Multiple Myeloma
Comprehensive Exam Focused Summary
1) Where Multiple Myeloma Fits (Monoclonal
Gammopathies / Plasma Cell Dyscrasias)
● Monoclonal gammopathies (plasma cell dyscrasias / paraproteinemias) include: MGUS, Multiple
Myeloma, Light-chain (AL) amyloidosis, Solitary plasmacytoma, Waldenstrom macroglobulinemia,
Heavy-chain disease.
● Normally, antibodies are gamma globulins made of: 5 heavy-chain isotypes (IgM, IgA, IgG, IgE, IgD) +
2 light-chain subtypes (kappa, lambda).
● In plasma cell dyscrasias, immunoglobulins or their fragments may be produced in excess; free light
chains are cleared by the kidney and can be detected in urine (e.g., UPEP).
● The immunoglobulin type is determined by immuno-electrophoresis / immunofixation.
● Bone marrow infiltration can lead to pancytopenia due to suppression of hematopoiesis.
Clinical Pearls
> A urine dipstick can be negative even with significant light-chain
proteinuria because dipsticks mainly detect albumin (!!classic test trap).
> Think of monoclonal gammopathy when you see an elevated total protein
with a ‘gamma gap’ and/or rouleaux formation.
2) Definition
● Multiple myeloma is a malignant plasma cell dyscrasia characterized by uncontrolled proliferation
and diffuse infiltration of monoclonal plasma cells in the bone marrow.
● Plasma cell dyscrasia = abnormal proliferation of the same (monoclonal) plasma cell type that may
secrete a monoclonal immunoglobulin and/or immunoglobulin fragment (e.g., light chain).
3) Epidemiology
● Sex: more common in males (≈ 3:2).
● Peak incidence: 50–70 years.
4) Classification (by Immunoglobulin Type)
● IgG and IgA: ‘typical’ multiple myeloma; the majority of patients.
● Bence Jones myeloma (free light chains excreted in urine): ~15–20% of multiple myelomas.
● IgD, IgE, and IgM: very rare subtypes.
Clinical Pearls
, > Bence Jones proteins = monoclonal immunoglobulin light chains produced
by neoplastic plasma cells; their presence strongly suggests a plasma cell
disorder.
5) Mechanism / Pathophysiology
A) Neoplastic proliferation of plasma cells
● Bone marrow infiltration by malignant plasma cells → suppression of hematopoiesis → leukopenia,
thrombocytopenia, and anemia.
● Cell proliferation → release of pro-osteoclastogenic factors (e.g., TNF-alpha, IL-1, RANK-L) →
osteolytic lesions → hypercalcemia(test trap!).
B) Overproduction of monoclonal immunoglobulin and/or light
chains
● Overproduction → dysproteinemia (pathologically increased synthesis of immunoglobulins and/or
their subunits) → kidney damage (e.g., myeloma cast nephropathy) and/or paraprotein tissue
deposition (may cause amyloidosis).
● Nonfunctioning antibodies → functional antibody deficiency → ↑ risk of infection.
● Increased serum viscosity → hyperviscosity syndrome (test trap!).
Clinical Pearls !
!!! CRAB organ damage is the classic clinical consequence of marrow + bone +
renal involvement.
!!! Osteolytic lesions in myeloma are typically ‘punched-out’ and lack sclerotic
margins.
6) Clinical Picture
● Often asymptomatic early.
● Constitutional symptoms: mild fever, night sweats, weakness, weight loss.
● Bone pain—especially back pain—is the most common symptom (important!).
● Symptoms of hypercalcemia (variable, can be subtle early).
● Spontaneous/pathological fractures.
● Foamy urine (Bence Jones proteins in urine).
● Increased risk of petechial bleeding (from thrombocytopenia).
● Increased risk of infection (functional antibody deficiency).
● Enlarged lymph nodes are NOT a typical finding (Beware!).
Clinical Pearls
>Back pain + anemia + high total protein (gamma gap) should immediately
trigger evaluation for myeloma.
Comprehensive Exam Focused Summary
1) Where Multiple Myeloma Fits (Monoclonal
Gammopathies / Plasma Cell Dyscrasias)
● Monoclonal gammopathies (plasma cell dyscrasias / paraproteinemias) include: MGUS, Multiple
Myeloma, Light-chain (AL) amyloidosis, Solitary plasmacytoma, Waldenstrom macroglobulinemia,
Heavy-chain disease.
● Normally, antibodies are gamma globulins made of: 5 heavy-chain isotypes (IgM, IgA, IgG, IgE, IgD) +
2 light-chain subtypes (kappa, lambda).
● In plasma cell dyscrasias, immunoglobulins or their fragments may be produced in excess; free light
chains are cleared by the kidney and can be detected in urine (e.g., UPEP).
● The immunoglobulin type is determined by immuno-electrophoresis / immunofixation.
● Bone marrow infiltration can lead to pancytopenia due to suppression of hematopoiesis.
Clinical Pearls
> A urine dipstick can be negative even with significant light-chain
proteinuria because dipsticks mainly detect albumin (!!classic test trap).
> Think of monoclonal gammopathy when you see an elevated total protein
with a ‘gamma gap’ and/or rouleaux formation.
2) Definition
● Multiple myeloma is a malignant plasma cell dyscrasia characterized by uncontrolled proliferation
and diffuse infiltration of monoclonal plasma cells in the bone marrow.
● Plasma cell dyscrasia = abnormal proliferation of the same (monoclonal) plasma cell type that may
secrete a monoclonal immunoglobulin and/or immunoglobulin fragment (e.g., light chain).
3) Epidemiology
● Sex: more common in males (≈ 3:2).
● Peak incidence: 50–70 years.
4) Classification (by Immunoglobulin Type)
● IgG and IgA: ‘typical’ multiple myeloma; the majority of patients.
● Bence Jones myeloma (free light chains excreted in urine): ~15–20% of multiple myelomas.
● IgD, IgE, and IgM: very rare subtypes.
Clinical Pearls
, > Bence Jones proteins = monoclonal immunoglobulin light chains produced
by neoplastic plasma cells; their presence strongly suggests a plasma cell
disorder.
5) Mechanism / Pathophysiology
A) Neoplastic proliferation of plasma cells
● Bone marrow infiltration by malignant plasma cells → suppression of hematopoiesis → leukopenia,
thrombocytopenia, and anemia.
● Cell proliferation → release of pro-osteoclastogenic factors (e.g., TNF-alpha, IL-1, RANK-L) →
osteolytic lesions → hypercalcemia(test trap!).
B) Overproduction of monoclonal immunoglobulin and/or light
chains
● Overproduction → dysproteinemia (pathologically increased synthesis of immunoglobulins and/or
their subunits) → kidney damage (e.g., myeloma cast nephropathy) and/or paraprotein tissue
deposition (may cause amyloidosis).
● Nonfunctioning antibodies → functional antibody deficiency → ↑ risk of infection.
● Increased serum viscosity → hyperviscosity syndrome (test trap!).
Clinical Pearls !
!!! CRAB organ damage is the classic clinical consequence of marrow + bone +
renal involvement.
!!! Osteolytic lesions in myeloma are typically ‘punched-out’ and lack sclerotic
margins.
6) Clinical Picture
● Often asymptomatic early.
● Constitutional symptoms: mild fever, night sweats, weakness, weight loss.
● Bone pain—especially back pain—is the most common symptom (important!).
● Symptoms of hypercalcemia (variable, can be subtle early).
● Spontaneous/pathological fractures.
● Foamy urine (Bence Jones proteins in urine).
● Increased risk of petechial bleeding (from thrombocytopenia).
● Increased risk of infection (functional antibody deficiency).
● Enlarged lymph nodes are NOT a typical finding (Beware!).
Clinical Pearls
>Back pain + anemia + high total protein (gamma gap) should immediately
trigger evaluation for myeloma.
