PA20.3 | Plasma Cell Dyscrasias (Multiple Myeloma) — Case Study

CLINICAL SCENARIO

A 68-year-old retired schoolteacher presents with a 4-month history of progressively worsening low-back pain, easy fatigability, and two episodes of confusion. He denies trauma. On examination he is pale, BP 148/90 mmHg, pulse 88/min; there is mid-thoracic vertebral tenderness and mild ankle oedema. Investigations: Hb 8.4 g/dL (normocytic normochromic), total serum proteins 10.8 g/dL, albumin 3.1 g/dL, serum calcium 11.9 mg/dL (corrected), creatinine 2.4 mg/dL, uric acid elevated, LDH normal. Urine dipstick is negative for protein (Bence-Jones protein requires a heat-precipitation or urine protein electrophoresis test). You are the Year-2 pathology student on the ward — your task is to recognise the pattern, design the diagnostic workup, apply the diagnostic criteria, and distinguish this disorder from related plasma cell dyscrasias.

Section 1 — Pattern Recognition and Differential Diagnosis

List the four cardinal features present in this patient that constitute the CRAB criteria. For each feature, state the underlying pathological mechanism in multiple myeloma. Then generate a focused differential diagnosis (at least 4 conditions) for this combination of back pain + anaemia + renal impairment + hypercalcaemia, ranked by likelihood, with a one-line rationale for each.

Guidance: CRAB = hyperCalcaemia, Renal insufficiency, Anaemia, Bone disease. Relate each CRAB feature to the pathobiology: osteoclast-activating cytokines (RANKL/IL-6/IL-1β) → lytic lesions → hypercalcaemia; monoclonal light-chain cast nephropathy + hypercalcaemia → renal failure; marrow replacement + EPO suppression → anaemia. Differential must include at least: multiple myeloma, metastatic carcinoma to bone, hyperparathyroidism with CKD, lymphoma, and Waldenström macroglobulinaemia.

Section 2 — Designing the Myeloma Workup

Design the complete diagnostic workup for suspected multiple myeloma. For each test, state (a) what you expect to find in this patient, (b) why that finding occurs pathologically, and (c) the clinical significance of the result. Tests must include: (i) serum protein electrophoresis (SPEP) and immunofixation, (ii) urine protein electrophoresis / Bence-Jones protein test, (iii) bone-marrow trephine biopsy, (iv) skeletal survey (plain X-rays or whole-body low-dose CT), (v) serum free light-chain assay, (vi) serum β2-microglobulin and LDH.

Guidance: Expected findings: SPEP — monoclonal M-spike in gamma region; immunofixation will type it (likely IgG-κ or IgA-κ). Urine — free κ or λ Bence-Jones protein (dipstick-negative because light chains do not react with albumin-specific reagents). Marrow — ≥10% clonal plasma cells (CD138+, κ or λ restriction on immunohistochemistry). Skeletal survey — multiple punched-out lytic lesions in skull, vertebrae, ribs, proximal humeri/femora (no osteoblastic reaction hence bone scan often negative). β2-microglobulin elevated → ISS staging. Students often confuse a negative urine dipstick with absence of proteinuria — clarify the Bence-Jones pitfall explicitly.

Section 3 — Applying Diagnostic Criteria

Using the IMWG (International Myeloma Working Group) 2014 diagnostic criteria, state whether this patient meets the definition of symptomatic (active) multiple myeloma. Identify which specific criteria are satisfied. Then classify the disease using the Revised International Staging System (R-ISS): which parameters do you need, and which stage does this patient most likely fall into based on available data?

Guidance: IMWG 2014: symptomatic MM requires ≥10% clonal bone-marrow plasma cells OR biopsy-proven plasmacytoma PLUS ≥1 myeloma-defining event (CRAB or SLiM: ≥60% clonal PCs, sFLC ratio ≥100, >1 focal MRI lesion). This patient satisfies CRAB (all four features). R-ISS requires β2-microglobulin, albumin, LDH, and cytogenetics (FISH for del17p, t(4;14), t(14;16)). With albumin 3.1 and elevated β2-microglobulin, likely ISS Stage II minimum; without LDH/cytogenetics final R-ISS cannot be assigned — students should state what additional tests are needed.

Section 4 — Distinguishing Related Plasma Cell Dyscrasias

Compare and contrast multiple myeloma with (a) MGUS (Monoclonal Gammopathy of Undetermined Significance) and (b) Waldenström macroglobulinaemia, using a structured table with the following rows: cell of origin / immunophenotype, M-protein type, % marrow involvement criterion, CRAB features present, risk of hyperviscosity syndrome, and management approach.

Guidance: MGUS: <10% marrow plasma cells, M-spike <3 g/dL, no CRAB, no treatment — watch and wait, 1%/year risk of progression. Multiple myeloma: ≥10% clonal PCs, ≥1 CRAB/SLiM criterion, requires treatment. Waldenström: lymphoplasmacytic lymphoma producing IgM monoclonal protein; IgM is a large pentamer → hyperviscosity (headache, visual disturbance, bleeding) is hallmark; lytic bone lesions are NOT typical; CXCR4/MYD88 mutations characteristic. Students commonly confuse IgM MGUS with Waldenström — stress that Waldenström requires lymphoplasmacytic infiltrate ≥10% marrow AND IgM M-protein; IgM MGUS has <10% infiltrate with no symptoms.

Section 5 — Integration and Clinical Correlation

Synthesise your findings into a one-paragraph clinico-pathological correlation (150–200 words) that explains how a single pathological event — the clonal expansion of a malignant plasma cell — produces every feature seen in this patient. Then answer: (a) Why did the urine dipstick show no protein despite significant renal damage? (b) Why might a bone scan be falsely negative in myeloma? (c) If this patient's M-protein is IgA-λ, what urinary light chain would you expect and why?

Guidance: (a) Dipstick detects albumin — Bence-Jones (free light chains) are not detected; requires urine protein electrophoresis or immunofixation. (b) Bone scan detects osteoblastic activity (99mTc uptake) — myeloma lesions are purely osteolytic with suppressed osteoblasts (DKK1 suppresses Wnt signalling), so bone scan is often normal or 'cold'; skeletal survey or whole-body low-dose CT/MRI is preferred. (c) IgA-λ myeloma → free λ light chains excreted in urine; test with urine immunofixation which will show free λ band. Clinico-pathological paragraph should link: IL-6/RANKL from tumour stroma → osteoclast activation → lytic lesions + hypercalcaemia; marrow replacement + IL-6 → normocytic anaemia; free light-chain casts in renal tubules → cast nephropathy + renal failure; all driven by a single clone secreting monoclonal immunoglobulin.

PEER REVIEW

You will be assigned one anonymous peer submission to review. Using the rubric criteria above, provide constructive written feedback on each of the five sections. For each section: (1) identify one strength — a specific observation, mechanism, or reasoning step your peer did well; (2) identify one area for improvement — a factual gap, missing criterion, or mechanistic error, with a brief explanation of the correct concept; (3) suggest one specific resource (Robbins chapter, IMWG guideline, or UpToDate topic) that would help your peer strengthen that section. Your review must be 200–300 words total, respectful in tone, and evidence-based. You will receive a rubric score for the quality of your review: a superficial 'looks good' review earns 0; a peer review with specific, accurate, and constructive feedback earns full marks.