GC030 An Old Man With Bone Pain And Anaemia
An elderly patient presenting with bone pain and anemia, most likely due to multiple myeloma — a malignant plasma cell neoplasm causing lytic bone lesions, marrow infiltration, and monoclonal immunoglobulin production.
An Old Man with Bone Pain and Anaemia: Multiple Myeloma & Monoclonal Gammopathy
This lecture is built around a classic clinical vignette — a 74-year-old man (Mr K) presenting with reduced exercise tolerance and low back pain — that leads to the diagnosis of multiple myeloma (MM). [1]
The lecture covers four learning objectives [1]:
- Recognise the clinical features of multiple myeloma
- Understand the clinical spectrum of plasma cell dyscrasia (MGUS → Smouldering Myeloma → MM)
- Explain the complications of myeloma and their underlying mechanisms
- List treatment options for myeloma
Why this matters for exams: Multiple myeloma is a favourite exam topic because it integrates haematology, renal medicine, bone disease, calcium metabolism, protein biochemistry, and immunology. It tests whether you can connect a clinical presentation (bone pain + anaemia + renal impairment + hypercalcaemia) to a unifying diagnosis, then investigate and manage systematically.
How it fits clinically: MM is the second most common haematological malignancy. It is almost exclusively a disease of the elderly. Any elderly patient with unexplained anaemia, bone pain, renal impairment, or hypercalcaemia should have MM on the differential.
Core Concepts and Mechanisms (First Principles)
Multiple myeloma is a neoplastic proliferation of a single clone of terminally differentiated plasma cells. [1]
Let's break this down from first principles:
- B cells normally differentiate into plasma cells in the bone marrow, which secrete polyclonal immunoglobulins (antibodies) — each plasma cell clone makes one specific antibody.
- In MM, a single clone of plasma cells has become malignant. It proliferates uncontrollably and produces a single type of immunoglobulin (or part of one) — this is the paraprotein (also called M-protein or monoclonal band).
- Because it's a single clone → single immunoglobulin type → monoclonal gammopathy.
The malignant plasma cells cause disease through several mechanisms [1]:
| Mechanism | Consequence |
|---|---|
| Marrow infiltration by clonal plasma cells | Anaemia, neutropenia, thrombocytopenia (reduced trilineage haematopoiesis) |
| Paraprotein production | Hyperviscosity (rare), rouleaux formation, immunoparesis |
| Cytokine secretion (RANKL, MIP, TNF) | Osteolytic bone lesions, hypercalcaemia |
| Free light chain excess | Cast nephropathy (myeloma kidney), amyloidosis |
| Immunoparesis (suppression of normal Ig) | Susceptibility to infections |
The Clinical Spectrum of Plasma Cell Dyscrasia
MGUS → Smouldering Myeloma → Multiple Myeloma (progression rates: 1% per year for MGUS; 10% per year in first 5 years for SMM) [1]
This is a critical exam concept. Plasma cell disorders exist on a spectrum:
~5% of population above 50 years of age. Defined by: paraprotein < 30 g/L AND bone marrow plasma cells < 10% without any evidence of B-cell lymphoproliferative disorder AND absence of organ damage. [1]
- Why it matters: MGUS is incredibly common in the elderly. Most patients with MGUS will never develop myeloma. But the risk is real — approximately 1% per year progress to myeloma or a related malignancy, and this risk persists lifelong.
- AL amyloidosis is a differential if the patient has suggestive symptoms (heart failure, nephrotic syndrome, macroglossia, peripheral neuropathy) [1].
- Risk factors for progression [1]:
- Size of paraprotein (larger = higher risk)
- Type of paraprotein (non-IgG types carry higher risk)
- Abnormal serum free light chain ratio
- Rate of rise in paraprotein
- Bone marrow morphology
Presence of > 10% clonal plasma cells in bone marrow AND paraprotein > 30 g/L, but ABSENCE of end-organ damage. Risk of progression to symptomatic myeloma: 10% per year in first 5 years, then 3% per year in subsequent 5 years. [1]
- Think of SMM as "myeloma that hasn't caused any damage yet." We watch and wait (in most cases), because treating asymptomatic disease has not always improved overall survival (though this is evolving with newer trials).
Full diagnostic criteria below.
Normally, our serum immunoglobulin represents the combined output from millions of different plasma cells — they are polyclonal. Paraproteinaemia refers to a monoclonal immunoglobulin band in the blood secreted by a single clone of neoplastic cells. The abnormal protein is called a paraprotein and is detected by protein electrophoresis of the serum. [1]
Why serum protein electrophoresis (SPEP) works:
- Normal serum has a broad, polyclonal gamma band (because millions of different plasma cells contribute different antibodies).
- In myeloma, one clone dominates → a sharp, tall spike appears in the gamma region (the "M-spike" or monoclonal band).
- Immunofixation then identifies the exact type (IgG kappa, IgA lambda, etc.).
High Yield
SPEP is the single most important initial test when you suspect myeloma. In the 2021 past paper (Q27), a patient with anaemia, renal impairment, hypercalcaemia, and raised globulin is asked "which subsequent blood test is MOST HELPFUL in making the diagnosis?" — the answer is serum protein electrophoresis [6].
Pathogenesis: Molecular and Microenvironment
Normal B-cell differentiation involves VDJ rearrangement, somatic hypermutation, and class switch recombination. Errors during these processes can lead to oncogenic translocations. [1]
IGH translocations occur in 40-50% of cases, with 5 recurrent patterns: t(11;14) [CCND1], t(4;14) [FGFR3/MMSET], t(16;23) [MAF], t(6;14) [CCND3], and t(20;11) [MAFB]. Hyperdiploidy with trisomies of odd chromosomes (3, 5, 7, 9, 11, 15, 19) is another common karyotypic abnormality. [1]
Why this matters: The genetic subtype determines prognosis and, increasingly, treatment choice.
The bone marrow microenvironment provides a sanctuary for myeloma cells. Neoplastic plasma cells escape apoptotic pathways and continue to proliferate in the bone marrow, eventually developing drug resistance. [1]
- Myeloma cells interact with stromal cells, osteoclasts, osteoblasts, endothelial cells, and immune cells within the marrow niche.
- These interactions promote survival signalling (IL-6, VEGF, IGF-1), angiogenesis, and immune evasion.
- This is why novel agents targeting the microenvironment (e.g., immunomodulatory drugs, monoclonal antibodies) have been transformative.
Diagnosis of Multiple Myeloma: IMWG 2014 Criteria
IMWG 2014 Diagnostic Criteria: [1]
- Clonal bone marrow plasma cells ≥ 10% or biopsy-proven bony or extramedullary plasmacytoma
- PLUS one or more myeloma-defining events:
| Letter | Criterion | Threshold | Why It Happens |
|---|---|---|---|
| C | Hypercalcaemia | Ca > 0.25 mmol/L above ULN or > 2.75 mmol/L | Osteoclast activation → bone resorption → Ca release |
| R | Renal insufficiency | Creatinine > 177 μmol/L or CrCl < 40 mL/min | Cast nephropathy, hypercalcaemia, dehydration |
| A | Anaemia | Hb < 10 g/dL or > 2 g/dL below lower limit of normal | Marrow infiltration, reduced EPO, dilution |
| B | Bone lesions | ≥ 1 osteolytic lesion on XR, CT, or PET-CT | Cytokine-mediated osteoclast activation |
These allow diagnosis even WITHOUT end-organ damage, because they predict very high (≥ 80%) risk of progression to organ damage within 2 years:
| Biomarker | Threshold |
|---|---|
| Clonal bone marrow plasma cells ≥ 60% | Massive clonal burden |
| Involved:uninvolved serum free light chain ratio > 100 (with involved FLC > 100 mg/L) | Very skewed light chain production |
| ≥ 1 focal lesion (≥ 5 mm) on MRI | Detects early bone disease before lytic lesions appear on XR |
Exam Trap
Don't confuse the old diagnostic criteria (requiring CRAB only) with the updated 2014 IMWG criteria that include SLiM biomarkers. An MCQ might present a patient with > 60% plasma cells but no CRAB features — this IS now classified as myeloma requiring treatment, not smouldering myeloma.
Complications of Multiple Myeloma (Detailed Mechanisms)
Why myeloma patients are anaemic: [1]
- Marrow replacement by plasma cells (the clonal plasma cells crowd out normal haematopoietic precursors)
- Reduced erythropoietin (renal impairment → decreased EPO production)
- Dilution by paraprotein (high paraprotein levels increase plasma volume)
- Rouleaux of red cells (paraprotein causes RBCs to stack → spuriously low Hb on automated counters, plus impaired microcirculation)
Typical picture: Normochromic normocytic anaemia (73% of patients) [4]. The blood film classically shows rouleaux formation.
Markedly increased bone resorption secondary to increased osteoclastic activity, caused by secretion of potent cytokines including RANKL, macrophage inflammatory factor, and TNF. [1]
Direct myeloma deposit causes the radiological appearance of punch-out lesions on the skull. [1]
Characteristically, osteoblastic activity is NOT increased. Therefore, in typical myeloma bone disease, ALP (a marker of osteoblastic activity) is NOT elevated. [1]
High Yield
ALP is typically NORMAL in myeloma bone disease. This is a classic exam discriminator. In metastatic bone disease (e.g., prostate, breast), ALP is often elevated because there is a mixed lytic/blastic response. In myeloma, it is purely lytic with suppressed osteoblasts → normal ALP. If ALP is elevated in a myeloma patient, think about healing fracture, liver disease, or another cause.
Consequences of bone disease [1]:
- Hypercalcaemia (bone resorption releases calcium into circulation)
- Lytic bone lesions (widespread decrease in bone density, punch-out skull lesions, pathological fractures)
- Vertebral collapse → loss of height, spinal cord compression (oncological emergency!)
Extramedullary plasmacytoma or fracture of vertebral body could lead to spinal cord compression. [1]
Bone imaging:
- Skeletal survey (XR): Traditional but misses early disease (needs > 30% bone loss to be visible)
- Whole-body low-dose CT: Better sensitivity, now preferred
- PET-CT: Detects metabolically active disease
- MRI: Best for spinal cord compression, detects focal lesions for SLiM criteria
Exam Trap
Bone scans (technetium-99m) are NOT useful in myeloma because bone scans detect osteoBLASTIC activity — and myeloma bone disease has suppressed osteoblastic activity. This is a common MCQ trap. Bone scans will be FALSE NEGATIVE in myeloma.
At least 50% of patients with newly diagnosed myeloma have renal involvement of various degree. [1]
Cast nephropathy is the predominant cause of kidney injury, also known as myeloma kidney. [1]
Other mechanisms of kidney injury include: hypercalcaemia, dehydration, amyloidosis, and direct myeloma deposition (the last two are rare). [1]
Cast Nephropathy (Myeloma Kidney) — The Key Mechanism
Excessive clonal free light chains are filtered freely through the glomeruli and exceed the reabsorption capacity of proximal tubular cells. They combine with uromodulin (Tamm-Horsfall protein) to form waxy casts. These obstruct distal renal tubules, causing tubulointerstitial nephritis as the tubules rupture. [1]
Step-by-step:
- Malignant plasma cells produce massive amounts of monoclonal free light chains (κ or λ)
- Light chains are small (~25 kDa) → freely filtered through glomeruli
- Normal proximal tubular cells reabsorb light chains via megalin/cubilin receptors
- In myeloma, the sheer quantity overwhelms this reabsorptive capacity
- Excess light chains reach the distal tubule and bind to uromodulin (Tamm-Horsfall protein)
- This forms dense, obstructing waxy casts
- Tubular obstruction → back-pressure → tubular rupture → interstitial inflammation → AKI
Renal biopsy findings in the case (Mr K) [1]:
- Mild tubular atrophy and interstitial fibrosis
- Angulated casts in the lumen of several renal tubules
- No deposits of immunoglobulin
- Congo red stain negative (ruling out amyloidosis)
The Congo red negative result is important — it tells you this is NOT AL amyloidosis (which shows apple-green birefringence under polarized light after Congo red staining). This is pure cast nephropathy [1] [5].
Myeloma patients are immunocompromised due to:
- Immunoparesis: Suppression of normal (non-clonal) immunoglobulin production → functional hypogammaglobulinaemia
- Neutropenia: From marrow infiltration or chemotherapy
- Impaired lymphocyte function
Most common organisms: encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae) and Gram-negative organisms [4].
- More common with IgM paraproteins (Waldenström macroglobulinaemia) because IgM is a pentamer.
- In MM, hyperviscosity is uncommon unless paraprotein levels are very high (more typical with IgA, which tends to polymerize).
- Symptoms: visual disturbance, headache, bleeding, confusion.
- Radiculopathy: T/L/S spine compression by paravertebral plasmacytoma
- Cord compression: Extramedullary plasmacytoma or vertebral collapse → ONCOLOGICAL EMERGENCY
- Peripheral neuropathy: Uncommon in MM alone; more associated with amyloidosis or POEMS
- Bleeding (platelet dysfunction, thrombocytopenia)
- AL Amyloidosis (light chain deposition in tissues)
- POEMS syndrome — Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes (a distinct entity from MM, typically osteosclerotic rather than osteolytic) [4]
Other entities with a paraprotein: [1]
- Some low-grade B-cell lymphomas
- Lymphoplasmacytic lymphoma (IgM paraprotein) — i.e., Waldenström macroglobulinaemia
- AL amyloidosis
- POEMS / TEMPI syndrome
| Feature | Finding | Significance |
|---|---|---|
| Demographics | M/74, PMH: BPH, HT, DM | Classic age for myeloma; comorbidities affect management |
| Presenting complaint | 3 months reduced exercise tolerance + low back pain | Anaemia + bone disease |
| Bone marrow | Pleomorphic plasma cells 64% of nucleated cells; trilineage haematopoiesis markedly reduced | Diagnostic: clonal plasma cells ≥ 10% (in fact ≥ 60% → also meets SLiM criterion) |
| Renal biopsy | Mild tubular atrophy, interstitial fibrosis; angulated casts; no Ig deposits; Congo red negative | Confirms cast nephropathy (NOT amyloidosis) |
Work-up includes: [1]
- History and Physical Examination
- Complete blood count
- Renal function, calcium, albumin, ALP, LDH
- Serum protein electrophoresis ± immunofixation
- Urine for protein
- Urine protein electrophoresis
- Serum free light chain level and ratio
- Serum beta-2 microglobulin
- Bone marrow aspirate and trephine + FISH analysis
- Skeletal survey / Whole-body PET-CT / Whole-body MRI / Whole-body low-dose CT
- Dental assessment
Why each investigation:
| Investigation | Why It's Needed |
|---|---|
| CBC | Detect anaemia, neutropenia, thrombocytopenia (marrow failure) |
| RFT, Ca, albumin | Detect CRAB features; calculate corrected calcium |
| ALP | Should be normal in myeloma (vs elevated in metastatic bone disease); elevated = think fracture healing or liver pathology |
| LDH | Prognostic marker; elevated LDH = high-risk feature |
| SPEP + immunofixation | Detect and type the paraprotein |
| Urine protein + UPEP | Detect Bence Jones proteinuria (free light chains in urine) |
| Serum free light chains | Quantify light chain production; calculate involved:uninvolved ratio (used in SLiM criteria and response monitoring) |
| Beta-2 microglobulin | Key prognostic marker used in ISS/R-ISS staging |
| BM aspirate + trephine + FISH | Confirm diagnosis (% plasma cells), assess cytogenetics for risk stratification |
| Imaging | Detect lytic lesions, assess bone disease extent, diagnose cord compression |
| Dental assessment | Required before starting bisphosphonates/denosumab because these agents can cause osteonecrosis of the jaw (ONJ) |
High Yield
Dental assessment is part of the standard myeloma work-up because anti-resorptive therapy (bisphosphonates like zoledronic acid or pamidronate, or denosumab) carries a risk of osteonecrosis of the jaw. Any dental procedures should ideally be completed BEFORE starting these agents.
Staging and Prognosis
Durie-Salmon Staging: [1]
| Stage | Criteria | Cell Mass |
|---|---|---|
| I | ALL of: Hb > 10, IgG < 5000, IgA < 3000, normal Ca, urine M-protein < 4 g/day, no generalised lytic lesions | Low ( < 0.6 × 10¹² cells/m²) |
| II | Neither I nor III | Intermediate |
| III | ONE or more of: Hb < 8.5, IgG > 7000, IgA > 5000, Ca > 3 mmol/L, urine M-protein > 12 g/day, advanced lytic lesions | High ( > 1.2 × 10¹² cells/m²) |
| Subclass A | Creatinine < 177 μmol/L | |
| Subclass B | Creatinine ≥ 177 μmol/L |
R-ISS: [1]
| Stage | Criteria | 5-Year OS |
|---|---|---|
| I | β2M < 3.5 mg/L + Albumin ≥ 35 g/L + Standard-risk FISH + Normal LDH | 82% |
| II | Neither I nor III | 62% |
| III | β2M ≥ 5.5 mg/L + High-risk FISH [del(17p), t(4;14), t(14;16)] and/or elevated LDH | 40% |
Why β2-microglobulin? It reflects both tumour burden (produced by myeloma cells) and renal function (cleared by kidneys). A high level can mean high tumour mass, poor renal function, or both — all associated with worse prognosis.
Mayo Stratification of Myeloma And Risk-Adapted Therapy (mSMART): [1]
| Risk Category | Cytogenetics | OS |
|---|---|---|
| Standard risk (60%) | t(11;14), t(6;14), Hyperdiploidy | 8-10 years |
| Intermediate risk (20%) | t(4;14), del(13), (1q gain) | 4-5 years |
| High risk (20%) | del(17p), t(14;16), t(14;20), Hypodiploid, P53 mutation, GEP high-risk | 3 years |
High Yield
High-risk FISH features to remember: del(17p), t(4;14), t(14;16), t(14;20), gain(1q). These dictate more intensive treatment strategies and predict shorter survival. Del(17p) = loss of P53 → loss of tumour suppressor → aggressive disease.
Treatment of Multiple Myeloma
Overall survival of myeloma patients has significantly improved in the past decade due to introduction of novel agents. [1]
The treatment landscape includes [1]:
- IMiDs (Immunomodulatory drugs): thalidomide, lenalidomide, pomalidomide
- Proteasome inhibitors: bortezomib, carfilzomib, ixazomib
- Monoclonal antibodies: daratumumab (anti-CD38), elotuzumab (anti-SLAMF7), belantamab mafodotin (anti-BCMA antibody-drug conjugate)
- Other novel agents: selinexor (nuclear export inhibitor), venetoclax (BCL-2 inhibitor), CAR-T cell therapy
- Autologous HSCT (haematopoietic stem cell transplant)
Important considerations: [1]
- Eligibility for autologous HSCT (generally age < 65-70, adequate organ function, good performance status)
- Presence of high-risk features: Plasma cell leukaemia, markedly elevated LDH, high-risk FISH [t(4;14), t(14;16), t(14;20), del(17p), gain(1q)]
- Need for adjunctive treatment: Radiotherapy (for painful bone lesions, cord compression) and anti-resorptives (bisphosphonates or denosumab)
Induction (triplet/quadruplet) → Autologous HSCT → Maintenance [1]
- Induction: Typically VRd (bortezomib + lenalidomide + dexamethasone) ± daratumumab (Dara-VRd = quadruplet)
- ASCT: Uses high-dose melphalan conditioning → autologous stem cell rescue
- Maintenance: Lenalidomide (standard risk) or bortezomib-based (high risk) — continues until progression or intolerance
Induction (Rd / triplet / quadruplet) → Maintenance [1]
- Rd = lenalidomide + dexamethasone (continuous until progression)
- VRd or Dara-Rd = triplet options for fitter elderly patients
IMiDs (thalidomide, lenalidomide, pomalidomide): [1]
- Bind to cereblon and activate cereblon E3 ligase activity
- Rapid ubiquitination and degradation of Ikaros (IKZF1) and Aiolos (IKZF3) — B-cell transcription factors essential for myeloma cell survival
- Anti-angiogenesis and immunomodulatory effect
- Increases risk of thromboembolism → require thromboprophylaxis (aspirin or LMWH)
Exam Trap
Thalidomide and lenalidomide are teratogenic (remember thalidomide's history). They also increase VTE risk. All patients on IMiDs need thromboprophylaxis and strict contraceptive measures if of reproductive age.
Proteasome inhibitors (bortezomib, carfilzomib, ixazomib): [1]
- Inhibition of the 26S proteasome
- Prevents proteolysis of tagged (ubiquitinated) proteins
- Cytotoxic to myeloma cells by affecting multiple signalling cascades (NF-κB, cell cycle regulators, pro-apoptotic proteins)
Why myeloma cells are especially sensitive: Myeloma cells produce enormous amounts of protein (immunoglobulin). They are heavily dependent on the proteasome to dispose of misfolded proteins. Blocking the proteasome causes an "unfolded protein response" → ER stress → apoptosis.
Side effects of bortezomib: Peripheral neuropathy (dose-limiting), GI upset, thrombocytopenia. Carfilzomib is associated with cardiotoxicity.
Novel agents: [1]
- Daratumumab (anti-CD38 monoclonal antibody) — now incorporated into frontline therapy
- Elotuzumab (anti-SLAMF7)
- Belantamab mafodotin (anti-BCMA antibody-drug conjugate) — risk of keratopathy
- Selinexor (nuclear export inhibitor — blocks XPO1)
- Venetoclax (BCL-2 inhibitor — particularly effective in t(11;14) myeloma)
- CAR-T cell therapy (targeting BCMA) — for relapsed/refractory disease
| Adjunct | Indication | Notes |
|---|---|---|
| Bisphosphonates (zoledronic acid, pamidronate) | All patients with bone disease | Reduce skeletal events; dental check first (ONJ risk); monitor renal function |
| Denosumab (anti-RANKL) | Alternative if renal impairment contraindicates bisphosphonates | Does not require renal dose adjustment |
| Radiotherapy | Painful bone lesions, cord compression, solitary plasmacytoma | |
| Erythropoiesis-stimulating agents | Symptomatic anaemia | Consider when Hb < 10 and EPO levels are low |
| IV immunoglobulin | Recurrent infections due to hypogammaglobulinaemia | |
| Vaccination | Pneumococcal, influenza, COVID | Immunocompromised → impaired vaccine responses |
Integration with Related GC Lectures
Hypercalcaemia is a common emergency in myeloma. Management principles [3]:
- IV normal saline (aggressive hydration to restore volume and promote calciuresis)
- IV bisphosphonates (zoledronic acid 4 mg IV over 15 min — inhibits osteoclasts)
- Calcitonin (rapid but transient effect via tachyphylaxis)
- Glucocorticoids (dexamethasone — particularly useful in myeloma because steroids also have direct anti-myeloma activity)
- Denosumab (anti-RANKL — for refractory cases)
- Dialysis (last resort for severe, refractory hypercalcaemia with renal failure)
When an elderly patient presents with anaemia, the differential is broad [2]:
- Iron deficiency (GI malignancy, NSAIDs)
- Anaemia of chronic disease
- B12/folate deficiency
- Renal anaemia
- Multiple myeloma — don't forget this!
Key discriminators from the blood film: Rouleaux formation and a raised ESR with raised globulin should immediately raise suspicion for myeloma [2][4].
From the nephrology teaching clinic [5]:
- Light chain cast nephropathy = "myeloma kidney"
- Presents with AKI and proteinuria
- Renal biopsy: tubular casts rimmed by macrophages, light chain restriction on immunohistochemistry
- Other renal diseases associated with monoclonal light chains: AL amyloidosis, light chain deposition disease, light chain proximal tubulopathy, Type I cryoglobulinaemic GN
Myeloma bone disease and osteoporosis both cause vertebral fractures in the elderly, but the mechanisms are different:
- Osteoporosis: Generalised reduction in bone density with balanced (but reduced) osteoblast/osteoclast activity
- Myeloma: Focal lytic lesions with markedly increased osteoclast activity and suppressed osteoblast activity
- Key lab difference: ALP normal in myeloma, may be elevated in osteoporosis with fracture healing
Myeloma epidemiology: [1]
- 1% of all malignancy, 10% of haematological malignancies
- Age-standardized incidence: ~5 per 100,000
- Slightly more common in men
- Median age: 66-70 years
- Extremely rare in < 30 years of age
| Feature | Mechanism | Key Investigation | Key Treatment |
|---|---|---|---|
| Calcium ↑ | RANKL-mediated osteoclast activation → bone resorption | Corrected calcium, PTH (suppressed) | IV saline, bisphosphonates, steroids |
| Renal impairment | Cast nephropathy (FLC + uromodulin), hypercalcaemia, dehydration | RFT, serum FLC, urine protein, ± renal biopsy | Hydration, treat hypercalcaemia, reduce FLC (chemotherapy), ± dialysis |
| Anaemia | Marrow infiltration, ↓EPO, dilution, rouleaux | CBC, reticulocyte count, PBS, bone marrow | Treat myeloma, ESA, transfusion if needed |
| Bone lesions | Osteoclast activation + osteoblast suppression | Low-dose whole-body CT, PET-CT, MRI | Bisphosphonates/denosumab, radiotherapy, orthopaedic input for fractures |
Likely Exam Questions
-
A 72-year-old man with back pain, Hb 8.5, Ca 3.1, Cr 250, globulin 85. Which investigation is most useful for diagnosis?
- Answer: Serum protein electrophoresis [6]
- Trap: β2-microglobulin is for staging, not diagnosis. CEA is for carcinoma. PTH would be suppressed, not diagnostic.
-
Which of the following is NOT typically elevated in myeloma bone disease?
- Answer: Alkaline phosphatase (osteoblasts are suppressed in myeloma → ALP normal)
-
A 68-year-old with pancytopenia, raised globulin, back pain, and XR showing "pepper-pot" skull. What is the most likely diagnosis?
- Answer: Multiple myeloma
-
Which bone imaging modality is LEAST useful in myeloma?
- Answer: Technetium-99m bone scan (detects osteoblastic activity, which is suppressed in myeloma → false negative)
-
Risk of progression from MGUS to myeloma per year?
- Answer: ~1% per year
-
List 4 causes of renal impairment in a patient with myeloma. (4 marks)
- Cast nephropathy (light chain precipitation in tubules)
- Hypercalcaemia
- Dehydration
- AL amyloidosis
- (Also accept: direct light chain deposition, nephrotoxic drugs including NSAIDs, uric acid nephropathy)
-
State the IMWG 2014 diagnostic criteria for multiple myeloma. (6 marks)
- Clonal BM plasma cells ≥ 10% or biopsy-proven plasmacytoma
- PLUS ≥ 1 myeloma-defining event:
- CRAB: HyperCalcaemia, Renal insufficiency, Anaemia, Bone lesions
- OR SLiM biomarkers: BM PC ≥ 60%, involved:uninvolved FLC ratio > 100, ≥ 1 focal MRI lesion ≥ 5 mm
-
Explain why ALP is typically normal in myeloma bone disease. (2 marks)
- Myeloma cytokines activate osteoclasts but do NOT stimulate osteoblasts
- ALP is a marker of osteoblastic activity → remains normal
From the 2022 Fourth Summative MCQ [7], a pancytopenia EMQ includes MM as an option:
- Q6 (aplastic anaemia): 24F, pale, hypocellular marrow → aplastic anaemia
- Q7 (AML/MDS): 80F, blasts with Auer rod → AML (from MDS)
- Q8 (pernicious anaemia): 65M, jaundiced, glossitis, macro-ovalocytes, hypersegmented neutrophils → B12 deficiency
- Q9 (primary myelofibrosis): 52M, massive splenomegaly, tear-drop cells, dry tap → PMF
Know the discriminators: MM typically does NOT have massive splenomegaly. Dry tap = fibrosis (PMF) not myeloma. Auer rods = myeloid neoplasm not plasma cell.
From the 2024 Fourth Summative SAQ Q10 [8]: A 60M with small cell lung CA, increased bone pain, confusion:
- DDx: brain metastases, hypercalcaemia of malignancy, opioid toxicity, SIADH, disease progression
- Investigations: corrected calcium, CT brain, blood glucose, medication review
This tests the differential for bone pain + confusion in malignancy — myeloma and metastatic bone disease share the hypercalcaemia mechanism but differ in ALP and paraprotein profile.
High Yield Summary
Multiple Myeloma in a Nutshell:
- What: Neoplastic proliferation of a single clone of terminally differentiated plasma cells producing monoclonal immunoglobulin (paraprotein)
- Who: Elderly (median 66-70y), slightly more males, 10% of haematological malignancies
- Spectrum: MGUS (1%/yr) → Smouldering myeloma (10%/yr × 5y) → Multiple myeloma
- Diagnosis (IMWG 2014): ≥ 10% clonal BM plasma cells + myeloma-defining event (CRAB or SLiM)
- Complications (CRAB): hyperCalcaemia (osteoclast activation, normal ALP), Renal failure (cast nephropathy), Anaemia (marrow replacement), Bone lesions (lytic, punch-out skull)
- Key investigations: SPEP + immunofixation, serum FLC, UPEP, BM biopsy + FISH, β2M, whole-body CT/PET-CT/MRI, dental check
- Staging: R-ISS (β2M, albumin, LDH, FISH)
- Treatment: Transplant-eligible → Induction → ASCT → Maintenance; Transplant-ineligible → Induction → Maintenance. Agents: IMiDs (cereblon → Ikaros/Aiolos degradation; VTE risk), Proteasome inhibitors (26S proteasome; neuropathy), Monoclonal Ab (daratumumab), CAR-T
- ALP is NORMAL in myeloma bone disease (osteoblasts suppressed)
- Bone scans are USELESS in myeloma (detect osteoblastic activity)
- SPEP is the MOST HELPFUL test for making the diagnosis when you suspect myeloma on clinical grounds
Active Recall - Lecture Notes
[1] Lecture slides: GC 030. An old man with bone pain and anaemia.pdf (all pages) [2] Lecture slides: GC 076. Pallor_diagnosis of anaemia; nutritional anaemia; anaemia of systemic diseases.pdf (p45) [3] Senior notes: Block A - Confused and dehydrated_ hypercalcaemia; hypocalcaemia.pdf (p9) [4] Senior notes: Ryan Ho Haemtology.pdf (p106, p78) [5] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf (p15, p35) [6] Past papers: 2021 Fourth Summative Assessment MCQ.pdf (Q27) [7] Past papers: 2022 Fourth Summative MCQ.pdf (Q6-9) [8] Past papers: 2024 Fourth Summative SAQ.pdf (Q10) [9] Senior notes: Block A - An old man with bone pain and anaemia_ multiple myeloma; monoclonal gammopathy.pdf (p1) [10] Senior notes: Maksim Medicine Notes.pdf (p153, p158) [11] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p1482)
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