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 predominantly a disease of older adults, although it is not confined to them. Unexplained anaemia, persistent bone pain, renal impairment, hypercalcaemia, recurrent infection, or a protein gap should prompt consideration of a plasma-cell disorder.
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. The lecture quotes average historical progression rates of about 1% per year for MGUS and 10% per year during the first 5 years for SMM, but individual SMM risk varies substantially and modern SLiM-CRAB criteria reclassify some formerly “smouldering” cases as active MM. [1][13]
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
The slide uses the older shorthand “> 10% clonal marrow plasma cells and paraprotein > 30 g/L.” Current IMWG wording is more precise: serum IgG/IgA M-protein ≥30 g/L or urine monoclonal protein ≥500 mg/24 h and/or clonal marrow plasma cells 10–60%, with no myeloma-defining event or amyloidosis. [13]
- Think of SMM as an asymptomatic precursor state that lacks a myeloma-defining event. Management is risk-adapted specialist surveillance; selected high-risk patients may be considered for early intervention or a clinical trial under contemporary guidance, rather than assuming one rule for every SMM patient. [14]
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 many intact-immunoglobulin myelomas, one clone dominates → a narrow peak (“M-spike”) appears, often in the gamma region but sometimes in the beta region.
- Immunofixation then identifies the exact type (IgG kappa, IgA lambda, etc.).
Reading the tracing on the slide: the normal plot has a tall albumin peak followed by smaller α1, α2, and β fractions and a broad γ region. The abnormal plot adds a very narrow gamma peak: narrowness signals clonality, while the area under the peak estimates the M-protein. Light-chain or oligosecretory disease may not produce this classic peak.
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 recurrent partners involving CCND1, FGFR3/NSD2 (formerly MMSET), MAF, CCND3, and MAFB. Hyperdiploidy with trisomies of odd chromosomes is another common pattern. [1]
The slide labels the partner loci (11q13, 4p16, 16q23, 6p21, 20q11). In standard translocation notation these are t(11;14), t(4;14), t(14;16), t(6;14), and t(14;20) because IGH lies at 14q32.
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.
The slide sequence makes two linked points that are easy to miss when only the labels are copied:
- Normal differentiation supplies the cell of origin: haematopoietic stem cell → lymphoid progenitor → B cell → antibody-secreting plasma cell. V(D)J recombination occurs during early B-cell development; somatic hypermutation and class switching occur after antigen activation. Errors around these DNA-remodelling steps help explain recurrent IGH rearrangements.
- Progression requires additional hits: a primary IGH translocation or hyperdiploidy can establish an MGUS clone; later RAS/MYC abnormalities, secondary translocations, epigenetic change, angiogenesis, and increased bone resorption can drive progression toward MM.
- Bone disease is a feed-forward circuit: myeloma cells increase osteoclast-activating signals and suppress osteoblast differentiation. Bone resorption releases growth factors that support the clone, while the altered niche can shelter residual or dormant myeloma cells.
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 CRAB end-organ damage because they identify a sufficiently high-risk biological state to warrant treatment under IMWG criteria:
| 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 |
| More than 1 focal lesion on MRI, each ≥5 mm | Detects early marrow disease before a lytic defect is evident 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.
Two imaging caveats matter: a PET-avid focus needs underlying osteolytic destruction on the CT component to satisfy the CRAB bone criterion, and osteoporosis or vertebral compression fractures without lytic lesions are not by themselves myeloma-defining bone disease. [13]
If marrow clonal plasma cells are < 10%, more than one bone lesion is required to distinguish MM from solitary plasmacytoma with minimal marrow involvement. CRAB abnormalities must also be attributable to the plasma-cell disorder, not merely coexist in an older patient. [13]
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 (the slide lists this with anaemia, but it is primarily a blood-film clue to increased plasma proteins, not a mechanism that ordinarily explains a low measured haemoglobin)
Typical picture: Normochromic normocytic anaemia (73% of patients) [4]. The blood film classically shows rouleaux formation.
How to read the image: rouleaux are long, orderly “stack-of-coins” chains of red cells. This differs from irregular agglutination; paraprotein reduces normal repulsive forces between red cells and also contributes to a high ESR.
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 often normal in active myeloma bone disease because the osteoblastic response is suppressed. This is a useful exam discriminator, not an absolute rule: ALP can rise with fracture healing, hepatic disease, or a concurrent osteoblastic process.
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]
What the case images show: the lateral lumbar radiograph demonstrates diffuse low bone density with several vertebral compression deformities, while the skull film shows numerous discrete lucent “punched-out” lesions. Compression fractures support the clinical suspicion but, without a lytic lesion, do not alone meet the modern CRAB bone criterion. The sagittal MRI later in the deck shows vertebral disease narrowing the spinal canal; new weakness, sensory change, gait disturbance, or bladder/bowel dysfunction therefore requires emergency MRI and same-day oncology/spinal assessment.
Bone imaging:
- Skeletal survey (XR): Traditional but substantially less sensitive than cross-sectional whole-body imaging
- 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
Conventional technetium bone scintigraphy depends on an osteoblastic response and has low sensitivity for the predominantly lytic lesions of myeloma, so it is not the routine staging test. Do not say every lesion must be false-negative: fractures or other areas with reactive bone formation may show uptake. Prefer whole-body low-dose CT, FDG PET-CT, or whole-body MRI according to the clinical question and local pathway. [13]
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
Reading the nephron diagram: uromodulin is produced in the thick ascending limb; free light chains bind it downstream, forming casts in distal nephron segments. High tubular concentration, acidity, sodium chloride, and calcium favour aggregation. Obstruction raises intratubular pressure; casts can breach the tubular basement membrane and provoke macrophage/giant-cell and cytokine-rich interstitial inflammation.
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 (no amyloid identified in the sampled tissue)
How to read the biopsy image: the casts are angular and “fractured,” with a surrounding inflammatory/giant-cell reaction; the slide notes a Tamm-Horsfall component staining magenta on PAS. Congo red negativity and absence of immunoglobulin deposits argue against amyloid and deposition disease in this specimen, while the cast morphology supports light-chain cast nephropathy. [1][5]
Renal impairment in suspected MM is an emergency because prompt clone-directed therapy and supportive care can preserve renal recovery. Current IMWG evaluation includes creatinine/eGFR, serum FLC, and 24-hour urine total protein, electrophoresis, and immunofixation. Marked albumin-predominant proteinuria or involved FLC < 500 mg/L makes an alternative monoclonal renal lesion more likely and strengthens the indication for renal biopsy. [16]
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 |
| CBC trend | Normocytic anaemia worsens from Hb 9.3 to 7.1 g/dL; mild thrombocytopenia develops | Marrow/renal disease; falling counts also show why serial results matter |
| Biochemistry | Creatinine 687–862 μmol/L, adjusted Ca 3.27–3.42 mmol/L, albumin 28 g/L, globulin 54–57 g/L; ALP not raised | Severe AKI + hypercalcaemia + protein gap, with no marked osteoblastic ALP response |
| Protein studies | IgG 3520 mg/dL, IgA suppressed, IgG-κ paraprotein 24.11 g/L | Monoclonal protein plus immunoparesis; the M-protein is below 30 g/L, illustrating that size alone does not distinguish MGUS from active MM |
| Imaging | Multiple skull lucencies and multilevel vertebral compression deformities | Classic lytic skull pattern; vertebral fragility and possible neurological risk |
| 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 | Morphology supports cast nephropathy and argues against amyloid/deposition disease in the sampled tissue |
Marrow-image key: the aspirate is dominated by atypical plasma cells with eccentric nuclei, deeply basophilic cytoplasm, and a pale perinuclear hof; marked pleomorphism and occasional large/binucleate forms contrast with the sparse residual trilineage precursors. The image shows both clonal burden and crowding-out of normal haematopoiesis.
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 | Often normal despite lytic disease because osteoblast activity is suppressed; elevation should prompt consideration of fracture healing, hepatic disease, or another bone process |
| LDH | Prognostic marker; elevated LDH = high-risk feature |
| SPEP + immunofixation | Detect and type an intact monoclonal protein; combine with serum FLC so light-chain disease is not missed |
| 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/R2-ISS staging |
| BM aspirate + trephine + FISH | Confirm diagnosis (% plasma cells), assess cytogenetics for risk stratification |
| Imaging | Whole-body low-dose CT, PET-CT, or whole-body MRI detects lytic/marrow disease; targeted urgent MRI assesses suspected cord compression. A plain skeletal survey is a legacy, less-sensitive option. [13] |
| 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 in the original R-ISS cohort |
|---|---|---|
| I | β2M < 3.5 mg/L + Albumin ≥ 35 g/L + Standard-risk FISH + Normal LDH | 82% |
| II | Neither I nor III | 62% |
| III | ISS stage III (β2M ≥ 5.5 mg/L) and 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.
The survival percentages on the slide describe the historical derivation cohort, not a timeless prognosis for an individual treated today. The 2025 EHA-EMN guideline incorporates the R2-ISS, a four-stage model that refines the large intermediate group by adding weighted 1q gain/amplification to ISS stage, LDH, del(17p), and t(4;14). [14][15]
Reading the survival plots: stage groups produce separated but overlapping Kaplan-Meier curves—they estimate risk for populations, not a date for one patient. The later cohort comparison in the lecture shows better survival in 2006–2010 than 2001–2005, with a conspicuous gain among patients older than 65; this supports the lecture’s message that novel therapy improved outcomes, but those historical curves should not be used for present-day counselling.
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) | 4-5 years |
| High risk (20%) | del(17p), t(14;16), t(14;20), gain(1q), hypodiploidy, P53 mutation, GEP high-risk | 3 years |
High Yield
The 2013 table is useful for recognising recurrent lesions, but its fixed “3/4–5/8–10 year” survival figures and three bins should not be used as current individual prognoses. Contemporary risk interpretation accounts for the exact lesion, clone size, co-occurring abnormalities, 1q copy number, stage, LDH, treatment, response/MRD, frailty, and renal function. Del(17p) involves the TP53 locus; it is not proof that every tumour has complete p53 loss.
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)
This is a lecture-era inventory, not a prescribing list. By 2025–2026, guidelines incorporate anti-CD38 quadruplets, BCMA-directed CAR-T and bispecific antibodies, and other regimen- and line-specific options; choice depends on transplant fitness, frailty, cytogenetics, renal function, previous exposure/refractoriness, access, and patient goals. [14][18]
Important considerations: [1]
- Eligibility for autologous HSCT (the slide suggests age < 65–70, but contemporary assessment is based on physiological fitness, frailty, comorbidity, organ function, and patient preference rather than a universal age cut-off)
- 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: A modern example is anti-CD38-based quadruplet therapy such as Dara-VRd; the FDA approved Dara-VRd induction/consolidation for newly diagnosed ASCT-eligible MM in 2024. Local formularies and guideline updates determine the preferred regimen. [17]
- ASCT: Uses high-dose melphalan conditioning → autologous stem cell rescue
- Maintenance: Lenalidomide (standard risk) or bortezomib-based (high risk) — continues until progression or intolerance
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 → perform formal VTE/bleeding-risk assessment and use regimen- and patient-appropriate prophylaxis
Exam Trap
Thalidomide, lenalidomide, and pomalidomide are teratogenic and require the applicable pregnancy-prevention programme. IMiD-containing regimens increase VTE risk, but the agent (for example aspirin, LMWH, or an anticoagulant) is selected from thrombosis and bleeding risk, renal function, interactions, and local guidance rather than one universal rule.
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) | Myeloma bone-disease prevention/treatment according to local protocol | Reduce skeletal events; dental review first where feasible; adjust/avoid according to renal function and monitor for ONJ |
| Denosumab (anti-RANKL) | Alternative anti-resorptive, including when renal toxicity limits bisphosphonates | No renal dose adjustment, but severe hypocalcaemia risk rises in advanced CKD: correct vitamin D/calcium problems and monitor closely |
| Radiotherapy | Painful bone lesions, cord compression, solitary plasmacytoma | |
| Erythropoiesis-stimulating agents | Selected persistent symptomatic anaemia after reversible causes and disease treatment are addressed | Balance transfusion avoidance against thrombotic risk; not an automatic Hb/EPO-threshold decision |
| Immunoglobulin replacement | Selected patients with significant hypogammaglobulinaemia and recurrent/severe infection | Not routine for an isolated low immunoglobulin level |
| Vaccination | Pneumococcal, influenza, COVID | Immunocompromised → impaired vaccine responses |
Integration with Related GC Lectures
Hypercalcaemia is a common emergency in myeloma. Management principles [3]:
- Isotonic IV saline when volume depleted, with rate and reassessment tailored to age, cardiac status, urine output, and renal failure—avoid reflex “aggressive” loading.
- Prompt anti-resorptive therapy selected and dosed for renal function; do not copy a fixed zoledronic-acid dose into severe AKI.
- Calcitonin (rapid but transient effect via tachyphylaxis)
- Urgent clone-directed treatment, often incorporating dexamethasone and a renal-compatible regimen, because rapid FLC reduction is central in myeloma renal impairment. [16]
- Dialysis when otherwise clinically indicated, including life-threatening/refractory hypercalcaemia or AKI when fluids/medical therapy are limited; it is not merely a chronological “last resort.”
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
- Useful clue, not a rule: ALP is often normal in active lytic myeloma and may rise during fracture healing or from another hepatic/bone source.
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 | Ionised or albumin-adjusted calcium; ECG/volume/renal assessment | Careful isotonic saline, renal-appropriate anti-resorptive, urgent anti-myeloma therapy |
| Renal impairment | Cast nephropathy (FLC + uromodulin), hypercalcaemia, dehydration | RFT, serum FLC, 24-h urine protein/electrophoresis/immunofixation, ± renal biopsy | Stop nephrotoxins, correct volume/Ca, urgent clone-directed therapy, dialysis when indicated |
| Anaemia | Marrow infiltration/inflammation, ↓EPO, haemodilution; treatment and other deficiencies may contribute | CBC, reticulocyte count, film, haematinics/haemolysis tests as indicated | Treat myeloma and reversible causes; transfusion/ESA selectively |
| Bone lesions | Osteoclast activation + osteoblast suppression | Low-dose whole-body CT, PET-CT, MRI | Bisphosphonates/denosumab, radiotherapy, orthopaedic input for fractures |
High Yield Summary
- Recognise the pattern: older patient + persistent bone pain + normocytic anaemia + AKI + hypercalcaemia + protein gap/immunoparesis.
- Read the images: punched-out skull lucencies, vertebral compression/possible canal compromise, pleomorphic marrow plasma cells replacing haematopoiesis, and fractured angular tubular casts with an inflammatory reaction.
- Diagnose with SLiM-CRAB: clonal marrow plasma cells ≥10% or plasmacytoma plus attributable CRAB damage or a biomarker (marrow plasma cells ≥60%; involved:uninvolved FLC ratio ≥100 with involved FLC ≥100 mg/L; more than one MRI focal lesion ≥5 mm). [13]
- Do not screen with SPEP alone: combine SPEP, serum immunofixation, and serum FLC; add urine studies, marrow/FISH, and modern whole-body imaging.
- Link mechanism to complication: osteoclast activation + osteoblast suppression → lytic lesions/hypercalcaemia; FLC–uromodulin casts → tubulointerstitial AKI; marrow replacement/renal disease/inflammation → anaemia; immunoparesis → infection.
- Interpret “classic” rules cautiously: ALP is often normal, not guaranteed; technetium bone scans have low sensitivity, not universal zero uptake; compression fracture without a lytic lesion is not itself a myeloma-defining event.
- Stage in context: the slides teach Durie-Salmon, R-ISS, and a 2013 mSMART table. Current guidance incorporates R2-ISS and avoids applying old fixed survival figures to an individual. [14][15]
- Treat through a specialist pathway: induction (often an anti-CD38 triplet/quadruplet) → ASCT if fit/appropriate → risk-adapted maintenance, or frailty-adapted non-transplant therapy, plus urgent management of renal, calcium, bone, infectious, and neurological complications. [14][17][18]
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) [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) [13] International Myeloma Foundation / IMWG. IMWG Criteria for the Diagnosis of Multiple Myeloma [14] European Hematology Association–European Myeloma Network. Evidence-Based Guidelines for Diagnosis, Treatment and Follow-up of Patients with Multiple Myeloma (2025) [15] European Myeloma Network. Second Revision of the International Staging System (R2-ISS) for Overall Survival in Multiple Myeloma (2022) [16] International Myeloma Working Group. Management of Multiple Myeloma-Related Renal Impairment (2023) [17] US Food and Drug Administration. Daratumumab with VRd for Newly Diagnosed, Transplant-Eligible Multiple Myeloma (2024) [18] National Cancer Institute. Plasma Cell Neoplasms Treatment (PDQ), Health Professional Version (updated 2025)
GC029 Am I Prescribing The Right Drug
A clinical decision-making framework that guides physicians in evaluating whether a selected medication is the most appropriate choice for a patient based on indication, efficacy, safety profile, patient-specific factors, and evidence-based guidelines.
GC031 Back Pain In An Elderly Woman: Osteoporosis And Related Fractures
Osteoporosis is a systemic skeletal disorder characterized by low bone mineral density and microarchitectural deterioration, predisposing elderly women to fragility fractures, commonly vertebral compression fractures presenting as acute or chronic back pain.