Multiple myeloma and related plasma cell disorders

General features of plasma cell tumors

• Tumors of plasma cells (terminal differentiated B-cells)
• Originate from a clone of B-cells that differentiate into plasma cells and secrete a single complete or partial immunoglobulin → detectable in serum as M protein (= monoclonal gammopathy)
• Affects middle-aged and elderly patients; peak at 70 years

6 major types:

1. Multiple myeloma (most important)
2. Solitary plasmacytoma
3. Lymphoplasmacytic lymphoma
4. Heavy-chain disease
5. Primary amyloidosis
6. Monoclonal gammopathy of undetermined significance (MGUS)

---

1. Multiple Myeloma

Definition

Clonal proliferation of neoplastic plasma cells (“myeloma cells”) in BM → multiple lytic lesions throughout the skeleton.

Pathogenesis

• Tumor proliferation supported by IL-6 from fibroblasts and macrophages in BM stroma
• Chromosomal translocations of IgH (chr. 14) with fusion partners cyclin D1, FGFR3, cyclin D3 → dysregulation of D cyclins → uncontrolled growth

Morphology

• BM: proliferating mature plasma cells → erode cortical bone → multifocal lytic lesions (vertebrae, ribs, skull, pelvis, femur)
• Bone resorption: myeloma cytokines → RANK-ligand → osteoclast activation
• Cells: oval, basophilic cytoplasm, prominent nucleoli
• Infiltrate spleen, liver, kidneys, lymph nodes later

Renal involvement (“myeloma kidney”):

• a) Bence-Jones proteins (free light chains) → obstructive casts in distal tubules → giant cell reaction → acute tubular necrosis
• b) Light chain deposition in glomeruli/interstitium → AL amyloidosis
• c) Hypercalcemia → metastatic calcification → nodular glomerular lesions

Clinical features

• Bone pain / pathologic fractures
• Hypercalcemia → neurological symptoms, renal dysfunction
• Anemia (marrow replacement)
• Infections (↓ normal Ig secretion)
• Renal insufficiency (Bence-Jones toxicity, hypercalcemia, infections)
• Hyperviscosity (large amounts of M-protein)
• Treatment: chemotherapy + autologous BM transplant
• Median survival: 4–6 years

---

2. Solitary Plasmacytoma

• Plasma cell tumor involving skeleton or soft tissue
• Same skeletal locations as multiple myeloma → progresses to multiple myeloma in 5–10 years
• Soft tissue (upper respiratory tract): rare; curable by local surgery

---

3. Lymphoplasmacytic Lymphoma (Waldenström Macroglobulinemia)

• Peak incidence 60–70 years
• Mixed B-cell proliferation: small lymphocytes + plasmacytic lymphocytes + plasma cells
• M component is IgM (unlike myeloma which is IgG/IgA)
• Large IgM → viscous blood → Waldenström macroglobulinemia
• BM, spleen, lymph node infiltration; no osteolysis (no lytic bone lesions)
• Treatment: chemotherapy + plasmapheresis

---

4. Heavy-Chain Disease

• Only heavy chains produced; most commonly IgA
• Found in IgA-producing tissues: small intestine, respiratory tract
• IgG subtype histologically resembles lymphoplasmacytic lymphoma

---

5. Primary Amyloidosis

• Monoclonal plasma cell proliferation → secretes free light chains
• Amyloid deposits: AL type

---

6. MGUS (Monoclonal Gammopathy of Undetermined Significance)

• M protein found in serum of asymptomatic persons >50 years
• Considered a form of neoplasia
• Same chromosomal translocations as multiple myeloma
• Progress to well-defined plasma cell dyscrasia at ~1% per year

💡 High-yield: Multiple myeloma = lytic bone lesions + Bence-Jones proteins + hypercalcemia + anemia + infections. Morphology: BM plasma cells, RANK-L osteoclast activation, myeloma kidney. M protein = IgG/IgA. Waldenström = IgM + hyperviscosity, NO bone lesions. MGUS → 1%/yr progression risk.