Question
A 76-year-old man is admitted with rapidly worsening bilateral leg weakness over 4 days. For several months he has experienced persistent thoracolumbar back pain and increasing fatigue. He has no urinary retention, faecal incontinence, or perineal numbness.
Investigations show:
- Hb: 108 g/L
- Creatinine: 275 µmol/L
- Serum electrophoresis: no detectable monoclonal paraprotein
- Serum free kappa light chains: 11,900 mg/L
- Serum free lambda light chains: 120 mg/L
- Kappa:lambda ratio: 99
- MRI: extensive abnormal vertebral marrow signal with a large paraspinal soft-tissue mass compressing the cauda equina
Which diagnosis best explains the complete picture?
A. Metastatic renal cell carcinoma
B. Multiple myeloma
C. Diffuse large B-cell lymphoma
D. Primary vertebral sarcoma
E. Metastatic prostate cancer
Answer
B. Multiple myeloma — specifically light-chain/oligosecretory myeloma, with an associated extramedullary plasmacytoma.
Explanation
The major trap is the statement “no paraprotein detected.” This does not exclude multiple myeloma.
The patient has several powerful clues pointing toward myeloma:
- Older age
- Persistent back pain
- Anaemia
- Marked renal impairment
- Diffuse marrow involvement
- Extremely elevated kappa free light chains
- Grossly abnormal kappa:lambda ratio
- Paravertebral plasma-cell mass
The serum free-light-chain result is particularly important. Both kappa and lambda concentrations can rise in renal impairment because renal clearance is reduced. However, this usually produces a relatively proportional rise in both chains rather than the massively skewed ratio seen with a monoclonal plasma-cell disorder.
Here:
Kappa = 11,900 mg/L
Lambda = 120 mg/L
Ratio ≈ 99
This strongly indicates a kappa-restricted monoclonal plasma-cell population.
Why can serum paraprotein be negative?
Typical myeloma produces an intact monoclonal immunoglobulin that appears as an M-protein on electrophoresis. However, some myelomas predominantly produce free light chains, and some secrete very little measurable intact immunoglobulin.
Therefore:
Negative SPEP/paraprotein ≠ exclusion of myeloma.
When clinical suspicion remains high, serum free light chains and immunofixation are crucial.
Why isn’t this a solitary plasmacytoma?
A solitary plasmacytoma should, by definition, represent localized plasma-cell disease without systemic myeloma.
This patient instead has:
Diffuse marrow disease + anaemia + renal impairment + monoclonal free-light-chain excess.
Therefore, the paravertebral mass is best regarded as plasmacytoma/extramedullary extension occurring as part of systemic multiple myeloma, rather than a solitary plasmacytoma.
Modern diagnostic point
For current exams, remember the SLiM-CRAB concept rather than relying on older “major/minor criteria.”
SLiM myeloma-defining biomarkers include:
- S = ≥60% clonal plasma cells in bone marrow
- Li = involved:uninvolved serum free-light-chain ratio ≥100, provided the involved light chain is ≥100 mg/L
- M = >1 focal lesion on MRI, each ≥5 mm
CRAB represents attributable end-organ injury:
- C = hypercalcaemia
- R = renal impairment
- A = anaemia
- B = bone lesions
A useful nuance here: the ratio is approximately 99, just below the ≥100 SLiM biomarker threshold. But that does not argue against myeloma because this patient already has systemic disease with renal dysfunction, anaemia and extensive marrow involvement.
Cheat Sheet for Exam
Multiple myeloma
Disease: clonal malignant proliferation of plasma cells.
Typical patient: older adult with bone/back pain, anaemia, renal dysfunction, hypercalcaemia, recurrent infection or pathological fracture.
CRAB
- C → hyperCalcaemia
- R → Renal impairment
- A → Anaemia
- B → Bone lesions
SLiM biomarkers
- ≥60% clonal marrow plasma cells
- FLC ratio ≥100 and involved FLC ≥100 mg/L
-
1 MRI focal lesion ≥5 mm
Serum free light chains
Normal plasma cells produce either kappa or lambda light chains.
Polyclonal/reactive process: both may rise → ratio relatively preserved.
Renal failure: both may rise because clearance falls → ratio usually not massively monoclonal.
Plasma-cell clone: one light chain rises disproportionately → markedly abnormal ratio.
Key exam trap
No serum paraprotein does NOT exclude multiple myeloma.
Think of:
Light-chain/oligosecretory myeloma → check serum free light chains.
Bone disease
Myeloma typically causes:
osteolytic lesions, not osteoblastic lesions.
Classic skull appearance:
“Punched-out” lesions / raindrop skull.
Prostate metastases are classically osteoblastic/sclerotic.
Renal failure
Important mechanisms include:
Light-chain cast nephropathy — major classic mechanism
- hypercalcaemia/dehydration
- amyloidosis
- light-chain deposition disease
Plasmacytoma
Solitary plasmacytoma = localized plasma-cell tumour without systemic myeloma-defining disease.
Multiple lesions/systemic organ damage → think multiple myeloma.
Flash Cards
1. Q: What mnemonic summarizes the classic end-organ manifestations of multiple myeloma?
A: CRAB — hyperCalcaemia, Renal impairment, Anaemia, Bone lesions.
2. Q: Does a negative serum paraprotein exclude multiple myeloma?
A: No. Light-chain or oligosecretory myeloma may have little or no detectable conventional serum paraprotein.
3. Q: What investigation is particularly useful when myeloma is suspected despite negative serum electrophoresis?
A: Serum free light chains, together with immunofixation as appropriate.
4. Q: Why can both kappa and lambda free light chains rise in renal failure?
A: Reduced renal clearance.
5. Q: What suggests monoclonality on serum free-light-chain testing?
A: A markedly abnormal kappa:lambda ratio, reflecting disproportionate production of one light-chain type.
6. Q: What is the serum free-light-chain SLiM criterion for myeloma?
A: Involved:uninvolved FLC ratio ≥100, provided the involved FLC is ≥100 mg/L.
7. Q: What does the “S” in SLiM represent?
A: ≥60% clonal plasma cells in bone marrow.
8. Q: What does the “M” in SLiM represent?
A: More than one focal MRI lesion, each ≥5 mm.
9. Q: What renal lesion classically causes severe renal impairment in light-chain myeloma?
A: Light-chain cast nephropathy.
10. Q: What type of bone lesions are characteristic of multiple myeloma?
A: Osteolytic/punched-out lesions.
11. Q: What is the classic skull appearance in myeloma?
A: Punched-out or “raindrop” skull lesions.
12. Q: Why is a paravertebral plasmacytoma plus widespread marrow disease not called a solitary plasmacytoma?
A: Because systemic plasma-cell disease/myeloma is present.
Challenging MCQs
MCQ 1
A 72-year-old patient has anaemia, renal impairment and persistent vertebral pain. Serum protein electrophoresis shows no M-spike. Kappa free light chains are markedly elevated with a profoundly abnormal kappa:lambda ratio. Which statement is most accurate?
A. Negative electrophoresis essentially excludes plasma-cell myeloma
B. Renal failure alone explains any degree of kappa:lambda ratio abnormality
C. Light-chain myeloma remains an important possibility
D. The findings establish metastatic prostate carcinoma
E. Free light chains have no diagnostic role without an M-spike
Answer: C. Light-chain myeloma remains an important possibility.
Explanation: Myeloma may predominantly secrete free light chains rather than detectable intact monoclonal immunoglobulin. Thus, a negative conventional paraprotein screen does not exclude myeloma. A markedly skewed FLC ratio is particularly important because renal impairment tends to increase both chains rather than producing the extreme monoclonal pattern typical of a clonal plasma-cell disorder.
MCQ 2
Which of the following is false regarding serum free light chains?
A. Plasma-cell clones may be kappa restricted
B. Renal dysfunction can increase absolute concentrations of both light chains
C. A markedly skewed ratio can indicate monoclonality
D. Every increase in serum kappa concentration proves kappa-restricted myeloma
E. Serum free-light-chain testing can identify disease not obvious on routine electrophoresis
Answer: D. Every increase in serum kappa concentration proves kappa-restricted myeloma.
Explanation: Absolute FLC elevation is nonspecific. Renal dysfunction, inflammation and polyclonal immune activation can raise FLC concentrations. Disproportionate elevation and the involved:uninvolved ratio are much more informative for monoclonality.
MCQ 3
Which finding independently constitutes a myeloma-defining biomarker in an appropriate clonal plasma-cell disorder?
A. Kappa:lambda ratio 30 with involved FLC 300 mg/L
B. Bone marrow containing 25% clonal plasma cells without CRAB features
C. One 8-mm focal MRI lesion
D. Involved:uninvolved FLC ratio 105 with involved FLC 150 mg/L
E. Serum M-protein of 15 g/L alone
Answer: D. Involved:uninvolved FLC ratio 105 with involved FLC 150 mg/L.
Explanation: The SLiM free-light-chain criterion requires an involved:uninvolved ratio ≥100 plus involved FLC ≥100 mg/L. Neither 25% marrow plasma cells alone nor a single MRI focal lesion meets the respective SLiM thresholds.
MCQ 4
A patient with a biopsy-proven paravertebral plasmacytoma also has diffuse marrow infiltration, renal impairment attributable to plasma-cell disease and anaemia. What is the best classification?
A. Multiple myeloma with plasmacytoma
B. Solitary extramedullary plasmacytoma
C. MGUS
D. Solitary bone plasmacytoma
E. Smouldering myeloma
Answer: A. Multiple myeloma with plasmacytoma.
Explanation: “Solitary” plasmacytoma requires absence of systemic myeloma-defining disease. Diffuse marrow involvement and attributable end-organ injury indicate systemic multiple myeloma.
MCQ 5
Which of the following is false regarding the skeletal manifestations of multiple myeloma?
A. Back pain is common
B. Pathological fractures may occur
C. Osteoclast activation contributes to bone destruction
D. Punched-out skull lesions may occur
E. Diffuse osteoblastic skeletal metastases are the characteristic radiological abnormality
Answer: E. Diffuse osteoblastic skeletal metastases are the characteristic radiological abnormality.
Explanation: Myeloma characteristically causes osteolytic disease due to increased osteoclastic activity with impaired effective bone formation. Osteoblastic/sclerotic metastases are much more characteristic of prostate carcinoma.
MCQ 6
A patient with severe renal failure has kappa FLC 190 mg/L and lambda FLC 160 mg/L. Which interpretation is most appropriate?
A. The results automatically establish kappa myeloma
B. The broadly parallel elevation may reflect impaired renal clearance
C. The patient necessarily has lambda myeloma
D. The values diagnose solitary plasmacytoma
E. Free-light-chain concentrations cannot be affected by renal function
Answer: B. The broadly parallel elevation may reflect impaired renal clearance.
Explanation: Renal failure reduces FLC clearance and may increase both kappa and lambda concentrations. A relatively preserved ratio suggests a polyclonal/clearance-related process rather than dramatic restriction to one light-chain type.
MCQ 7
Which mechanism most classically explains acute or severe renal dysfunction in a patient with a very high burden of monoclonal free light chains?
A. Anti-GBM antibody deposition
B. Renal artery stenosis
C. Light-chain cast nephropathy
D. Minimal-change disease
E. Renal papillary necrosis
Answer: C. Light-chain cast nephropathy.
Explanation: Filtered monoclonal free light chains interact with tubular proteins and form obstructive/inflammatory casts, producing myeloma cast nephropathy, an important cause of severe kidney injury in myeloma.
MCQ 8
Which of the following is not part of the classic CRAB framework?
A. Hypercalcaemia
B. Renal impairment
C. Anaemia
D. Bone lesions
E. Recurrent bacterial infection
Answer: E. Recurrent bacterial infection.
Explanation: Infection is clinically important in myeloma because normal immunoglobulin production is suppressed, but it is not one of the four CRAB components. CRAB = Calcium elevation, Renal dysfunction, Anaemia, Bone disease.
MCQ 9
An asymptomatic patient has 65% clonal plasma cells in the bone marrow but no hypercalcaemia, renal dysfunction, anaemia or bone lesions. Which statement is most accurate?
A. Absence of CRAB features excludes active myeloma
B. This can satisfy criteria for multiple myeloma because ≥60% clonal marrow plasma cells is a myeloma-defining biomarker
C. The diagnosis must be MGUS
D. The diagnosis requires an M-protein >30 g/L
E. Treatment can only be considered after a pathological fracture occurs
Answer: B. This can satisfy criteria for multiple myeloma because ≥60% clonal marrow plasma cells is a myeloma-defining biomarker.
Explanation: Modern criteria expanded beyond CRAB. ≥60% clonal bone-marrow plasma cells is one of the SLiM biomarkers associated with sufficiently high risk of progression to justify classification as active myeloma in the appropriate setting.
MCQ 10
A patient has an involved:uninvolved serum FLC ratio of 99.6 and an involved FLC concentration of 12,450 mg/L. Which statement is most precise?
A. The FLC biomarker automatically satisfies the SLiM ≥100 criterion
B. The enormous involved FLC level makes the ratio irrelevant
C. The ratio itself falls marginally below the ≥100 SLiM threshold, but myeloma may still be diagnosed through other myeloma-defining features
D. The result excludes monoclonal plasma-cell disease
E. A ratio below 100 is considered normal
Answer: C. The ratio itself falls marginally below the ≥100 SLiM threshold, but myeloma may still be diagnosed through other myeloma-defining features.
Explanation: This is an important high-level distinction. The SLiM FLC criterion specifically requires a ratio ≥100 as well as involved FLC ≥100 mg/L. A ratio of 99.6 therefore does not technically satisfy that particular biomarker threshold. It remains profoundly abnormal and highly suggestive of monoclonality, while other evidence can establish symptomatic myeloma.
Summary for Quick Exam Revision
Multiple myeloma is a clonal plasma-cell malignancy occurring predominantly in older adults and commonly presenting with back pain, anaemia, renal impairment, hypercalcaemia or pathological fractures. Remember the classic end-organ manifestations using CRAB: hyperCalcaemia, Renal impairment, Anaemia and Bone lesions. Modern diagnostic thinking adds the SLiM biomarkers: ≥60% clonal marrow plasma cells, an involved:uninvolved free-light-chain ratio ≥100 with involved FLC ≥100 mg/L, or more than one MRI focal lesion ≥5 mm. A crucial MRCP trap is that absence of a conventional serum paraprotein does not exclude multiple myeloma. Light-chain or oligosecretory disease may be detected principally through serum free-light-chain testing and immunofixation. Renal failure itself can elevate both kappa and lambda free light chains because their clearance decreases, so an isolated elevation in one absolute value should not automatically be interpreted as myeloma. In a monoclonal plasma-cell disorder, however, one light-chain type is produced disproportionately, creating a markedly abnormal kappa:lambda ratio. Severe light-chain excess can cause cast nephropathy, an important mechanism of renal failure in myeloma. Marrow replacement contributes to anaemia and, with more extensive disease, other cytopenias. Myeloma stimulates osteoclastic bone resorption, producing lytic lesions, vertebral pain, pathological fractures and classic punched-out skull lesions. This contrasts with the predominantly osteoblastic skeletal metastases of prostate carcinoma. A plasmacytoma may occur as part of systemic myeloma and can extend into paravertebral soft tissues, occasionally causing spinal or cauda equina compression. A lesion should not be labelled a solitary plasmacytoma when widespread marrow disease or myeloma-defining systemic features are present. Finally, remember the central exam principle: negative paraprotein + unexplained anaemia/renal impairment/bone disease → do not dismiss myeloma; examine the serum free light chains and their ratio.