Multiple myeloma

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How the diagnosis is reached

Back pain that wakes a 68-year-old at night and no longer answers to paracetamol is not mechanical, and the constipation, exhaustion and afternoon muddle beside it are one complaint rather than three: a calcium of 12.4 mg/dL. With the anemia and a creatinine of 2.3 mg/dL, the CRAB tetrad is complete. Several details then separate myeloma from its mimics. A normal alkaline phosphatase alongside extensive lytic disease is characteristic: myeloma lesions come from osteoclast activation with osteoblasts suppressed, so there is no reparative bone formation to raise the ALP or light up an isotope scan. That is why the negative scan misleads and why skeletal survey or whole-body CT is the right imaging; metastatic carcinoma provokes an osteoblastic reaction and is usually scan-positive. A suppressed parathyroid hormone excludes primary hyperparathyroidism as the cause of hypercalcemia. The very high total protein with low albumin, marked rouleaux and an ESR over 100 all reflect the circulating paraprotein. Recurrent infections follow from immunoparesis, visible here as suppressed IgA and IgM. The diagnosis requires clonal plasma cells of 10% or more plus end-organ damage; at 42% with clear CRAB features this is symptomatic myeloma, not MGUS or smouldering disease. The t(4;14) on FISH marks high-risk cytogenetics, and a beta-2 microglobulin of 6.8 mg/L with an albumin of 2.9 g/dL puts her at an advanced stage. Induction is a bortezomib-based triplet with lenalidomide and dexamethasone, the proteasome inhibitor mattering most here because it partly offsets the prognosis t(4;14) carries, followed by autologous stem cell transplant if she is fit enough. Supportive care weighs as heavily: bisphosphonates, hydration for the calcium and kidneys, prompt treatment of infection, and radiotherapy for intractable bone pain or the cord compression that the L2 wedge fracture makes a live concern.

Key clinical clues

• CRAB: hypercalcemia, renal impairment, anemia and lytic bone lesions together
• Normal alkaline phosphatase and a negative bone scan despite extensive lytic disease
• High total protein with low albumin, rouleaux on film, ESR over 100
• Suppressed PTH excludes primary hyperparathyroidism as the hypercalcemia cause
• Monoclonal IgG kappa band with skewed free light chain ratio and 42% clonal plasma cells

The case in full

1

Presenting complaint

Patient history

A 68-year-old woman has four months of worsening lower back pain that now wakes her at night and no longer responds to paracetamol. She is exhausted, constipated and has lost 5 kg, and her family say she seems muddled in the afternoons. She has had two chest infections in six months.

2

Blood count and chemistry

Laboratory results

Initial bloods are sent.

Measurements

Parameter	Value	Reference
Hemoglobin	8.6 g/dLRef 12.0–15.5	12.0–15.5
Mean cell volume	91 fLRef 80–100	80–100
Corrected calcium	12.4 mg/dLRef 8.5–10.2	8.5–10.2
Creatinine	2.3 mg/dLRef 0.5–1.1	0.5–1.1
Total protein	10.8 g/dLRef 6.0–8.3	6.0–8.3
Albumin	2.9 g/dLRef 3.5–5.0	3.5–5.0

3

Additional markers

Laboratory results

Further tests are added. The blood film is reported as showing marked rouleaux formation.

Measurements

Parameter	Value	Reference
ESR	118 mm/hRef <30	<30
Alkaline phosphatase	82 U/LRef 44–147	44–147
Beta-2 microglobulin	6.8 mg/LRef 0.8–2.2	0.8–2.2
Parathyroid hormone	8 pg/mLRef 15–65	15–65
Uric acid	9.4 mg/dLRef 2.4–6.0	2.4–6.0

4

Skeletal imaging

Imaging

A skeletal survey is performed; the lateral skull film is shown below. Imaging of the spine also identifies a wedge compression fracture at L2. An isotope bone scan requested earlier by her family doctor was reported as unremarkable.

5

Protein studies

Laboratory results

Serum and urine protein studies are sent to characterise the raised globulin fraction.

Measurements

Parameter	Value	Reference
Serum electrophoresis	Dense monoclonal band, gamma regionRef No monoclonal band	No monoclonal band
Immunofixation	IgG kappa paraproteinRef No paraprotein	No paraprotein
Paraprotein concentration	48 g/LRef Not detected	Not detected
Serum free light chain ratio (κ:λ)	184Ref 0.26–1.65	0.26–1.65
Urine Bence-Jones protein	PresentRef Absent	Absent
IgA / IgM	Both suppressedRef IgA 0.8–4.0, IgM 0.5–2.0 g/L	IgA 0.8–4.0, IgM 0.5–2.0 g/L

6

Bone marrow biopsy

Pathology

Bone marrow aspirate and trephine show 42% plasma cells with atypical morphology, including binucleate forms. Flow cytometry confirms a kappa-restricted clonal population. Cytogenetics by FISH show t(4;14).