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PA20.3 | Multiple Myeloma — Lab Findings & Diagnosis — SDL Guide (Part 2)

Laboratory Findings — The High-Yield Core

Four-panel medical diagram showing SPEP M-spike, rouleaux formation, marrow plasma cells, and urinary Bence-Jones proteins in multiple myeloma. — **Panel A:** Normal or polyclonal SPEP curve versus pathological monoclonal M-spike, with Albumin, alpha-1, alpha-2, beta, and gamma fractions labeled.. **Panel B:** Peripheral blood film showing rouleaux formation with erythrocytes stacked in coin-roll patterns.. **Panel C:** Bone marrow plasma cells with eccentric nucleus, clock-face chromatin, basophilic cytoplasm, and perinuclear hof.. **Panel D:** Urine electrophoresis showing Bence-Jones protein peak from filtered free kappa or lambda light chains..

The laboratory findings in myeloma are unusually specific and form the cornerstone of diagnosis.

1. Serum Protein Electrophoresis (SPEP) — M-spike
Monoclonal gammopathy appears as a tall, narrow, sharply demarcated peak (the M-spike) in the γ or β-γ region — in contrast to the broad, diffuse polyclonal hypergammaglobulinaemia seen in infection or inflammation.
• Most common: IgG (~55%), then IgA (~25%)
• Immunofixation electrophoresis (IFE) confirms the M-protein class (IgG/IgA/IgM/IgD/IgE) and light chain type (κ or λ) — it is more sensitive than SPEP for detecting small M-proteins

Four-panel medical diagram showing diagnostic features of multiple myeloma including SPEP tracing with M-spike, rouleaux formation in blood, plasma cells in bone marrow, and Bence-Jones protein detection. — **Panel A:** Normal vs pathological SPEP showing polyclonal gamma peak versus M-spike, labeled protein fractions (albumin, alpha1, alpha2, beta, gamma). **Panel B:** Peripheral blood film showing rouleaux formation with RBCs stacked in coin-roll patterns, high-power magnification. **Panel C:** Bone marrow biopsy showing increased plasma cells with eccentric nuclei, clock-face chromatin, basophilic cytoplasm, perinuclear hof. **Panel D:** Urine protein electrophoresis demonstrating Bence-Jones protein peak with light chain identification.

2. Bence-Jones Protein (Urine)
Free light chains (κ or λ) are small enough to be filtered by the glomerulus and appear in urine. Bence-Jones protein has the classic heat behaviour: precipitates at 40–60°C, redissolves at 100°C. Urine protein electrophoresis (UPEP) or urine IFE is needed — standard urine dipstick detects albumin, NOT light chains, so a negative dipstick does NOT exclude Bence-Jones proteinuria.

3. Blood Film — Rouleaux and High ESR
Rouleaux formation: erythrocytes stack like coins due to elevated M-protein coating their surfaces and reducing electrostatic repulsion. Blood film shows long chains of RBCs (rouleaux). This directly drives a markedly elevated ESR (often >100 mm/h).

Three-panel diagram showing multiple myeloma diagnostic features: rouleaux formation in blood, plasma cell infiltration in bone marrow, and lytic bone lesions on skull X-ray. — **Panel A:** Peripheral blood film showing rouleaux formation with RBCs stacked in coin-roll patterns. **Panel B:** Bone marrow biopsy with normal vs myeloma plasma cells, eccentric nuclei, clock-face chromatin pattern. **Panel C:** Lateral skull X-ray showing multiple punched-out lytic lesions creating pepper-pot appearance.

4. Bone Marrow Biopsy
>10% clonal plasma cells in the marrow is a key diagnostic criterion. Morphology: plasma cells with eccentric nucleus, clock-face (cartwheel) chromatin, abundant basophilic cytoplasm, perinuclear hof (Golgi zone). Abnormal forms: multinucleated, flame cells (IgA-secreting), Mott cells (Russell bodies — grape-like Ig inclusions).

Bone marrow biopsy showing normal versus myeloma plasma cells with detailed morphological comparison highlighting eccentric nuclei and clock-face chromatin pattern. — **Panel A:** High-power H&E bone marrow biopsy showing sheets of plasma cells with arrows distinguishing normal vs myeloma cells. **Panel B:** Detailed myeloma plasma cell showing eccentric nucleus, clock-face chromatin pattern, and abundant eosinophilic cytoplasm. **Panel C:** Normal plasma cell morphology with central round nucleus and typical basophilic cytoplasm.

5. Plain X-Ray / Skeletal Survey
Classic "punched-out" lytic lesions — round, well-defined osteolytic defects with no sclerotic rim, most striking in the skull ("pepper-pot skull"), vertebrae, and long bones.

Three-panel diagram showing multiple myeloma lytic bone lesions with lateral skull X-ray, detailed lesion morphology, and normal versus pathological bone comparison. — **Panel A:** Lateral skull X-ray showing multiple round lytic lesions throughout calvarium with arrows indicating representative lesions. **Panel B:** Magnified view of individual lytic lesions demonstrating characteristic punched-out borders without sclerotic margins. **Panel C:** Comparison of normal trabecular bone architecture versus plasma cell infiltration causing bone destruction.

6. Other Biochemical Findings
• Total protein elevated (due to M-protein), albumin reduced → reversed albumin-to-globulin (A:G) ratio (normal A:G ~2:1; in myeloma often <1)
• β2-microglobulin (β2M): shed by plasma cells; elevated levels correlate with tumour burden and are a key prognostic marker (high β2M = poor prognosis in the ISS staging system)
• Serum calcium: elevated (CRAB C)
• Creatinine: elevated if renal involvement
• LDH: elevated in high tumour burden
• CBC: normocytic normochromic anaemia; leukopenia and thrombocytopenia in advanced disease

CLINICAL PEARL

The urine dipstick trap — a favourite exam question: standard urine dipstick tests detect ALBUMIN only (they use a colorimetric albumin-binding dye). Bence-Jones protein (free light chains) does NOT bind this dye and therefore gives a NEGATIVE or trace result on dipstick even when urinary light chain levels are very high. Always request urine protein electrophoresis (UPEP) or urine immunofixation in suspected myeloma — do not be falsely reassured by a normal dipstick.

SELF-CHECK

Which of the following laboratory findings is MOST specific for multiple myeloma compared with a reactive plasmacytosis?

A. Elevated ESR

B. Normocytic normochromic anaemia

C. Monoclonal M-spike on serum protein electrophoresis

D. Increased total serum protein

Reveal Answer

Answer: C. Monoclonal M-spike on serum protein electrophoresis

A monoclonal M-spike on SPEP reflects clonal expansion of a single immunoglobulin-producing cell line — the hallmark of a plasma cell neoplasm. Reactive plasmacytosis (seen in infections, connective tissue disease, liver disease) produces a polyclonal hypergammaglobulinaemia — a broad diffuse rise in the gamma region, not a narrow spike. Elevated ESR, anaemia, and raised total protein can all occur in reactive states. Immunofixation then characterises the heavy and light chain class of the M-protein, which is diagnostic.

Diagnostic Criteria (Brief)

Infographic summarizing IMWG multiple myeloma diagnostic criteria, myeloma-defining events, and distinctions from smouldering myeloma and solitary plasmacytoma. — **Panel A:** IMWG criteria: clonal bone marrow plasma cells ≥10% or biopsy-proven plasmacytoma, M-protein in serum and/or urine, and myeloma-defining event.. **Panel B:** Myeloma-defining events: CRAB features including hypercalcaemia, renal impairment, anaemia, bone lesions, plus biomarkers including marrow plasma cells ≥60%, serum free light chain ratio ≥100, and >1 focal MRI lesion.. **Panel C:** Comparison of Multiple Myeloma, Smouldering Myeloma, and Solitary Plasmacytoma by M-protein, marrow plasma cell percentage, myeloma-defining events, systemic involvement, and management clue..

The IMWG (International Myeloma Working Group) criteria require ALL THREE:

1. Clonal bone marrow plasma cells ≥10% (or biopsy-proven plasmacytoma)
2. M-protein in serum and/or urine (any level)
3. Myeloma-defining events — either CRAB criteria (end-organ damage) OR biomarkers of malignancy:
• Clonal marrow plasma cells ≥60%
• Serum free light chain ratio ≥100
• >1 focal lesion on MRI

> Note: You do NOT need all four CRAB features — one is sufficient if the plasma cell and M-protein criteria are met.

Smouldering myeloma: M-protein present + marrow plasma cells 10–59% but NO myeloma-defining events — watchful waiting, no treatment.

Solitary plasmacytoma: single bony or extramedullary lesion of clonal plasma cells without systemic involvement.

Differential Diagnosis

A four-panel medical diagram compares MGUS, multiple myeloma, Waldenstrom macroglobulinaemia, and reactive plasmacytosis using diagnostic branching, SPEP patterns, marrow findings, and clinical discriminators. — **Panel A:** Diagnostic branching from monoclonal protein detected on SPEP to MGUS, Multiple Myeloma, Waldenstrom Macroglobulinaemia, and Reactive Plasmacytosis, emphasizing M-protein level, marrow plasma cells, CRAB features, IgM, and polyclonality.. **Panel B:** SPEP trace patterns showing small sharp M-spike in MGUS, large sharp M-spike in myeloma, IgM M-spike in Waldenstrom Macroglobulinaemia, and broad gamma rise in reactive plasmacytosis.. **Panel C:** Bone marrow patterns showing scattered plasma cells under 10% in MGUS, sheets of plasma cells at least 10% in myeloma, lymphoplasmacytic infiltrate in Waldenstrom Macroglobulinaemia, and mixed reactive plasma cells in reactive plasmacytosis.. **Panel D:** Clinical discriminators showing MGUS as incidental with no CRAB, myeloma as CRAB and lytic bone lesion dominant, Waldenstrom as IgM hyperviscosity with absent lytic lesions, and reactive plasmacytosis associated with chronic infection, autoimmune disease, and cirrhosis..

Three key entities to distinguish:

MGUS (Monoclonal Gammopathy of Undetermined Significance)
• M-protein present (usually <30 g/L) AND marrow plasma cells <10%
• No CRAB features, no end-organ damage
• Incidental finding; ~1% annual risk of progression to myeloma
• The most important DDx — do NOT treat MGUS as myeloma

Waldenström Macroglobulinaemia
• Clonal lymphoplasmacytic lymphoma secreting IgM monoclonal protein
• IgM is a large pentameric molecule → hyperviscosity syndrome is the dominant feature (vs. myeloma where bone disease dominates)
• Lytic bone lesions and CRAB features are characteristically ABSENT
• Marrow shows lymphoplasmacytic infiltrate, not sheets of plasma cells
• CXCR4/MYD88 mutations are characteristic

Reactive Plasmacytosis
• Seen in chronic infections (TB, endocarditis), autoimmune diseases, liver cirrhosis
• Plasma cells usually <10% of marrow
• Polyclonal hypergammaglobulinaemia (broad gamma rise on SPEP, NOT a sharp M-spike)
• No Bence-Jones protein, no CRAB features

Feature	MGUS	Myeloma	Waldenström
M-protein	<30 g/L	Any level	IgM
Marrow PC	<10%	≥10%	Lymphoplasmacytic
CRAB	Absent	Present (≥1)	Absent
Bone lesions	None	Lytic	None
Hyperviscosity	Rare	Occasional	Common

SELF-CHECK

A 70-year-old woman is found to have an IgG M-spike of 18 g/L on SPEP during routine check-up. Bone marrow biopsy shows 7% plasma cells. She has no anaemia, normal calcium, normal creatinine, and no bone lesions on skeletal survey. The correct diagnosis and management is:

A. Multiple myeloma — start chemotherapy

B. MGUS — observe with annual monitoring

C. Smouldering myeloma — start lenalidomide

D. Waldenström macroglobulinaemia — check for hyperviscosity

Reveal Answer

Answer: B. MGUS — observe with annual monitoring

This patient fulfils the criteria for MGUS: M-protein present BUT marrow plasma cells <10% (7%) AND no CRAB features (no anaemia, no hypercalcaemia, no renal failure, no bone lesions). MGUS requires no treatment — only annual monitoring for progression to myeloma (~1% per year). Smouldering myeloma requires ≥10% plasma cells (this patient has 7%). Waldenström involves IgM paraprotein and a lymphoplasmacytic (not plasma cell) infiltrate.

Prognosis and a Note on Staging

Infographic showing improved survival in multiple myeloma with modern therapy and the ISS staging system based on beta-2 microglobulin and serum albumin. — **Panel A:** Malignant plasma cells in bone marrow, earlier therapy median survival ~3 years, modern therapy median survival 5-7+ years, proteasome inhibitors, IMiDs, anti-CD38 monoclonal antibodies, autologous stem-cell transplant. **Panel B:** β2-microglobulin shed by plasma cells, tumour burden, renal function, IL-6 activity, serum albumin inverse correlation. **Panel C:** ISS Stage I, ISS Stage II, ISS Stage III, β2M thresholds, albumin threshold, median survival ~62 months, ~44 months, ~29 months.

Myeloma is currently incurable in most patients but is treatable; median survival has improved from 3 years to 5–7+ years with modern therapy (proteasome inhibitors, IMiDs, anti-CD38 monoclonal antibodies, autologous stem-cell transplant).

International Staging System (ISS) — the two key markers:
• β2-microglobulin — shed by plasma cells; reflects tumour burden + renal function
• Serum albumin — inverse correlate of IL-6 activity

ISS Stage	β2M	Albumin	Median Survival
I	<3.5 mg/L	≥35 g/L	~62 months
II	Neither I nor III	—	~44 months
III	≥5.5 mg/L	—	~29 months

High-risk cytogenetics (del 17p, t(4;14), t(14;16)) further stratify prognosis in the Revised ISS (R-ISS).