (it is not elevated in light-chain myeloma), formation of erythrocyte “rouleaux”, and hyperviscosity syndrome. Replacement of the bone marrow by tumor masses leads to normocytic normochromic anemia, neutropenia, and thrombocytopenia, making patients extremely susceptible to infections.
Kidney damage develops due to hypercalcemia, nephrocalcinosis, and filtration of low-molecular-weight Bence Jones protein, leading to uremia.
Laboratory diagnostics and cytology
To confirm the diagnosis, serum protein electrophoresis is used, where paraproteins are visualized as dense bands in the globulin zone, alongside confirmatory methods (immunoelectrophoresis).
Cytological examination of bone marrow aspirate reveals a predominance of plasmablasts, mature plasmacytes, and intermediate forms with signs of atypia (multinucleation). A characteristic morphological feature is intracellular protein aggregates—Russell bodies. Normally, plasma cells account for less than 10% of the cellular composition, whereas in myeloma this figure is multiplied many times over.
Briefly: answers to topical questions
What pathological processes underlie the development of myeloma nephropathy (myeloma kidney)?
Myeloma nephropathy is caused by damage to nephron structures by monoclonal light chains. Key pathological processes include:
- Cast nephropathy — formation of protein casts in the tubules, necrosis of the surrounding epithelium, and development of a granulomatous reaction in the interstitium.
- Overflow proteinuria — increased production of low-molecular-weight proteins, including Bence Jones protein, the amount of which exceeds the reabsorption capacity of the tubules.
- Nephrocalcinosis — as a consequence of polyuria and hypercalciuria.
- Associated processes — AL amyloidosis, light-chain disease (glomerulopathy), and membranous nephropathy.
Which classes of immunoglobulin heavy chains can be secreted in multiple myeloma besides IgG?
Besides IgG, the following classes of immunoglobulin heavy chains can be secreted in multiple myeloma:
- IgA — detected in 25% of patients.
- IgM — less common.
- IgD and IgE — rarely secreted.
A light-chain disease variant is also possible, in which heavy chains are not synthesized, and only light chains are produced.
Which pathologies require differential diagnosis with multiple myeloma?
Differential diagnosis of multiple myeloma includes:
- Secreting lymphoma.
- Plasmacytoma.
- Monoclonal gammopathy of undetermined significance, in which the M-component is detected in clinically healthy individuals.
- Hairy cell leukemia: detection of significant monoclonal secretion is an indication to revise the diagnosis.
What clinical and laboratory signs are included in the CRAB diagnostic symptom complex?
The CRAB diagnostic symptom complex includes the classic tetrad of clinical and laboratory signs:
- Hypercalcemia (Calcium) — develops as a result of intensive osteolysis.
- Renal failure (Renal failure) — occurs due to kidney damage.
- Anemia (Anemia) — results from the displacement of normal hematopoiesis by tumor plasmacytes in the bone marrow.
- Bone lesions (Bone lesions) — include lytic lesions, pathological fractures, and bone pain (mainly in the spine, ribs, and skull bones).
MBN-MENYE: Myeloma, Bence Jones protein, Monoclonal rouleaux, Extreme osteolysis (punched-out holes), Neutropenia with anemia, Y (high ESR), Even kidneys (uremia).
Class and exam questions
What is Bence Jones protein and in which form is it excreted?
These are free immunoglobulin light chains (monomers or dimers with a mass of 25 kDa) that are excreted in the urine and precipitate upon cooling. They are detected in light-chain disease (in 20% of patients) or combined synthesis.
Why do bones break down in multiple myeloma?
Tumor plasma cells secrete specific factors that activate osteoclasts, enhancing bone resorption. The tumor grows from the bone marrow toward the cortical layer, forming characteristic osteolytic lesions (“punched-out holes”).
What are the main causes of death in patients with myeloma?
Common causes of death include severe infectious complications (due to neutropenia and hypogammaglobulinemia), renal failure (uremia against the background of nephrocalcinosis and proteinuria), as well as severe consequences of vertebral collapse and pathological fractures.
What else to study on this topic
- Solitary myeloma (plasmacytoma) and its differences from the systemic process
- Monoclonal gammopathy of undetermined significance (benign gammopathy)
- Heavy chain diseases and primary immunocyte-associated amyloidosis
- Blood hyperviscosity syndrome: mechanisms of development and microscopy
- Extramedullary foci of tumor growth and plasma cell leukemia
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