= hematologic malignancy characterized by monoclonal proliferation of mature plasma cells

Precursor: premalignant asymptomatic monoclonal gammopathy of undetermined significance (MGUS) with cumulative risk for progression to multiple myeloma of 1% per year / Waldenström macroglobulinemia / lymphoma / primary amyloidosis / chronic lymphocytic leukemia

Frequency: 10% of all hematologic malignancies

• Most common primary malignant neoplasm in adults!
• Most frequent primary neoplasm of bone marrow!
• Most common primary osseous malignancy in elderly
• 2^nd most common hematologic malignancy after NHL

Incidence: 22,350 new patients + 10,710 deaths in USA (2013)

Histo: normal / pleomorphic plasma cells (NOT PATHOGNOMONIC), may be mistaken for lymphocytes (lymphosarcoma, reticulum cell sarcoma, Ewing tumor, neuroblastoma)

1. diffuse infiltration: myeloma cells intimately admixed with hematopoietic cells
2. tumor nodules: displacement of hematopoietic cells by masses entirely composed of myeloma cells

Median age: 66 years (range, 5^th–8^th decade); 98% >40 years; rare <30 years; M÷F = 2÷1

Genetics: deletion of chromosome 13q14 (del13q14), amplification of chromosome 1q21 (amp1q21), deletion of chromosome 17p13 (del17p13)

Forms: (a) DISSEMINATED FORM: >40 years of age (98%); M÷F = 3÷2

(b) SOLITARY FORM: mean age 50 years

Clinical manifestation:

1. Plasma cell leukemia = aggressive form with a proportion of circulating plasma cells of >20%
2. Nonsecretory multiple myeloma (3%) = positive bone marrow biopsy WITHOUT elevated level of M protein

• Symptomatic multiple myeloma:
  mnemonic: CRAB
  • Calcium elevation = hypercalcemia (30–50%)
  • Renal insufficiency (55%)
  • Anemia = normochromic normocytic anemia (62–73%)
  • Bone abnormalities (lysis, osteopenia), bone pain (68%)
• fatigue, weight loss
• cutaneous / subcutaneous nodules (in <5%)
• RBC rouleaux formation
• proteinuria (88%), Bence-Jones proteinuria (50%):
  • ↑globulin production (= monoclonal gammopathy) of heavy chain (typically IgG or IgA) and light chain (typically κ)

Location:

1. DISSEMINATED FORM:
   scattered; axial skeleton predominant site; vertebrae (50%) >ribs >skull >pelvis >long bones (distribution correlates with normal sites of red marrow)
2. SOLITARY PLASMACYTOMA OF BONE (<5%):
   vertebrae >pelvis >skull >sternum >ribs → progression to multiple myeloma within 3 years
3. SPINAL PLASMA CELL MYELOMA
   • sparing of posterior elements (no red marrow) (DDx: metastatic disease)
   • paraspinal soft-tissue mass with extradural extension
   • scalloping of anterior margin of vertebral bodies (osseous pressure from adjacent enlarged lymph nodes)

Extraosseous manifestations of multiple myeloma are radiologically detectable in 10–16%, most commonly involving lymph nodes, pleura, and liver.

Staging (Durie & Salmon Plus System):

• Detection of bone lesions at conventional radiography best correlates with measured myeloma cell mass

Spread: to extramedullary sites (in 70%)

• generalized osteopenia only (15%) with accentuation of trabecular pattern, especially in spine (early)
• widespread punched-out osteolytic lesions (skull, long bones) with endosteal scalloping and of uniform size
• diffuse osteolysis (pelvis, sacrum)
• expansile osteolytic lesions (ballooning) in ribs, pelvis, long bones
• soft-tissue mass adjacent to bone destruction (= extrapleural + paraspinal mass adjacent to ribs / vertebral column)
• periosteal new-bone formation exceedingly rare
• involvement of mandible (rarely affected by metastatic disease)
• sclerosis may occur after chemotherapy, radiotherapy, fluoride administration
• sclerotic form of multiple myeloma (1–3%)
  1. solitary sclerotic lesion: frequently in spine
  2. diffuse sclerosis
  
  Associated with:POEMS syndrome
  • Polyneuropathy
    • distal symmetric sensorimotor neuropathy (50%) affecting sensory + motor + autonomic neurons → severe disabling numbness, tingling, weakness in feet, legs, hands
  • Organomegaly
    • hepatosplenomegaly, Castleman disease
  • Endocrine abnormalities
    • amenorrhoea, gynecomastia, erectile dysfunction, testicular atrophy, type 2 diabetes, hypothyroidism, adrenal insufficiency
  • Monoclonal paraprotein (IgA / IgG in 75%)
    • osteosclerotic lesions mimicking metastatic prostate carcinoma
  • Skin lesions
    • hypertrichosis, hirsutism, sclerodermatous thickening, hyperpigmentation, hemangiomas
  • papilledema, pseudotumor cerebri (66%)
  • edema: peripheral, pulmonary, pleural effusion, ascites, anasarca

MR (recognition dependent on knowledge of normal range of bone marrow appearance for age):

• pattern of multiple myeloma infiltration:
  • normal marrow
  • micronodular pattern = variegated / salt-and-pepper
  • focal pattern
  • diffuse pattern
    • Diffuse infiltration apparent only if at least 20–30% of bone marrow infiltrated
    • Whole-body MRI detects additional lesions in 10%
• hypointense multiple focal areas on T1WI (25%)
• hyperintense multiple focal areas on T2WI (53%)
• absence of fatty infiltration (nonspecific)

PET/CT (for staging, prognosis, monitoring treatment after suspension of corticosteroids for >5 days):

• metabolic activity of bone lesions
• extraosseous manifestations of disease
• quantification of marrow metabolic activity (SUV)

SENSITIVITY OF BONE SCANS VS. RADIOGRAPHS

• Radiographs: in 90% of patients and 80% of sites
• Bone scan: in 75% of patients and 24–54% of sites
• Gallium scan: in 55% of patients and 40% of sites

• 30% of lesions only detected on radiographs
• 10% of lesions only detected on bone scans

Cx:

1. Renal involvement frequent
2. Predilection for recurrent pneumonias ← leukopenia
3. Secondary amyloidosis in 6–15%
4. Pathologic fractures occur often

Prognosis: 43% 5-year survival; death from renal insufficiency, bacterial infection, thromboembolism

Rx: thalidomide, lenalidomide, bortezomib, autologous stem cell transplantation (ASCT), monoclonal antibodies

DDx:

• with osteopenia:
  1. Postmenopausal osteoporosis
  2. Hyperparathyroidism
  3. Steroid use
• with lytic lesion:
  1. Metastatic disease
  2. Amyloidosis
  3. Myeloid metaplasia
• with sclerotic lesion:
  1. Osteopoikilosis
  2. Lymphoma
  3. Osteoblastic metastasis
  4. Mastocytosis
  5. Myelosclerosis
  6. Fluorosis
  7. Renal osteodystrophy

10–20% of patients with multiple myeloma have normal findings at conventional radiography and differentiation of osteopenia from osteoporosis, steroid use, or excessive alcohol intake is difficult.