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

CLINICAL SETTING

Subramaniam, a 64-year-old master tailor from Coimbatore, Tamil Nadu, is brought to the government medical college emergency department by his daughter after he collapsed at his workshop. For the past five months he has had worsening pain across his lower back and right shoulder that he attributed to 'old age and bending over the sewing machine'. Two weeks ago his hands began to feel weak and numb, and last week he noticed he could no longer thread a needle — his fine-finger dexterity was gone. This morning, after rising from his charpoy, he collapsed with severe back pain and was unable to stand. On examination: an elderly gentleman in severe pain, pale, confused (MMSE 22/30). BP 148/94 mmHg. Spine: exquisite tenderness over T8 and L2 vertebrae. No hepatosplenomegaly. No peripheral lymphadenopathy. Urine dipstick: negative for protein.

Trigger 1: Initial Presentation — The Crumbling Bones

The emergency physician orders a skeletal survey and basic investigations: • Hb: 7.8 g/dL (normocytic normochromic) • MCV: 88 fL; reticulocytes 0.9% • WBC: 4.6 × 10⁹/L (differential normal) • Platelets: 142 × 10⁹/L • Peripheral blood film: prominent rouleaux (red cells in stacked-coin arrangement) • Serum calcium: 12.4 mg/dL (corrected) • Creatinine: 2.8 mg/dL; BUN elevated • Total serum protein: 11.2 g/dL; albumin: 2.8 g/dL • ESR: 138 mm/h (markedly elevated) • Skeletal survey (X-ray): multiple 'punched-out' lytic lesions in the skull vault, T8 vertebral collapse, lytic lesion right proximal humerus. No sclerosis. • Urine dipstick: negative for protein (repeated by nurse to confirm)

DISCUSSION POINTS

  • Identify the four myeloma-defining organ damage events encoded in the mnemonic CRAB. Map each to Subramaniam's presenting findings — which CRAB criteria does he satisfy?
  • The urine dipstick is negative for protein despite significant renal impairment. What type of protein might be present in the urine that is NOT detected by the standard dipstick, and what is the pathological mechanism of kidney injury in this disease?
  • The peripheral blood film shows prominent rouleaux. What causes rouleaux formation in this disease, and how does it explain the markedly elevated ESR?
  • The skeletal X-rays show purely lytic lesions with no sclerosis — even in areas adjacent to the lytic holes. What molecular mechanism specifically prevents osteoblast activity in this disease, and why does this make the disease invisible on a bone scan (why is a bone scan unreliable for staging)?
Click to reveal Trigger 2: Investigations — The Monoclonal Fingerprint (discuss previous trigger first!)

Trigger 2: Investigations — The Monoclonal Fingerprint

The haematology team is consulted. They order a serum protein electrophoresis (SPEP) and request a bone marrow biopsy. SPEP result: A tall, narrow, sharply demarcated peak in the gamma region (M-spike) — quantified at 4.8 g/dL. Immunofixation electrophoresis (IFE): IgG-κ (kappa light chain) confirmed. Urine protein electrophoresis (UPEP) on a 24-hour urine collection (NOT dipstick): Free κ light chains detected (Bence-Jones protein). Bone marrow trephine biopsy: 42% clonal plasma cells with eccentric nuclei, clock-face chromatin, and prominent perinuclear hof. Amyloid staining: negative. β2-microglobulin: 8.2 mg/L (markedly elevated). LDH: mildly elevated.

DISCUSSION POINTS

  • What is the significance of the 'M-spike' on serum protein electrophoresis? What does a monoclonal spike tell you about the biology of the abnormal clone — how is it fundamentally different from a polyclonal hypergammaglobulinaemia seen in chronic infection?
  • Subramaniam has 42% clonal plasma cells, an M-spike of 4.8 g/dL, and CRAB features. Apply the IMWG diagnostic criteria: which three elements must ALL be present for a diagnosis of symptomatic multiple myeloma?
  • Compare multiple myeloma with MGUS (monoclonal gammopathy of undetermined significance) and smouldering myeloma: what is the key distinguishing criterion for each, and what is the annual risk of progression from MGUS to myeloma?
  • Why is β2-microglobulin used as a prognostic marker rather than a diagnostic one? What does a high β2-microglobulin level reflect at the cellular level?
Click to reveal Trigger 3: Diagnosis & Management — Complications and Prognosis (discuss previous trigger first!)

Trigger 3: Diagnosis & Management — Complications and Prognosis

Subramaniam is diagnosed with multiple myeloma (IgG-κ), ISS Stage III (β2-microglobulin 8.2 mg/L, albumin 2.8 g/dL). He is started on a bortezomib-based regimen. Six weeks into treatment his creatinine improves (from 2.8 to 1.6 mg/dL) and M-spike reduces from 4.8 to 2.1 g/dL. However, he develops a new problem: recurrent chest infections — two episodes of Streptococcus pneumoniae pneumonia in eight weeks. At his follow-up, his daughter asks the haematologist: 'My father's protein was very high when he came in — why does he keep getting infections? Doesn't protein mean he has too many antibodies?'

DISCUSSION POINTS

  • Explain the paradox of immunodeficiency in a disease characterised by massive overproduction of immunoglobulin. Why does Subramaniam have low levels of normal (polyclonal) immunoglobulins despite a total serum protein of 11.2 g/dL?
  • What term describes the suppression of normal immunoglobulin production in myeloma, and what is the mechanism? How does this explain the susceptibility to encapsulated bacterial infections specifically?
  • Subramaniam's renal function improved with treatment. Describe the two main mechanisms by which myeloma causes renal impairment — 'myeloma cast nephropathy' (myeloma kidney) and hypercalcaemia-induced injury — and explain why the urine dipstick remained negative throughout.
  • The haematologist explains that myeloma is currently incurable in most patients but 'highly manageable'. What is the pathological basis for relapse after initial response? Connect the concept of clonal evolution and secondary mutations to why a disease that initially responds to a proteasome inhibitor eventually becomes resistant.

Group Task Assignments

Group 1: Pathogenesis and cellular biology of myeloma

  • Trace the normal B-lymphocyte development pathway from naive B cell to plasma cell, identifying the stage at which malignant transformation occurs in myeloma. Explain why myeloma plasma cells home to bone marrow and what role IL-6 plays in their survival.
  • Explain why myeloma produces ONLY lytic bone lesions (never sclerotic): describe the DKK-1 pathway and its effect on the RANK-L/OPG axis, contrasting this with the mixed lytic-sclerotic lesions of metastatic prostate cancer.

Competencies: PA20.3

Group 2: Laboratory diagnosis — SPEP, IFE, and marrow

  • Draw a schematic serum protein electrophoresis lane and label the five major protein bands (albumin, α1, α2, β, γ). Mark where the M-spike appears in myeloma. Contrast the sharp monoclonal peak with the broad polyclonal hypergammaglobulinaemia of chronic infection.
  • Explain why the urine dipstick misses Bence-Jones protein, and describe the correct urine test to detect it. What is the pathological significance of Bence-Jones proteinuria in terms of renal damage?

Competencies: PA20.3

Group 3: CRAB criteria and diagnostic workup

  • Apply the IMWG diagnostic criteria to Subramaniam's case: verify that all three required components (clonal plasma cells ≥10%, M-protein, myeloma-defining event) are met and specify which CRAB events are present.
  • Create a differential diagnosis for a patient with hypercalcaemia + lytic bone lesions + renal impairment + anaemia, distinguishing myeloma from bone metastases from a solid tumour (breast, lung, renal) — list at least three distinguishing laboratory features.

Competencies: PA20.3

Group 4: Distinguishing myeloma from MGUS and smouldering myeloma

  • Construct a three-row comparison table: MGUS / smouldering myeloma / symptomatic myeloma — criteria for each, annual progression risk, and management (observe vs treat).
  • Explain why an elderly patient with an incidentally discovered M-protein of 1.2 g/dL, 7% marrow plasma cells, normal calcium, normal renal function, and no bone lesions does NOT require chemotherapy — and what follow-up schedule is appropriate.

Competencies: PA20.3

Group 5: Complications — immunoparesis, renal failure, bone disease

  • Explain the paradox of immunodeficiency in myeloma: define 'immunoparesis' (suppression of non-myeloma immunoglobulins), describe the mechanism, and explain why pneumococcal pneumonia is the characteristic infective complication.
  • Describe myeloma cast nephropathy (myeloma kidney): what accumulates in the tubules, how does it cause obstruction and inflammation, and why does the urine dipstick remain negative? Contrast with amyloid-associated renal disease in myeloma.

Competencies: PA20.3

Learning Issues

Research these questions and bring your findings to the discussion.

  1. [PA20.3] What is multiple myeloma, what are its pathogenesis, clinical features (CRAB criteria), laboratory findings (serum protein electrophoresis, Bence-Jones protein, bone marrow biopsy findings), diagnostic criteria (IMWG), differential diagnosis from MGUS and smouldering myeloma, and the mechanisms of its major complications (bone disease, renal failure, immunoparesis)?