Multiple myeloma is a malignant plasma cell neoplasm arising in the bone marrow, characterized by monoclonal immunoglobulin production, lytic bone lesions, anaemia, hypercalcaemia, and renal impairment (CRAB).

Exam domain	One-glance essentials
Definition / diagnosis	*Multifocal bone-marrow neoplasm of clonal plasma cells producing monoclonal immunoglobulin/light chain* ^[1] Active MM requires ≥10% clonal marrow plasma cells or plasmacytoma plus ≥1 SLiM-CRAB myeloma-defining event ^[2]
Epidemiology / risks	Predominantly older adults; median age about 70 ^[1] All cases evolve through MGUS/SMM biology; MGUS progresses ~1%/year and SMM ~10%/year initially ^[1]
Core mechanism	RANKL↑/OPG↓ + DKK1↑ → osteoclast activation + osteoblast suppression → purely lytic bone disease ^[1] Free light chains + Tamm-Horsfall protein → obstructing casts → cast nephropathy ^[1] Marrow replacement and immunoparesis → anaemia and infection ^[1]
Clinical picture	*Older patient with persistent axial bone pain, anaemia and raised ESR/globulin* ^[1] CRAB: hypercalcaemic confusion/constipation/polyuria, renal impairment, fatigue/pallor and lytic lesions/fractures ^[1] Recurrent infection; cord compression presents with back pain, weakness and sphincter dysfunction ^[1]
Investigations	SPE/IFE + serum FLC + UPE/urine IFE; light-chain disease may lack a serum M-spike ^[2] BM aspirate/trephine: clonal CD138+ plasma cells with κ/λ restriction; FISH for risk ^[2] Use WBLDCT, MRI or PET-CT; *never rely on radionuclide bone scan* because osteoblasts are suppressed ^[2]
Management	Treat active MM only; first determine transplant fitness ^[3] Induction backbone: proteasome inhibitor + IMiD + dexamethasone, often with daratumumab ^[3] Eligible patients: induction → high-dose melphalan + autologous HSCT → maintenance; provide concurrent renal, bone and infection support ^[3]
Complications	Cast nephropathy is a renal emergency; hydrate, stop nephrotoxins and start rapid clone-directed therapy ^[3] Pathological fracture/cord compression, hypercalcaemia, infection, marrow failure, AL amyloidosis and rare hyperviscosity ^[1] Treatment: neuropathy/VZV with bortezomib, VTE with IMiDs, ONJ with bisphosphonates ^[3]
Prevention / follow-up	Hydrate; avoid NSAIDs/contrast nephrotoxicity; give antiviral prophylaxis with bortezomib and thromboprophylaxis with IMiDs ^[3] Dental review before bisphosphonate; use denosumab when severe renal impairment precludes IV bisphosphonate ^[3] Vaccinate against influenza and pneumococcus ^[3]
Exam traps	SLiM: BM plasma cells ≥60%, involved/uninvolved FLC ratio ≥100, or > 1 MRI focal lesion ≥5 mm → active MM even without CRAB ^[2] *ALP and bone scan may be normal despite extensive lytic disease* ^[2] Urine dipstick detects albumin poorly, not light chains—request formal electrophoresis/FLC testing ^[2]

References

^[1] Lecture slides: GC 030. An old man with bone pain and anaemia.pdf ^[2] Senior notes: Ryan Ho Haemtology.pdf (Multiple Myeloma diagnosis, imaging and complications, p.104–107) ^[3] Senior notes: Block A - An old man with bone pain and anaemia: multiple myeloma; monoclonal gammopathy.pdf (management and renal emergency)

Multiple Myeloma

Multiple myeloma (MM) — "multiple" refers to the multifocal nature of disease (multiple bone marrow sites involved), "myeloma" from Greek myelos (marrow) + -oma (tumour) — is a bone marrow–based, multifocal neoplasm of terminally differentiated plasma cells (the antibody-secreting cells of the immune system). It is characterised by two hallmark features ^[1]^[2]:

Abnormal clonal proliferation of plasma cells in the bone marrow (defined as ≥10% of bone marrow cellularity)
Production of a monoclonal immunoglobulin (paraprotein / M-protein) — a single species of antibody (or its fragment) secreted by the malignant clone

The clinical consequence is end-organ damage, classically captured by the mnemonic CRAB ^[1]^[2]^[3]:

Calcium elevation (hypercalcaemia)
Renal insufficiency
Anaemia
Bone lytic lesions

"Basically myeloma is a spectrum/timeline, and multiple myeloma is considered to be the 'end-of-the-spectrum' manifestation of plasma cell dyscrasia." ^[1]

Key Concept — Myeloma as a Spectrum

Multiple myeloma does not arise de novo. It always evolves through a pre-malignant phase (MGUS → Smouldering Myeloma → Active Myeloma). The critical distinction is that only active myeloma (with end-organ damage or myeloma-defining events) requires treatment; MGUS and smouldering myeloma require monitoring only. ^[1]

Epidemiology

1–2% of all cancers, ~17% of all haematological malignancies ^[2]
Incidence: 4–5 per 100,000 per year in Western populations; may be lower in Asian populations ^[2]
Incidence is rising modestly due to ageing populations and improved diagnostics
Accounts for ~10% of haematological malignancy deaths

Median age at diagnosis: 66–70 years ^[1]^[2]
Only ~10% of patients are < 50 years old ^[2] — myeloma is predominantly a disease of the elderly
Males > Females (ratio ~1.4:1) ^[2]
3.7× increased risk in first-degree relatives of myeloma patients ^[2]
Higher incidence in African Americans (~2–3× compared to Caucasians); lowest in Asian populations

90% of cases are > 50 years old; median age ~70 years old ^[4]
Among haematological malignancies managed at QMH/HKWC, myeloma is a significant proportion
Hong Kong Cancer Registry data show a gradually increasing incidence, tracking with ageing demographics
Less common than lymphoma and leukaemia overall, but remains an important cause of pathological fractures and AKI in elderly Hong Kong patients

Risk Factor	Mechanism / Explanation
Age > 60 years	Accumulated somatic mutations and progressive immune senescence; MGUS prevalence rises with age
Male sex	Unclear mechanism; possibly hormonal or occupational exposure-related
African descent	Genetic susceptibility; 2–3× higher MGUS prevalence
Family history (first-degree relative)	3.7× increased risk — shared genetic predisposition ^[2]
Pre-existing MGUS	1% per year risk of progression to myeloma ^[1]
Pre-existing smouldering myeloma	10% per year progression in the first 5 years, lower beyond 5 years ^[1]
Radiation exposure	Increased risk in atomic bomb survivors, nuclear workers
Chronic immune stimulation	Chronic infections, autoimmune diseases — sustained antigenic stimulation of plasma cells
Obesity	Chronic inflammatory state; elevated IL-6 (a key myeloma growth factor)
Occupational exposures	Pesticides, herbicides, petroleum products — epidemiological association

Risk Factors for MGUS → MM Progression

Risk factors increasing a patient's risk of progression from MGUS to myeloma ^[1]:

Size of paraprotein — larger amounts = higher risk
Type of paraprotein — non-IgG MGUS (especially IgA or IgM) carries higher risk
Abnormal serum free light chain ratio
Bone marrow plasma cell percentage approaching 10%
Immunoparesis (suppression of uninvolved immunoglobulins)

Anatomy and Function — Normal Plasma Cell Biology

To understand myeloma, you must understand what plasma cells do normally:

Origin: B-lymphocytes → after antigen stimulation in germinal centres of lymph nodes → class-switch recombination and somatic hypermutation → differentiation into plasma cells (the "antibody factories")
Location: Predominantly reside in the bone marrow (also spleen, lymph nodes, mucosal tissues)
Function: Secrete large quantities of immunoglobulin (antibody) — each plasma cell secretes only ONE type of antibody (i.e., it is naturally "monoclonal" at the single-cell level)
Immunoglobulin structure: Each antibody consists of:
- 2 heavy chains (IgG, IgA, IgM, IgD, or IgE class)
- 2 light chains (either κ (kappa) or λ (lambda) — never both)
- The ratio of κ:λ in normal serum is approximately 2:1

Normal bone marrow contains < 5% plasma cells
The marrow stroma provides a supportive microenvironment with:
- Stromal cells, extracellular matrix, cytokines (IL-6, VEGF, RANKL)
- A tightly regulated balance between osteoblasts (bone formation) and osteoclasts (bone resorption)
- This balance is maintained by the RANK/RANKL/OPG axis:
  - RANKL (on stromal cells/osteoblasts) binds RANK (on osteoclast precursors) → osteoclast activation → bone resorption
  - OPG (osteoprotegerin) is a "decoy receptor" that binds RANKL and blocks osteoclast activation
  - Normally, OPG and RANKL are in balance → net bone homeostasis

Aetiology and Pathophysiology

The precise cause of myeloma is unknown, but it arises from the malignant transformation of post-germinal-centre plasma cells ^[2]. The key aetiological model is:

"Aberrant response to antigenic stimulation → abnormal, sustained proliferative signal for plasma cells → increased proliferative rate → increased risk of mutation → cytogenetic abnormalities → clonal evolution" ^[2]

Pathogenesis — The Multi-Hit Model

Myeloma develops through a step-wise accumulation of genetic hits, progressing through defined pre-malignant stages:

Aberrant response to antigen stimulation: an unknown antigenic stimulus produces an abnormal, sustained proliferative signal
Primary cytogenetic changes arise:
- IgH translocations — the immunoglobulin heavy chain locus (14q32) is a "hot spot" because it is actively rearranging during class-switch recombination → translocations place oncogenes under the control of the strong IgH enhancer
  - Common partners: t(4;14) — FGFR3/MMSET, t(11;14) — Cyclin D1, t(14;16) — MAF
- Hyperdiploidy (trisomies) — gains of odd-numbered chromosomes (3, 5, 7, 9, 11, 15, 19, 21) → alternative pathway to MGUS
These are considered mutually exclusive primary events (IgH translocations vs hyperdiploidy)

Secondary cytogenetic changes accumulate:
- IgH translocation (additional)
- Deletion 17p13 (TP53) — loss of tumour suppressor → resistance to apoptosis (high-risk feature)
- RAS mutations (KRAS, NRAS) — constitutive activation of proliferative signalling
- NFκB-activating mutations — pro-survival signalling
Cell cycle dysregulation: overactive Cyclin D → uncontrolled G1/S progression
Apoptosis dysregulation → immortalisation of the plasma cell clone

BM microenvironment changes favour myeloma cell growth with homing (migration to BM)
Increased induction of angiogenesis → increased nutrient supply for tumour
Paracrine/cytokine loop: MM cells bind to BM stromal cells → interaction and activation of signal transduction pathways → stimulate proliferation and develop malignant features, e.g., chemoresistance
- Key cytokines: IL-6 (major myeloma growth factor, produced by stromal cells), VEGF, TNF-α, IGF-1
- MM cells also produce DKK1 (Dickkopf-1) — an inhibitor of the Wnt signalling pathway → suppresses osteoblast differentiation → contributes to the purely lytic nature of myeloma bone disease

Pathophysiology of End-Organ Damage

This is the crux of understanding myeloma's clinical features. Every symptom and sign can be traced back to one of these mechanisms:

Osteoblast suppression + osteoclast activation (↑ RANKL:OPG ratio) ^[2]
Myeloma cells secrete factors that:
- Increase RANKL expression on stromal cells → more osteoclast activation
- Decrease OPG (the decoy receptor) → less osteoclast inhibition
- Increase DKK1 → blocks Wnt pathway → suppresses osteoblast activity
- Secrete MIP-1α (macrophage inflammatory protein) → direct osteoclast activation
Net effect: uncoupled bone remodelling with excessive resorption and no compensatory formation
This is why myeloma produces purely lytic lesions (not blastic) — osteoblasts are suppressed, so there is no new bone formation
This is also why bone scans (technetium-99m) are often NEGATIVE in myeloma — bone scans detect osteoblastic activity, which is absent in myeloma

Why are bone scans negative in myeloma?

A common exam pitfall. Technetium-99m bone scans detect areas of increased osteoblastic activity (new bone formation). Myeloma suppresses osteoblasts while activating osteoclasts, producing purely lytic lesions. Therefore, bone scans will underestimate the extent of disease. Use skeletal survey (plain X-rays), low-dose whole-body CT, or PET-CT instead.

Due to osteoclast activation → increased bone resorption → increased calcium release into blood ^[2]
Mechanisms:
- Local osteolysis due to local active factors — IL-6, TNF-β ^[5]
- Impaired renal calcium excretion (due to concurrent renal impairment)
- Volume depletion (from polyuria due to hypercalcaemia → nephrogenic DI) worsens the hypercalcaemia
Occurs in ~30% of patients at diagnosis

"The most common cause of kidney failure in multiple myeloma is due to proteins secreted by the malignant cells" ^[6]

Cast nephropathy (most common mechanism) ^[2]^[6]:
- Precipitation of light chains in renal tubules → formation of obstructing casts → induce giant cell reaction → interstitial nephritis and fibrosis ^[2]
- The casts are intensely eosinophilic and appear "brittle" because they are lamellated and fractured frequently ^[6]
- The casts are often surrounded by macrophages and giant cells ^[6]
- This is a medical emergency — does NOT necessarily produce heavy chain proteinuria ^[6]
- Can result in acute kidney failure (intrarenal tubular obstruction) ^[6]
- Light chain cast nephropathy occurs in 30–50% of patients with multiple myeloma ^[4]
- Light chains (particularly λ) are small enough to be filtered by the glomerulus → overwhelm tubular reabsorptive capacity → precipitate with Tamm-Horsfall protein in distal tubules → obstruction
Hypercalcaemia leading to nephrogenic DI and thus dehydration → pre-renal AKI component and nephrocalcinosis ^[2]
AL Amyloidosis — a distant third in the causation ^[6]:
- Misfolded light chains deposit as amyloid fibrils in glomeruli and vessels
- Other renal diseases associated with monoclonal light chains ^[4]:
  - Amyloidosis (AL type)
  - Light chain deposition disease
  - Light chain proximal tubulopathy
  - Type I cryoglobulinaemic glomerulonephritis
Hyperuricaemia (from high cell turnover) → urate nephropathy
NSAID use for bone pain → further nephrotoxicity
Dehydration from reduced oral intake (nausea, confusion)

Bone marrow infiltration by malignant plasma cells → "crowding out" of normal haematopoietic precursors (erythroid, myeloid, megakaryocytic)
Cytokine-mediated suppression of erythropoiesis (IL-6, TNF-α suppress EPO production and erythroid progenitors)
Renal impairment → reduced EPO production
Dilutional component if hyperviscosity is present
Anaemia is present in ~70% at diagnosis; typically normocytic normochromic (anaemia of chronic disease / marrow infiltration pattern)

The malignant clone produces one type of (non-functional) immunoglobulin in excess, while suppressing normal polyclonal immunoglobulin production → immunoparesis ^[1]^[7]
- This manifests as reduced levels of uninvolved immunoglobulins (e.g., a patient with IgG myeloma will have suppressed IgA and IgM)
Additional factors: neutropenia from marrow infiltration, therapy-related immunosuppression
Net effect: increased susceptibility to infections — the leading cause of death in myeloma
- Particularly: encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae) in early disease; gram-negative organisms and fungi in later/treated disease

Large quantities of circulating M-protein (especially IgA which tends to polymerise, or very high levels of any class) increase serum viscosity
More common in Waldenström macroglobulinaemia (IgM) but can occur in IgA myeloma
Leads to sludging of blood in microvasculature → visual disturbance, headache, confusion, bleeding

Classification

Type	Frequency	Clinical Notes
IgG myeloma	~50–55%	Most common; classic presentation
IgA myeloma	~20–25%	Higher risk of hyperviscosity (IgA polymerises); may present with more aggressive disease
Light chain only (Bence Jones myeloma)	~15–20%	Secrete free light chains only (no intact immunoglobulin); higher risk of renal damage (cast nephropathy, AL amyloidosis)
IgD myeloma	~1–2%	Rare; often presents with renal failure, extramedullary disease
IgM myeloma	< 1%	Very rare (IgM-producing neoplasms are usually Waldenström macroglobulinaemia, not myeloma)
IgE myeloma	Extremely rare	Case reports only
Non-secretory myeloma	~2–3%	No detectable M-protein in serum or urine; diagnosis by BM biopsy

κ (kappa): ~60–65%
λ (lambda): ~35–40%
An abnormal free light chain ratio (κ:λ outside 0.26–1.65) is a sensitive marker of clonal plasma cell disease

The R-ISS incorporates serum β2-microglobulin, serum albumin, LDH, and high-risk cytogenetics to stratify prognosis:

Stage	Criteria	Median OS
R-ISS I	β2-microglobulin < 3.5 mg/L AND albumin ≥ 35 g/L AND standard-risk cytogenetics AND normal LDH	~82 months
R-ISS II	Neither I nor III	~62 months
R-ISS III	β2-microglobulin ≥ 5.5 mg/L AND (high-risk cytogenetics [del(17p), t(4;14), t(14;16)] OR elevated LDH)	~40 months

Why β2-microglobulin?

β2-microglobulin is a component of MHC class I molecules, present on all nucleated cells. In myeloma, it is elevated because:

It is shed from the surface of proliferating myeloma cells (tumour burden marker)
It is renally cleared — so it also reflects renal function

Therefore, an elevated β2-microglobulin reflects BOTH high tumour burden AND renal impairment — two key prognostic factors.

Stages in the development of myeloma ^[1]:

Entity	BM Plasma Cells	M-protein	End-Organ Damage (CRAB)	Risk of Progression	Treatment
MGUS	< 10%	< 30 g/L	Absent	1% per year	Monitoring only
Smouldering Myeloma (SMM)	≥ 10% (or M-protein ≥ 30 g/L)	≥ 30 g/L (or BM ≥10%)	Absent	10% per year (first 5 years)	Monitoring (± clinical trial)
Active Multiple Myeloma	≥ 10%	Usually present (any level)	Present (CRAB or MDE)	—	Requires treatment

"Only multiple myeloma patients will be symptomatic with organ involvement → requires treatment. Other forms do not require treatment → require monitoring." ^[1]

Cytogenetic Abnormality	Significance
del(17p) / TP53 deletion	High risk — loss of major tumour suppressor
t(4;14)	High risk — FGFR3/MMSET overexpression
t(14;16)	High risk — MAF overexpression
t(14;20)	High risk
Gain(1q21)	Adverse prognosis
t(11;14)	Standard risk (may respond to venetoclax)
Hyperdiploidy	Standard risk (generally better prognosis)

Clinical Features

Myeloma is a disease of the elderly presenting with a constellation of symptoms and signs that all trace back to four core pathophysiological mechanisms: (1) bone destruction, (2) bone marrow failure, (3) paraprotein-related damage, and (4) immune dysfunction.

"An old man with bone pain and anaemia" — the classic GC lecture title and the quintessential presentation ^[3]

Symptoms

Pathophysiology: Osteoclast activation with osteoblast suppression → purely lytic bone lesions → structural weakening → pain
Character: Persistent, dull, aching pain; worse with movement/weight-bearing; may be sudden onset if pathological fracture
Location: Most common in the axial skeleton — lower back (most common), ribs, pelvis, skull — reflecting the distribution of red (haematopoietic) marrow in adults
Pathological fractures:
- Vertebral compression fractures → back pain, loss of height, kyphosis
- Long bone fractures from trivial trauma
Spinal cord compression: A medical emergency — posterior extension of vertebral body lesion or pathological fracture → epidural compression → paraplegia, sensory level, sphincter dysfunction

High Yield — Back Pain in the Elderly

When an elderly patient presents with new-onset back pain, especially with associated anaemia and raised ESR/globulin, always consider myeloma. This is a classic exam question setup from "GC 031 — Back pain in an elderly woman: osteoporosis and related fractures" ^[8] and "GC 030 — An old man with bone pain and anaemia" ^[3].

Pathophysiology: Marrow infiltration → reduced erythropoiesis → normocytic normochromic anaemia → reduced oxygen-carrying capacity → fatigue, decreased exercise tolerance, dyspnoea on exertion
Often the first symptom noticed, but frequently attributed to "ageing"

Pathophysiology: Osteoclast activation → excessive calcium release → hypercalcaemia
Bones: bone pain, fractures
Stones: renal calculi, nephrocalcinosis, polyuria (hypercalcaemia impairs renal concentrating ability → nephrogenic DI → polyuria → dehydration → worsens hypercalcaemia — a vicious cycle)
Abdominal groans: nausea, vomiting, constipation, anorexia, abdominal pain
Psychiatric overtones: confusion, drowsiness, lethargy, psychosis — calcium is a key second messenger in neurons; excess disrupts neuronal function

"Confused and dehydrated — hypercalcaemia" — a classic GC scenario where myeloma is in the differential ^[9]

Pathophysiology: Immunoparesis (suppression of normal immunoglobulins by the malignant clone) + neutropenia (marrow infiltration) → impaired humoral immunity
Pneumonia, UTI, skin infections — especially with encapsulated organisms (S. pneumoniae, H. influenzae)
Infections are the leading cause of morbidity and mortality in myeloma

Pathophysiology: Cast nephropathy (light chain precipitation), hypercalcaemia, dehydration, hyperuricaemia, amyloidosis
May present with oliguria, peripheral oedema, nausea, pruritus
Some patients present with acute kidney injury as the first manifestation — especially light chain myeloma
"Presentations: acute renal failure and proteinuria" ^[4]

Pathophysiology:
- Thrombocytopenia from marrow infiltration
- Paraprotein coating platelets → impaired platelet function
- Paraprotein interfering with clotting factors
- Hyperviscosity → endothelial damage
Epistaxis, gum bleeding, easy bruising, purpura

Pathophysiology: High concentration of M-protein → increased serum viscosity → sludging in microvasculature
Visual disturbance (blurred vision, diplopia) — retinal vein engorgement
Headache, confusion, somnolence
Bleeding (mucosal)
Raynaud phenomenon

Pathophysiology:
- Direct nerve compression by plasmacytomas
- Amyloid deposition in peripheral nerves (AL amyloidosis complicating myeloma)
- Paraprotein-related demyelination (anti-MAG antibodies, more common in IgM MGUS/WM)
Peripheral neuropathy: numbness, tingling, weakness in a stocking-glove distribution
Autonomic neuropathy with postural hypotension — especially if AL amyloidosis is present ^[7]

Weight loss, anorexia, night sweats, fever — reflecting high tumour burden and cytokine release (IL-6)

Signs

Pallor — anaemia (marrow infiltration, EPO deficiency)
Dehydration — hypercalcaemia-induced polyuria, reduced oral intake
Cachexia — advanced disease

Localised bony tenderness — over affected bones (spine, ribs, pelvis, skull)
Kyphosis / loss of height — vertebral compression fractures
Pathological fractures — may see deformity of long bones
Skeletal deformities — in advanced disease ^[10]

Spinal cord compression signs: motor weakness (upper motor neuron pattern below the level), sensory level, urinary retention, decreased anal tone — a medical emergency
Peripheral neuropathy: stocking-glove sensory loss, reduced reflexes
Altered mental state — hypercalcaemia, uraemia, hyperviscosity

Hepatomegaly / splenomegaly — uncommon in myeloma (unlike lymphoma); when present, suggests extramedullary disease or amyloid infiltration
- Splenomegaly is rare because myeloma cells home to bone marrow, not spleen
Renal angle tenderness — if renal impairment/nephrocalcinosis

Rarely: cutaneous plasmacytomas (violaceous nodules)
Purpura / ecchymoses — bleeding tendency
Skin complexion changes — if AL amyloidosis (waxy, periorbital purpura → "raccoon eyes" from amyloid infiltration of blood vessel walls → fragile vessels)

Hyperviscosity signs: dilated, tortuous retinal veins ("sausage-link" appearance), retinal haemorrhages, papilloedema
Rare but characteristic

Macroglossia — if AL amyloidosis (amyloid deposited in tongue)
Dental examination for early osteoporosis signs ^[11]

Tachycardia, flow murmur — anaemia
Heart failure — if AL amyloid cardiomyopathy (restrictive pattern)
Postural hypotension — amyloid autonomic neuropathy

Clinical Feature	Pathophysiological Basis
Back pain, bone pain, pathological fractures	Osteolytic bone destruction (↑RANKL:OPG, ↑DKK1, ↓osteoblast)
Loss of height, kyphosis	Vertebral compression fractures
Spinal cord compression	Vertebral body collapse / epidural plasmacytoma
Fatigue, pallor, dyspnoea	Anaemia (marrow infiltration, ↓EPO, cytokine suppression)
Confusion, nausea, constipation, polyuria	Hypercalcaemia (osteoclast activation → Ca²⁺ release)
Oliguria, oedema, elevated creatinine	Renal failure (cast nephropathy, hypercalcaemia, dehydration)
Recurrent infections	Immunoparesis (↓normal Ig) + neutropenia
Bleeding, purpura	Thrombocytopenia + paraprotein interference with haemostasis
Visual disturbance, headache, confusion	Hyperviscosity (high M-protein concentration)
Peripheral neuropathy	Amyloid deposition, direct compression, paraprotein-related
Macroglossia, periorbital purpura, cardiomyopathy	AL amyloidosis complication (~10–15%)
Weight loss, night sweats	High tumour burden, IL-6 excess

Even before formal diagnostic workup, several routine lab findings should trigger consideration of myeloma:

Finding	Explanation
Raised ESR (often > 100 mm/hr)	Rouleaux formation due to high paraprotein → RBCs stack → sediment faster
Reversed A:G ratio with ↑ globulin	Monoclonal immunoglobulin raises the globulin fraction ^[12]
Normocytic normochromic anaemia	Marrow infiltration, cytokine suppression
Raised total protein with normal albumin	The "extra" protein is paraprotein (globulin) ^[5]
Raised calcium	Osteolytic bone resorption
Raised creatinine	Renal damage from light chains, hypercalcaemia
Rouleaux on blood film	Non-specific sign of ↑ protein; "indicates ↑ protein level, non-specific" ^[12]
Presence of paraprotein +/- immunoparesis → "Multiple myeloma"	As stated in the haematological investigations lecture ^[13]

High Yield GC Lecture Point — Serum Protein Electrophoresis

"Presence of paraprotein +/- immunoparesis. What does this indicate? → Multiple myeloma" ^[13]. This is a direct GC lecture slide teaching point. When you see a monoclonal band (M-spike) on serum protein electrophoresis with suppression of other immunoglobulin classes, the diagnosis of myeloma must be actively pursued.

Exam Pitfall — High Calcium with High Globulin

"Significantly ↑ total protein with normal albumin → ↑ globulin. Apparent high Ca → due to high globulin." ^[5] Remember that total calcium is partly protein-bound. In myeloma, very high globulin (paraprotein) can bind calcium, causing factitious hypercalcaemia on total calcium measurement. Always check ionised calcium to confirm true hypercalcaemia. Similarly, "Ig may precipitate with PO₄, interfering with measurement" — phosphate levels may be artefactually abnormal ^[5].

"Very common — 5% of the population above 50 years of age" ^[1]
Formal definition: paraprotein < 30 g/L, BM plasma cells < 10%, no B-cell lymphoproliferative disorder, absence of organ damage ^[1]
By definition asymptomatic ^[12]
"Most important differential diagnosis of MGUS? → AL amyloidosis — especially if the patient has suggestive symptoms" ^[1]
Progression rates: Non-IgM MGUS: 0.8%/year → MM, plasmacytoma, AL amyloidosis ^[12]
Laboratory features: Reversed A:G ratio, ↑ESR, ↑globulin, rouleaux formation on PBS ^[12]
"Some patients can convert from MGUS back to normal" ^[1]
Laboratory artifacts: "circulating M protein may interfere with other lab tests, e.g., spuriously low HDL-C, high bilirubin, altered inorganic phosphate" ^[12]

BM plasma cells ≥10% OR M-protein ≥30 g/L, BUT no CRAB/MDE
10% per year progression in first 5 years, lower beyond 5 years ^[1]
Monitoring with regular bloodwork and clinical assessment

"One of the plasma cell dyscrasias, distinct from myeloma — but also some relationship, with AL amyloidosis possibly arising as a complication of myeloma in 10% of cases" ^[7]
"Amyloidosis affects the whole body" — cardiac (restrictive cardiomyopathy), renal (nephrotic syndrome), neuropathy, hepatomegaly, macroglossia ^[7]
"Congo red stain, salmon pink colour → indicative of amyloid deposition; electron microscopy shows non-branching fibrils in the extracellular compartment" ^[7]
"AL vs AA vs β2-microglobulin vs transthyretin — AL most common" ^[7]

IgM-secreting lymphoplasmacytic lymphoma
Different entity from myeloma (bone marrow lymphoplasmacytic infiltrate, not plasma cell)
Higher risk of hyperviscosity (IgM is a pentamer → large molecule)

High Yield Summary

Multiple Myeloma — Key Points for Exams:

Definition: BM-based neoplasm of clonal plasma cells (≥10% BM) with monoclonal protein production and end-organ damage (CRAB)
Epidemiology: Median age ~70, M > F, rare < 50; ~17% of haematological malignancies
Spectrum: MGUS (1%/yr) → SMM (10%/yr first 5y) → Active MM — only active MM needs treatment
CRAB: Calcium ↑, Renal insufficiency, Anaemia, Bone lytic lesions
Pathophysiology of bone disease: ↑RANKL:OPG ratio + ↑DKK1 → osteoclast activation + osteoblast suppression → purely lytic lesions → bone scan negative (no osteoblastic activity)
Renal damage: Cast nephropathy (most common — light chain precipitation in tubules), hypercalcaemia, amyloidosis
Immunoparesis: Suppression of normal Ig → recurrent infections (leading cause of death)
Key lab clues: Raised ESR, reversed A:G ratio, normocytic anaemia, raised calcium, raised creatinine, M-spike on SPEP
Paraprotein + immunoparesis = think myeloma
High-risk cytogenetics: del(17p), t(4;14), t(14;16)
AL amyloidosis can complicate myeloma in ~10% of cases
Bone scans are NEGATIVE in myeloma — use skeletal survey/LDCT/PET-CT instead

Active Recall - Multiple Myeloma (Definition, Epidemiology, Pathophysiology, Clinical Features)

^[1] Senior notes: Block A - An old man with bone pain and anaemia: multiple myeloma; monoclonal gammopathy.pdf (Development of myeloma, MGUS sections) ^[2] Senior notes: Ryan Ho Haemtology.pdf (pp. 104–105, Multiple Myeloma and MGUS sections) ^[3] Lecture slides: GC 030. An old man with bone pain and anaemia.pdf ^[4] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf (Light Chain Cast Nephropathy section, p. 15) ^[5] Senior notes: Ryan Ho Chemical Path.pdf (p. 23, Malignancy-associated hypercalcaemia and paraproteinaemia) ^[6] Senior notes: Block A – Nephrology Data Interpretation.pdf (p. 5, Pathophysiology of Multiple Myeloma) ^[7] Senior notes: Block A - Hematology Data Interpretation.pdf (p. 1, Amyloidosis case) ^[8] Lecture slides: GC 031. Back pain in an elderly woman: osteoporosis and related fractures.pdf ^[9] Senior notes: Block A - Confused and dehydrated: hypercalcaemia; hypocalcaemia.pdf (p. 13) ^[10] Senior notes: Block A - Family history of anaemia: inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (p. 12) ^[11] Senior notes: Ryan Ho Endocrine.pdf (p. 49, Approach to Established Osteoporosis) ^[12] Senior notes: Ryan Ho Haemtology.pdf (p. 104, MGUS section) ^[13] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (p. 28)

Differential Diagnosis of Multiple Myeloma

The differential diagnosis of myeloma must be thought about from the presenting complaint, because myeloma is a great mimicker — it can present through any of its CRAB features or through incidental lab findings. A systematic approach considers differentials for each major clinical presentation.

The key question is: what is the patient's presenting problem? Myeloma can enter the differential through several "front doors":

Bone pain / pathological fracture in the elderly
Unexplained anaemia (normocytic normochromic)
Hypercalcaemia
Acute or chronic kidney injury
Raised ESR / raised globulin / paraprotein on electrophoresis
Recurrent infections / immunodeficiency

Each of these presentations has its own differential list, and myeloma sits within all of them. Below, we work through each systematically.

This is the classic "front door" presentation from GC 030: "An old man with bone pain and anaemia" ^[3] and GC 031: "Back pain in an elderly woman" ^[8].

"What are the differential diagnosis of bone pain? → Hyperparathyroidism, Osteoporosis, Bone metastasis (breast cancer, prostate cancer)" ^[14]

Differential	Key Distinguishing Features	Why it's different from myeloma
Multiple myeloma	Lytic lesions (axial skeleton), anaemia, raised globulin, paraprotein, hypercalcaemia, renal impairment	The index diagnosis — CRAB features
Bone metastases	History of known primary (lung, breast, prostate, kidney, thyroid); metastases can be lytic OR blastic; bone scan usually positive (blastic mets); PSA raised in prostate	Prostate and breast mets are often blastic (bone scan positive); myeloma is purely lytic (bone scan negative). Metastatic disease typically has an identifiable primary
Primary hyperparathyroidism	Isolated hypercalcaemia with inappropriately elevated or non-suppressed PTH; low phosphate; subperiosteal resorption on X-ray	PTH is high in 1° HPT but suppressed in myeloma (the hypercalcaemia is PTH-independent). Phosphate tends to be low in 1° HPT
Osteoporosis	Generalised reduced bone density, compression fractures; normal ALP, no paraprotein, no anaemia, no hypercalcaemia	"In osteoporosis, bone mass decreases, but the ratio of bone mineral to bone matrix is normal; ALP is normal" ^[15]. No lytic "punched-out" lesions. Normal blood counts and biochemistry
Osteomalacia	Bone pain, proximal myopathy, raised ALP, low calcium, low phosphate, low vitamin D	"In osteomalacia, the ratio of bone mineral to bone matrix is low — due to impaired mineralisation" ^[15]. ALP is elevated (unlike osteoporosis). Looser zones on X-ray
Paget's disease	Elderly, localised bone pain/deformity, markedly elevated ALP, mixed lytic/sclerotic on X-ray, skull thickening	ALP is very high. Radiologically: mixed lytic and sclerotic pattern, enlarged bones — very different from punched-out lytic lesions of myeloma
Infection (TB spine, osteomyelitis, epidural abscess)	Fever, localised pain, raised inflammatory markers (CRP, WCC), risk factors (immunosuppression, IVDU)	Infective markers raised; imaging shows disc involvement (discitis) which myeloma typically spares; no paraprotein
Primary bone tumours	Younger patients; osteosarcoma (metaphyseal, sunburst), Ewing sarcoma (diaphyseal, onion-skinning)	Age group is very different (children/young adults); characteristic radiological appearance

Exam Pitfall — Pepper-pot Skull vs Raindrop Skull

"Salt and pepper / pepper pot skull is a term often used synonymously (although inaccurately) with the raindrop skull appearance of multiple lytic lesions of multiple myeloma" ^[16]. The pepper-pot skull is classically seen in hyperparathyroidism (generalised osteopenia with small, diffuse lucencies from subperiosteal resorption), while the raindrop skull of myeloma has discrete, well-defined punched-out lytic lesions. Don't confuse these in exams.

Myeloma causes a normocytic normochromic (NcNc) anaemia from marrow infiltration, cytokine suppression, and renal impairment. The differential of NcNc anaemia is broad:

Category	Examples	How to distinguish from myeloma
Anaemia of chronic disease / inflammation	RA, SLE, chronic infections, malignancy	Low iron, low TIBC, raised ferritin; no paraprotein; underlying inflammatory condition identifiable
Chronic kidney disease	Any cause of CKD (DM, HTN, GN)	Reduced EPO; small kidneys on USS (unless myeloma or amyloid → normal/large kidneys); no paraprotein
Bone marrow infiltration	Metastatic cancer, myelofibrosis, leukaemia	Leukoerythroblastic film in myelofibrosis (tear-drop cells, nucleated RBCs); metastases have known primary; myeloma has rouleaux, not tear-drop cells
Aplastic anaemia	Pancytopenia, hypocellular marrow	"Aplastic anaemia → pancytopenia, no abnormal cells, just the absence of normal cells" ^[7]. Marrow is hypocellular (empty), not infiltrated
Myelodysplastic syndrome (MDS)	Elderly, macrocytosis common, dysplastic features on PBS, cytogenetic abnormalities	Dysplastic changes in ≥1 lineage; may have ring sideroblasts; no paraprotein
Haemolytic anaemia	Raised reticulocytes, raised LDH, raised unconjugated bilirubin, low haptoglobin	Active haemolysis markers present; no paraprotein

"Bone pain → indicates multiple myeloma" — when anaemia is found alongside bone pain, myeloma must be at the top of the list ^[17]

"Hypercalcemia, most common (90%) is malignancy + primary hyperparathyroidism" ^[18]

Cause	PTH	Key Features
Primary hyperparathyroidism	High or inappropriately normal	Most common cause overall; solitary adenoma 85%; low phosphate; raised ALP; check for MEN ^[16]
Malignancy (including myeloma)	Suppressed	"Usually noted with appropriately suppressed PTH level; should trigger workup for cancer" ^[5]. In myeloma: lytic lesions, raised globulin, paraprotein; in solid tumours: PTHrP may be elevated
Myeloma specifically	Suppressed	"Lymphokine production by haematological malignancies that activate osteoclasts (e.g. multiple myeloma)" ^[16]; mechanism is local osteolysis via IL-6, TNF-β, RANKL — NOT PTHrP
FHH	Normal to low	"Exclude FHH for hypercalcemia → not due to parathyroid, so don't unnecessarily refer these patients to surgery" ^[18]. Low urine calcium:creatinine clearance ratio (< 0.01). CaSR mutation
Granulomatous disease	Suppressed	Endogenous 1,25-dihydroxyvitamin D production by macrophages in granulomas
Vitamin D excess / Milk-alkali	Suppressed	Dietary / supplement history; raised 25-OH vitamin D

High Yield — How to Distinguish Myeloma from 1° HPT as Cause of Hypercalcaemia

The single most useful discriminator is PTH level. In myeloma, PTH is suppressed because the hypercalcaemia is driven by osteoclast-activating factors (not PTH). In primary hyperparathyroidism, PTH is elevated or inappropriately non-suppressed. Additionally, myeloma will have a paraprotein on SPEP, raised globulin, anaemia, and renal impairment — features absent in straightforward 1° HPT.

"Atypical back pain → consider (1) multiple myeloma and (2) bony metastasis of cancer" — in the context of CKD/AKI workup ^[19]

Myeloma is an important and commonly tested cause of renal impairment, especially when the presentation is atypical (e.g., AKI with disproportionate proteinuria in an elderly patient).

Cause of AKI/CKD	Distinguishing Features
Myeloma (cast nephropathy)	"Light chain cast nephropathy — occurs in 30–50% of patients with MM" ^[4]; AKI + proteinuria + anaemia + hypercalcaemia; normal-sized kidneys on USS; proteinuria may be predominantly light chains (not detected by standard dipstick)
Diabetic nephropathy	Long history of DM, other microvascular complications (retinopathy, neuropathy), gradual deterioration, nephrotic-range albuminuria
Drug-induced AKI (NSAIDs, herbal medicines)	Temporal relationship with drug exposure; the case of the 35-year-old woman with herbal medicine intake initially thought to be drug-induced TIN — but turned out to be light chain cast nephropathy ^[4]
AL amyloidosis	Nephrotic syndrome (heavy proteinuria + oedema + hypoalbuminaemia); Congo red stain positive; large kidneys on USS (amyloid infiltration → enlarged kidneys) ^[20]
Light chain deposition disease	Similar to amyloidosis but Congo red negative; nodular glomerulosclerosis on biopsy
Hypertensive nephrosclerosis	Long history of HTN, small kidneys, proteinuria usually modest
Obstructive uropathy	Hydronephrosis on USS; prostatic symptoms in males

The differential diagnosis at renal biopsy level includes ^[6]^[19]:

Light and heavy chain deposition disease — complication of monoclonal gammopathy
Amyloidosis
NSAID-induced AKI

High Yield — Normal-Sized Kidneys with High Creatinine

"Someone comes in with high creatinine with a normal sized kidney → Acute kidney injury → parenchymal, vascular kidney problems → will require a kidney biopsy" ^[20]. In myeloma, kidneys are typically normal-sized (or even slightly large from cast/amyloid deposition), which is a crucial clue that this is NOT just long-standing CKD with shrunken kidneys.

"Presence of paraprotein +/- immunoparesis → Multiple myeloma" ^[13]

When a monoclonal band (M-spike) is detected on serum protein electrophoresis, the differential diagnosis includes the entire spectrum of monoclonal gammopathies:

Condition	M-protein	BM Plasma Cells	End-Organ Damage	Key Features
MGUS	< 30 g/L	< 10%	Absent	"5% of the population above 50" ^[1]; most important DDx is AL amyloidosis ^[1]; monitoring only
Smouldering myeloma	≥ 30 g/L (or BM ≥ 10%)	≥ 10% but < 60%	Absent	Higher risk of progression (10%/yr first 5 years) ^[1]; monitoring ± clinical trial
Active multiple myeloma	Usually present	≥ 10%	Present (CRAB or MDE)	Requires treatment
Waldenström macroglobulinaemia (WM)	IgM	Lymphoplasmacytic infiltrate	Hyperviscosity more common	IgM-secreting; different cell type (lymphoplasmacytic, not pure plasma cell); hyperviscosity, cryoglobulinaemia
AL amyloidosis	Often low-level	Often < 10%	Organ damage from amyloid (heart, kidney, nerve, liver)	"One of the plasma cell dyscrasias, distinct from myeloma — but also some relationship, with AL amyloidosis possibly arising as a complication of myeloma in 10% of cases" ^[7]; Congo red positive
Solitary plasmacytoma	Usually absent or small	< 10%	Single bony or extramedullary mass	Single lesion; may progress to myeloma over years
Heavy chain disease	Heavy chain fragments only	Variable	Variable	Very rare; α, γ, or μ heavy chain disease
CLL / NHL / Lymphoma	May produce small M-protein	Lymphocytic infiltrate	Lymphadenopathy, splenomegaly	Different cell lineage; different morphology; different immunophenotype
Reactive plasmacytosis	Polyclonal ↑ Ig (no M-spike)	May have ↑ plasma cells but polyclonal	Depends on underlying cause	Causes: autoimmune disease, metastatic carcinoma, chronic liver disease, AIDS ^[14]; κ:λ ratio remains ~2:1 (normal)

"IgD very low level, lab doesn't care, unless you are talking about 5% of IgD myeloma → an important differential for panimmunoparesis pattern on SPE (the other two being light chain myeloma, and non-secretory myeloma)" ^[21]

Panimmunoparesis on SPE — Think of Three Diagnoses

When serum protein electrophoresis shows suppression of all immunoglobulin classes (panimmunoparesis) without a visible M-spike, consider three diagnoses ^[21]:

Light chain myeloma — secretes free light chains only (too small to form a visible M-spike on SPE; detected by serum free light chains and UPE)
Non-secretory myeloma — no detectable M-protein at all
IgD myeloma — very rare; IgD levels so low that routine quantification may miss it

Myeloma causes a secondary immunodeficiency through immunoparesis. The differential for recurrent infections in the elderly includes:

Cause	Mechanism	Distinguishing Features
Multiple myeloma	Immunoparesis (↓ normal Ig), neutropenia	Paraprotein, CRAB features
CLL	Hypogammaglobulinaemia, neutropenia	Lymphocytosis, smudge cells on PBS, mature lymphocytes
HIV/AIDS	CD4+ T cell depletion	Risk factors, HIV serology
Diabetes mellitus	Impaired neutrophil function, glycosuria	Hyperglycaemia, HbA1c
CVID	Low immunoglobulins (polyclonal)	Younger onset; no paraprotein; all Ig classes low
Drug-induced	Steroids, chemotherapy, immunosuppressants	Drug history

The classic exam stem from GC 030 ^[3] and past papers ^[14] presents a 71-year-old male with malaise, weight loss, bone pain, pancytopenia, raised creatinine, raised calcium, low albumin, and markedly raised globulin with rouleaux on PBS:

"Q: What is your preliminary diagnosis? → Multiple myeloma" ^[14]

"Hypercalcemia, bone pain, marrow failure as evidenced by fever and pancytopenia, high globulin level" ^[14]

The differentials to consider and exclude:

Presenting Feature	Main Differentials to Consider	Key Discriminating Investigation
Bone pain + lytic lesions	Bone metastases, 1° HPT, osteoporosis, Paget's, infection	SPEP/immunofixation, PTH, ALP, PSA, bone biopsy
NcNc anaemia	ACD, CKD, marrow infiltration (MF, metastases), MDS, aplastic	SPEP, serum free light chains, BM biopsy
Hypercalcaemia	1° HPT, other malignancy, granulomatous disease, FHH, vitamin D excess	PTH (suppressed in myeloma), SPEP, calcium:creatinine clearance ratio
AKI / proteinuria	Diabetic nephropathy, drug-induced, obstruction, GN, AL amyloidosis, LCDD	SPEP, serum free light chains, urine protein electrophoresis, renal biopsy
Raised globulin / paraprotein	MGUS, SMM, WM, AL amyloidosis, CLL, NHL, reactive	BM biopsy + immunophenotyping, CRAB assessment
Recurrent infections	CLL, HIV, CVID, DM, drug-induced immunosuppression	SPEP, Ig levels, HIV serology, lymphocyte subsets

High Yield Summary — Differential Diagnosis of Myeloma

Bone pain DDx: Bone metastases (blastic or lytic — check for known primary), 1° HPT, osteoporosis (normal ALP, no paraprotein), osteomalacia (raised ALP, low vit D), Paget's (very high ALP, mixed lytic/sclerotic)
Hypercalcaemia DDx: 90% is malignancy + 1° HPT → distinguish by PTH level (suppressed in myeloma, elevated in HPT)
AKI DDx: Cast nephropathy is a medical emergency; distinguish from diabetic nephropathy, drug-induced AKI, amyloidosis
Paraprotein DDx: MGUS vs SMM vs active MM — distinguish by BM plasma cell %, M-protein level, and presence of CRAB/MDE
Key discriminator: The triad of raised globulin (paraprotein) + lytic bone lesions + normocytic anaemia essentially clinches myeloma; no other condition reliably produces all three
Don't forget: Light chain myeloma, non-secretory myeloma, and IgD myeloma can present with panimmunoparesis without a visible M-spike on SPE — check serum free light chains and UPE
Pepper-pot skull (HPT) ≠ raindrop skull (myeloma) — common exam pitfall

Active Recall - Differential Diagnosis of Multiple Myeloma

References

^[1] Senior notes: Block A - An old man with bone pain and anaemia: multiple myeloma; monoclonal gammopathy.pdf (Development of myeloma, MGUS sections) ^[3] Lecture slides: GC 030. An old man with bone pain and anaemia.pdf ^[4] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf (Light Chain Cast Nephropathy section, p. 15) ^[5] Senior notes: Ryan Ho Chemical Path.pdf (p. 23, Malignancy-associated hypercalcaemia and paraproteinaemia) ^[6] Senior notes: Block A – Nephrology Data Interpretation.pdf (p. 5, Pathophysiology of Multiple Myeloma) ^[7] Senior notes: Block A - Hematology Data Interpretation.pdf (p. 1, Amyloidosis case) ^[8] Lecture slides: GC 031. Back pain in an elderly woman: osteoporosis and related fractures.pdf ^[13] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (p. 28) ^[14] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp. 1476, 1482) ^[15] Senior notes: Block A - Back pain in an elderly woman: osteoporosis and related fractures.pdf (p. 8, osteomalacia vs osteoporosis) ^[16] Senior notes: Block A - Confused and dehydrated: hypercalcaemia; hypocalcaemia.pdf (pp. 15, 24) ^[17] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p. 555) ^[18] Senior notes: Chemical Pathology Data interpretation.pdf (p. 3) ^[19] Senior notes: Block A – Nephrology Data Interpretation.pdf (pp. 2, 4) ^[20] Senior notes: Block A - Chronic Kidney Disease and its Complications.pdf (pp. 8, 13) ^[21] Senior notes: Block A - Pallor: diagnosis of anaemia; nutritional anaemia; anaemia of systemic diseases.pdf (p. 23)

Diagnostic Criteria, Algorithm and Investigations for Multiple Myeloma

Diagnostic Criteria — IMWG 2014 (Updated)

The gold-standard diagnostic criteria come from the International Myeloma Working Group (IMWG) 2014, which is the version taught on the GC 030 lecture slides ^[3] and in the senior notes ^[1]. Understanding the logic behind these criteria is critical.

High Yield GC Lecture Point — IMWG 2014 Diagnostic Criteria

"Diagnosis of multiple myeloma — International Myeloma Working Group (IMWG) 2014 diagnostic criteria" ^[3]:

Both of the following must be present:

A. Clonal bone marrow plasma cells ≥ 10% OR biopsy-proven bony or extramedullary plasmacytoma

B. One or more myeloma-defining events (MDE):

Either CRAB criteria (evidence of end-organ damage):

HyperCalcaemia: Serum calcium > 0.25 mmol/L above upper limit of normal OR > 2.75 mmol/L
Renal insufficiency: Creatinine > 177 μmol/L (> 2 mg/dL) OR creatinine clearance < 40 mL/min
Anaemia: Hb < 10 g/dL OR Hb > 2 g/dL below lower limit of normal
Bone lesions: ≥ 1 osteolytic lesion on skeletal radiography, CT, or FDG PET-CT

OR any ≥ 1 biomarker of malignancy (SLiM criteria):

Sixty: Clonal bone marrow plasma cells ≥ 60%
Light chain ratio: Involved:uninvolved serum free light chain ratio > 100 (with involved FLC > 100 mg/L)
MRI: ≥ 1 focal lesion (≥ 5 mm) on MRI

Before 2014, you needed CRAB symptoms to diagnose active myeloma. The problem was that some patients with very high tumour burden (e.g., 80% plasma cells in the marrow) had not yet developed overt organ damage — but were at > 80% risk of progression within 2 years. Waiting for CRAB to develop meant waiting for irreversible organ damage (kidney failure, fractures). The SLiM biomarkers identify patients with "ultra-high-risk smouldering myeloma" who are virtually certain to progress and should be treated immediately, even before CRAB develops ^[1]^[3].

"IF NO CRAB SYMPTOMS, must fulfil any one or more of the following biomarkers of malignancy" ^[1]

Feature	MGUS	Smouldering Myeloma	Active Multiple Myeloma
M-protein (SPE)	< 30 g/L	≥ 30 g/L (or BM ≥ 10%)	Usually present (any level)
BM plasma cells	< 10%	10–60%	≥ 10% (or ≥ 60% alone qualifies)
End-organ damage (CRAB)	Absent	Absent	Present
Biomarkers of malignancy (SLiM)	Absent	Absent	Present (if no CRAB)
Progression risk	1%/year	10%/year (first 5 years)	—
Treatment required?	No — monitor	No — monitor (± trial)	Yes

Source: ^[1]^[3]^[22]

SLiM-CRAB Mnemonic

SLiM CRAB ^[22] — the complete set of myeloma-defining events:

Sixty percent BM plasma cells
Light chain ratio > 100
MRI focal lesions ≥ 1
Calcium ↑
Renal insufficiency
Anaemia
Bone lytic lesions

This mnemonic covers both the biomarkers of malignancy (SLiM) and the traditional end-organ damage (CRAB).

The diagnostic workup proceeds in a logical sequence: suspect → screen → confirm → stage.

Investigation Modalities — Detailed Breakdown

Investigation	Key Findings in Myeloma	Pathophysiological Basis
CBC with differential	Normocytic normochromic anaemia (Hb often < 10); ± leukopenia (~20%), thrombocytopenia (~5%) ^[2]	Marrow infiltration by plasma cells → crowding out of normal haematopoiesis; cytokine suppression of erythropoiesis
Peripheral blood smear	Rouleaux formation (> 50%) ^[2]; rarely circulating plasma cells	Rouleaux = RBCs stacking like coins due to elevated serum proteins (paraprotein) reducing the zeta potential between RBCs → aggregation. "Circulating plasma cells > 2 × 10⁹/L or > 20% WCC → indicative of plasma cell leukaemia" ^[2]
RFT	Raised creatinine (> 177 μmol/L is CRAB criterion)	Cast nephropathy, hypercalcaemia, dehydration
Calcium, phosphate	Raised adjusted calcium (> 2.75 mmol/L is CRAB criterion)	Osteoclast activation → bone resorption → Ca²⁺ release
LFT / Total protein	Reversed A:G ratio: normal albumin but markedly raised globulin ^[2]^[5]	The "extra" globulin IS the paraprotein. Albumin may be low (negative acute phase reactant, renal loss, poor nutrition)
ALP	Usually normal ^[22]	Because osteoblasts are SUPPRESSED in myeloma → ALP (produced by osteoblasts) is not elevated. This distinguishes myeloma from bone metastases (where ALP is often elevated) and Paget's disease (markedly elevated ALP)
LDH	May be raised — prognostic marker (R-ISS Stage III if elevated)	Reflects tumour cell turnover
ESR	Markedly elevated (often > 100 mm/hr)	Rouleaux → faster sedimentation
Urate	Often elevated	High cell turnover
Glucose, HBsAg, anti-HBc, G6PD	Pre-treatment baseline ^[2]^[22]	HBV reactivation risk with immunosuppressive therapy; G6PD status needed before certain drugs

Why is ALP Normal in Myeloma?

This is a common exam question. ALP is produced by osteoblasts. In myeloma, osteoblasts are suppressed (by DKK1 and other factors), so despite massive bone destruction, ALP remains normal. In contrast:

Bone metastases (especially prostate, breast) → osteoblastic reaction → raised ALP
Paget's disease → intense osteoblastic activity → markedly raised ALP
Osteomalacia → impaired mineralisation with compensatory osteoblast activity → raised ALP

This is the cornerstone of diagnosis. The goal is to detect, quantify, and characterise the monoclonal protein.

"Screening of monoclonal gammopathy" ^[22]:

Investigation	What It Does	Key Findings	Clinical Significance
Serum protein electrophoresis (SPE)	Separates serum proteins by charge on a gel → produces a densitometry tracing	M-spike (monoclonal band) in the gamma or beta-gamma region	"SPE: quantification of M protein" ^[22]. Detects and quantifies the paraprotein. Normal = smooth, broad gamma peak (polyclonal). Myeloma = sharp, narrow spike (monoclonal)
Serum immunofixation	Identifies the heavy chain class (IgG, IgA, IgD, IgM) and light chain type (κ or λ) of the M-protein	e.g., IgG-κ (most common)	"Immunofixation: characterise type of M protein, e.g. IgGκ (most common)" ^[22]. More sensitive than SPE for detecting small M-proteins
Serum free light chains (sFLC)	Measures free κ and free λ light chains in serum; calculates κ:λ ratio	Abnormal ratio (normal 0.26–1.65): indicates monoclonal excess of one light chain type	"Serum FLC: more sensitive for monoclonal FLC; κ:λ ratio also suggests monoclonal origin" ^[22]. Critical for light chain myeloma where SPE may show no M-spike. 90% of myeloma patients have an abnormal FLC ratio ^[2]
Serum IgG, IgA, IgM levels (quantitative immunoglobulins)	Quantifies each immunoglobulin class	Elevation of involved Ig class; immunoparesis (suppression of uninvolved Ig classes)	"In MGUS, there should be no immunoparesis → only occurs in MM" ^[1]. Immunoparesis confirms significant clonal suppression of normal B cell function
Urine protein electrophoresis (UPE) + immunofixation	Detects monoclonal light chains (Bence Jones protein) in urine	Monoclonal light chain band	"Both SPE & UPE at diagnosis is mandatory: 50% LC MM is SPE -ve but UPE +ve" ^[22]. Essential — some light chain myelomas produce only free light chains that are too small to form a visible M-spike on serum electrophoresis but are detectable in urine
24-hour urine protein	Quantifies total urinary protein and Bence Jones protein excretion	Often elevated (light chains + albumin if nephrotic)	Assesses renal light chain burden

"All that Bence Jones Protein stuff, which is obsolete since you can just do urine protein electrophoresis now" ^[13] — the old heat precipitation test for Bence Jones protein has been superseded by UPE and serum FLC assays.

Four Patterns on Serum Protein Electrophoresis

Four patterns of serum protein electrophoresis ^[13]:

Normal Ig pattern, absence of paraprotein → Normal (but could also be non-secretory myeloma!)
Panimmunoparesis → Inherited/acquired immunodeficiencies, OR certain forms of myeloma (light chain myeloma, IgD myeloma, non-secretory myeloma) ^[13]
Raised immunoglobulin, absence of paraprotein → Polyclonal hypergammaglobulinaemia → reactive process (infection, cirrhosis, autoimmune disease) → NOT a plasma cell problem → DO NOT refer to haematology ^[13]
Presence of paraprotein ± immunoparesis → Multiple myeloma ^[13]

Exam Pitfall — Urine Dipstick is Negative in Myeloma

Standard urine dipstick primarily detects albumin and will often be negative in myeloma, even when there is massive light chain proteinuria. This is because the dipstick reagent (bromophenol blue) reacts with albumin but not immunoglobulin light chains. "Dipstick: -ve for protein usually (primarily detects albumin)" ^[2]. You must request urine protein electrophoresis or measure urine albumin:creatinine ratio (UACR) — "undetectable urine protein by dipstick but ↑↑UACR" ^[23] suggests light chain proteinuria. A sulfosalicylic acid test can detect all proteins including light chains.

"Bone marrow aspirate and trephine + FISH analysis" ^[1]

Component	What It Shows	Key Findings in Myeloma
BM aspirate (cytology)	Cell morphology, differential count	≥ 10% clonal plasma cells (diagnostic threshold). Myeloma cells: "round, eccentric 'clock-face' nucleus with marked perinuclear cytoplasmic clearing" ^[2]. May show atypical forms (pleomorphic, blastic, grape-like inclusions). May be falsely negative due to patchy involvement ^[2]
BM trephine biopsy (histology)	Marrow cellularity, architecture, pattern of infiltration, fibrosis	Confirms extent and pattern of plasma cell infiltration; more reliable than aspirate for patchy disease
Immunophenotyping	CD markers and light chain restriction	CD138+ (plasma cell marker), monoclonal κ or λ light chain expression ^[2]. Normal κ:λ ratio in BM = 2:1; ratio > 4:1 or < 1:2 indicates monoclonality ^[14]. Distinguishes clonal myeloma from reactive plasmacytosis
FISH cytogenetics	Detects specific chromosomal abnormalities	Standard risk: t(11;14), hyperdiploidy. High risk: del(17p), t(4;14), t(14;16), gain(1q21) ^[2]. Essential for R-ISS staging and treatment decisions

"Bone marrow biopsy to look for abnormal monoclonal plasma cells" ^[6]

Why FISH and Not Conventional Karyotyping?

Myeloma cells have a low proliferative rate (they are terminally differentiated plasma cells, not rapidly dividing). Conventional cytogenetics (G-banding) requires cells to be in metaphase (dividing), so it has low sensitivity (~30% abnormality detection rate) in myeloma. FISH (Fluorescence In Situ Hybridisation) can detect chromosomal abnormalities in non-dividing (interphase) cells, making it far more sensitive for myeloma cytogenetics.

The goal is to detect osteolytic bone lesions — one of the CRAB criteria.

"Skeletal survey, whole body PET-CT or whole body MRI or whole body low-dose CT" ^[1]

Modality	Description	Findings	Advantages / Limitations
Skeletal survey (conventional X-rays)	"Series of X-rays of all bones: PA chest, AP/lateral skull, AP pelvis, AP/lateral C/T/L-spine, AP/lateral femur and humerus" ^[14]	"Punched-out lytic lesions (60%), diffuse osteopenia, pathological fractures (20%)" ^[2]. Most frequent sites: vertebral bodies, skull, thoracic cage, pelvis, proximal humerus and femur ^[2] — sites of active haematopoiesis	Traditional first-line; low cost; widely available. Limitation: requires > 30% cortical bone loss before a lesion is visible → low sensitivity for early disease
Whole-body low-dose CT (WBLDCT)	CT scan of entire skeleton at low radiation dose	Same lytic lesions but detected earlier and with greater sensitivity than X-ray	Now preferred over skeletal survey due to higher sensitivity; fast scan time; detects lesions missed by plain X-ray
Whole-body MRI	Detects BM infiltration directly (diffuse or focal)	Focal or diffuse BM signal abnormality; soft tissue extension	Most sensitive for detecting BM disease; "≥ 1 focal lesion ≥ 5 mm on MRI = SLiM criterion" ^[3]. No radiation. Limited availability; long scan time
FDG PET-CT	Combines metabolic (FDG uptake) and anatomical (CT) information	Hypermetabolic lytic lesions; extramedullary disease; treatment response assessment	"FDG correlates with areas of active lytic bone disease" ^[14]. Excellent for detecting extramedullary disease and assessing treatment response. Often preferred at QMH ^[2]
Radionuclide bone scan (Tc-99m)	Detects osteoblastic activity	NEGATIVE in myeloma	"NEVER be done in multiple myeloma since there will be suppressed osteoblastic activity and no uptake of radionuclide" ^[14]. This is a classic exam pitfall

Exam Must-Know — Never Order a Bone Scan for Myeloma

This is asked repeatedly in MCQs and SAQs. "Radionuclide bone scan should NEVER be done in multiple myeloma since there will be suppressed osteoblastic activity and no uptake of radionuclide" ^[14]. Bone scans detect osteoBLASTIC activity. Myeloma suppresses osteoblasts → purely lytic lesions → no tracer uptake → false negative.

When renal impairment is present, further workup is needed to determine the mechanism:

Investigation	Purpose	Findings
Urinalysis (dipstick + microscopy)	Screen for proteinuria, haematuria	Dipstick often negative (doesn't detect light chains); "classically a bland urine sediment" ^[2] — no active sediment (unlike GN)
24-hour urine protein + UPE	Quantify and characterise proteinuria	Heavy proteinuria (often light chains); UPE identifies monoclonal light chains
Renal USS	Kidney size, obstruction	Normal-sized kidneys (distinguishes from chronic CKD with small kidneys) ^[4]
Renal biopsy	Histopathological diagnosis of renal lesion	Cast nephropathy: tubular casts rimmed by macrophages, lambda or kappa light chain restriction on immunohistochemistry ^[4]; or amyloidosis (Congo red positive), or LCDD

"Should do a renal biopsy — to know the cause of acute renal failure — histopathological diagnosis" ^[6]

Investigation	Purpose	Interpretation
Serum β2-microglobulin	Tumour burden + renal function	Must check before induction therapy ^[22]. < 3.5 mg/L = good; ≥ 5.5 mg/L = poor
Serum albumin	Nutritional status, liver function, inverse acute phase reactant	≥ 35 g/L = good; < 35 g/L = adverse
LDH	Cell turnover	Elevated = adverse (R-ISS III if combined with other criteria)
FISH cytogenetics	Risk stratification	High risk: del(17p), t(4;14), t(14;16) ^[2]

R-ISS Stage	Criteria	Median OS
Stage I	β2M < 3.5 AND albumin ≥ 35 AND standard-risk cytogenetics AND normal LDH	~82 months
Stage II	Not Stage I or III	~62 months
Stage III	β2M ≥ 5.5 AND (high-risk cytogenetics OR elevated LDH)	~40 months

"Original ISS: albumin, β2-microglobulin. Revised ISS: above + LDH + FISH cytogenetics" ^[22]

Investigation	Indication
Serum viscosity	"If M protein > 5 g/dL or S/S of hyperviscosity" ^[2] — measure to confirm hyperviscosity syndrome
Congo red stain (tissue biopsy)	If AL amyloidosis suspected — "salmon pink colour → indicative of amyloid deposition" ^[7]
Echocardiography	If cardiac amyloidosis suspected (restrictive cardiomyopathy, diastolic dysfunction)
Nerve conduction studies	If peripheral neuropathy present — distinguish amyloid neuropathy from drug-related
Fat pad / rectal biopsy	Less invasive screening for amyloid if systemic AL amyloidosis suspected

"Name all the investigations that could be ordered in the work-up for a patient with paraprotein" ^[1]:

Category	Specific Investigations
History and Physical Examination	Directed at CRAB symptoms, infections, neuropathy
Basic bloods	CBC, RFT, calcium, albumin, ALP, LDH ^[1]
Paraprotein detection	SPE + immunofixation, UPE + immunofixation, serum free light chains, quantitative Ig levels (IgG/A/M) ^[1]
Bone marrow	Aspirate + trephine + FISH analysis ^[1]
Staging	Serum β2-microglobulin ^[1]
Skeletal imaging	Whole body PET-CT or whole body MRI or whole body low-dose CT (or skeletal survey) ^[1]
Pre-treatment	HBsAg, anti-HBc ± HBV DNA, G6PD ^[2]^[22]
Additional if indicated	Serum viscosity, Congo red stain, echo, NCS

"The diagnostic workup requires serum free light chains, bone marrow biopsy, and skeletal survey to assess disease burden and staging" ^[24]

High Yield Summary — Diagnostics

IMWG 2014 criteria: BM plasma cells ≥ 10% + myeloma-defining event (CRAB or SLiM)
SLiM-CRAB: Sixty (≥ 60% BM PC), Light chain ratio > 100, MRI focal lesions ≥ 1 + Calcium, Renal, Anaemia, Bone
Paraprotein workup: SPE + immunofixation + serum FLC + UPE + immunofixation — all four are mandatory at diagnosis
50% of light chain myeloma is SPE-negative but UPE-positive — never skip urine studies
Urine dipstick is negative — it detects albumin, not light chains
BM biopsy: ≥ 10% clonal plasma cells; immunophenotyping (CD138, κ/λ); FISH for cytogenetics
Skeletal imaging: WBLDCT or PET-CT or WB-MRI preferred; skeletal survey if unavailable
NEVER order a Tc-99m bone scan — osteoblasts suppressed → false negative
ALP is typically normal — osteoblasts suppressed (distinguishes from metastases/Paget's)
R-ISS staging: β2-microglobulin + albumin + LDH + FISH cytogenetics — check before treatment starts
Rouleaux ≠ myeloma diagnostic — it indicates raised proteins (non-specific) but should prompt SPE

Active Recall - Diagnostic Criteria, Algorithm and Investigations

References

^[1] Senior notes: Block A - An old man with bone pain and anaemia: multiple myeloma; monoclonal gammopathy.pdf (pp. 15, 20, 27) ^[2] Senior notes: Ryan Ho Haemtology.pdf (pp. 105–107) ^[3] Lecture slides: GC 030. An old man with bone pain and anaemia.pdf (p. 23) ^[4] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf (p. 15) ^[5] Senior notes: Ryan Ho Chemical Path.pdf (p. 23) ^[6] Senior notes: Block A – Nephrology Data Interpretation.pdf (p. 5) ^[7] Senior notes: Block A - Hematology Data Interpretation.pdf (p. 1) ^[13] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (pp. 27–28) ^[14] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp. 1476, 1478, 1482) ^[22] Senior notes: Maksim Medicine Notes.pdf (pp. 180–181) ^[23] Senior notes: Ryan Ho Critical Care.pdf (p. 27) ^[24] Senior notes: Learning_Points_All_Lectures.txt (Haematology section)

Management of Multiple Myeloma

Before diving into specifics, understand the overarching logic of myeloma management:

Only active multiple myeloma (with CRAB or SLiM criteria) requires treatment — MGUS and smouldering myeloma are monitored ^[1]
The first decision in any newly diagnosed active myeloma patient is: "Is this patient eligible for autologous haematopoietic stem cell transplant (ASCT)?" ^[1]
Treatment follows a phased approach: Induction → (ASCT if eligible) → Consolidation → Maintenance
Supportive care runs in parallel throughout the entire disease course and is equally important as disease-directed therapy
Myeloma is currently incurable in most patients — the goal is deep, sustained remission and prolongation of progression-free and overall survival with maintained quality of life

"Literally the first question you ask yourself: is this patient suitable for transplant?" ^[1]

Factor	Transplant Eligible	Transplant Ineligible
Age	< 70 years	≥ 70 years
Comorbidities	Low comorbidity burden	Significant cardiac, pulmonary, hepatic, or renal comorbidities ^[1]
Performance status	Good (ECOG 0–2)	Poor (ECOG ≥ 3)
Patient preference	Willing	Declined

Why does age matter? Autologous HSCT requires high-dose melphalan as a conditioning regimen, which causes profound and prolonged pancytopenia. Older or frailer patients cannot tolerate this degree of myelosuppression — the treatment-related mortality becomes unacceptably high.

"< 70, go for auto-HSCT; > 70 / with comorbidity, not indicated" ^[1]

B. Supportive Treatment

Supportive care is not optional — it addresses the immediate life-threatening complications of myeloma and runs in parallel with disease-directed chemotherapy. This is commonly examined in SAQs ^[22].

"Supportive treatment" ^[22]:

"TLS prophylaxis: IV fluid + allopurinol / febuxostat" ^[22]
Why? When you start treating myeloma, rapid tumour cell death releases intracellular contents (potassium, phosphate, uric acid, nucleic acids) into the bloodstream → hyperuricaemia, hyperkalaemia, hyperphosphataemia, hypocalcaemia → AKI, cardiac arrhythmias
How?
- Aggressive IV hydration (≥ 3 L/day) to maintain high urine output and dilute uric acid
- Allopurinol (xanthine oxidase inhibitor) — prevents conversion of hypoxanthine/xanthine → uric acid
- Febuxostat — alternative xanthine oxidase inhibitor (non-purine analogue)
- Rasburicase — recombinant urate oxidase, converts uric acid → allantoin (water-soluble, easily excreted); reserved for high TLS risk or established TLS

Must-Know Pre-Treatment Check

"What must be done for every single patient before starting allopurinol? → Check for HLA-B5801 → risk of SJS/TEN"* ^[25]. This is especially important in Chinese/Hong Kong patients where HLA-B*5801 prevalence is ~6–8%, much higher than in Caucasians. A positive result means allopurinol is absolutely contraindicated — use febuxostat instead.

"Hypercalcaemia / Bone disease: local RT for pain relief, aggressive hydration > 3L/day, bisphosphonates e.g. pamidronate (osteoclast inhibitor), denosumab (RANKL inhibitor)" ^[22]

Treatment	Mechanism	Indications	Key Points
Bisphosphonates (e.g., zoledronic acid, pamidronate)	Bind to hydroxyapatite on bone surface → taken up by osteoclasts → inhibit farnesyl pyrophosphate synthase → osteoclast apoptosis → reduced bone resorption	All myeloma patients with bone disease; prevention of skeletal-related events	IV bisphosphonates cannot be used in patients with eGFR < 35 mL/min ^[26]. Side effects: osteonecrosis of the jaw (ONJ) — dental review before starting; nephrotoxicity (especially zoledronic acid). Given monthly for ~2 years
Denosumab (anti-RANKL mAb)	Binds RANKL → prevents RANKL-RANK interaction → inhibits osteoclast formation and activation	Three indications: (1) refractory hypercalcaemia despite IV bisphosphonates; (2) contraindicated for IV bisphosphonates due to severe renal impairment; (3) persistent hypercalcaemia of malignancy ^[26]	Not renally excreted — can be given to CKD patients; risk of rebound hypercalcaemia on cessation; ensure vitamin D is replenished before starting → "or else, may cause hypocalcaemia" ^[26]
Radiotherapy (local)	Direct radiation to painful bone lesions → tumour cell kill → pain relief	"Effective in treating local disease and for pain control" ^[14]; spinal cord compression; pathological fracture risk	Usually low-dose palliative RT (e.g., 8 Gy single fraction or 20 Gy in 5 fractions)
Orthopaedic intervention	Surgical stabilisation	Impending or completed pathological fractures; spinal cord compression with instability	Prophylactic intramedullary nailing for long bone lesions at fracture risk
Vertebroplasty / kyphoplasty	Cement injection into collapsed vertebral bodies	Painful vertebral compression fractures refractory to analgesia	Provides structural support and immediate pain relief

Hypercalcaemia in myeloma is an emergency — it worsens renal function (via nephrogenic DI → dehydration → pre-renal AKI + nephrocalcinosis), causes confusion, and can precipitate cardiac arrhythmias.

Step	Treatment	Mechanism
1st	Aggressive IV hydration (0.9% NaCl, ≥ 3 L/day)	Restores intravascular volume; increases renal calcium excretion by increasing GFR and reducing proximal tubular calcium reabsorption
2nd	IV bisphosphonate (zoledronic acid 4 mg over 15 min)	Inhibits osteoclast-mediated bone resorption; onset 2–4 days; peak effect ~7 days
3rd	Denosumab	If bisphosphonate contraindicated (eGFR < 35) or refractory; takes 2–4 days for serum calcium to fall ^[26]
4th	Calcitonin (salmon calcitonin SC/IM)	Rapid but transient effect (~48h); tachyphylaxis develops; useful as bridge while waiting for bisphosphonate to take effect
5th	Dialysis	"Reserved for very severe forms of hypercalcaemia → serum Ca > 4.5 mmol/L; usually in patients with refractory severe hypercalcaemia, complicated by renal failure" ^[26]

Concurrent: start definitive myeloma chemotherapy — this is the most effective way to control hypercalcaemia long-term by reducing the tumour burden.

"Renal failure: hydration, avoid nephrotoxin (e.g., NSAID), dialysis prn" ^[22]

Aggressive hydration — prevents cast formation by diluting light chains in tubules and maintaining tubular flow
Avoid nephrotoxins: NSAIDs (often used by patients for bone pain before diagnosis — must be stopped), contrast dye (if possible), aminoglycosides
"Myeloma kidney is an emergency, must act immediately to save the kidney → possible that with good and early treatment, kidney can be saved" ^[1]
Dialysis if needed for established AKI with indications (refractory hyperkalaemia, acidosis, fluid overload, uraemia)
Plasmapheresis / high-cut-off dialysis — may be considered in severe cast nephropathy to rapidly remove circulating free light chains (evidence debated; MYRE trial showed potential benefit with high-cut-off haemodialysis)

Vaccination: pneumococcal, influenza, COVID-19, HBV (if non-immune) — before immunosuppressive therapy if possible
Antibiotic prophylaxis: consider aciclovir (VZV prophylaxis during bortezomib therapy — bortezomib reactivates VZV); cotrimoxazole for PJP prophylaxis during steroid-heavy regimens
IVIG may be considered for patients with recurrent severe infections and documented immunoparesis
HBV screening: HBsAg, anti-HBc ± HBV DNA ^[22] — risk of HBV reactivation with immunosuppressive therapy; entecavir prophylaxis if indicated

Blood transfusion for symptomatic anaemia (Hb < 7–8 g/dL or symptomatic at higher levels)
Erythropoiesis-stimulating agents (ESA) — subcutaneous EPO for persistent anaemia despite chemotherapy, especially if renal impairment contributes

Myeloma patients on IMiDs (lenalidomide, thalidomide, pomalidomide) + dexamethasone have increased VTE risk
Aspirin for standard-risk patients; LMWH or warfarin/DOAC for high-risk patients (prior VTE, immobility, concurrent erythropoietin)

WHO analgesic ladder: paracetamol → weak opioids → strong opioids
Avoid NSAIDs (nephrotoxic)
Local radiotherapy for refractory bone pain
Neuropathic pain agents (gabapentin, pregabalin) if amyloid or drug-related neuropathy

"Plasmapheresis for hyperviscosity syndrome" ^[14] — emergency plasma exchange to rapidly reduce serum viscosity while initiating definitive chemotherapy

C. Disease-Directed Chemotherapy

"Specific chemotherapy: only indicated in active MM" ^[22]

"Asymptomatic patients with smouldering disease may require no treatment until there is disease progression" ^[14]

Phase 1: Induction Therapy

The goal of induction is to rapidly reduce the tumour burden (achieve deep response) before ASCT or as definitive therapy in transplant-ineligible patients.

"The quadruplet induction regimen is known as Dara-VRd" ^[1]:

Drug	Class	Mechanism	Key Side Effects
Bortezomib (Velcade) — "V"	Proteasome inhibitor (PI)	"Inhibition of 26S proteasome → prevent proteolysis of ubiquitin-tagged protein → cytotoxic to myeloma cells by affecting multiple signalling cascades within cells" ^[1]. Myeloma cells produce vast quantities of paraprotein → heavily dependent on the proteasome (the cell's "recycling bin") to dispose of misfolded/excess proteins. Blocking the proteasome causes toxic accumulation of proteins → ER stress → apoptosis. Normal cells are less dependent on this pathway → relative selectivity	Peripheral neuropathy ^[22] (dose-limiting; subcutaneous > IV to reduce risk); GI upset; thrombocytopenia; herpes zoster reactivation (give aciclovir prophylaxis)
Lenalidomide (Revlimid) — "R"	Immunomodulatory drug (IMiD)	Binds cereblon (a component of the E3 ubiquitin ligase complex) → causes selective ubiquitination and degradation of Ikaros and Aiolos (transcription factors essential for myeloma cell survival) → also enhances T-cell and NK-cell activity against myeloma	Myelosuppression (neutropenia, thrombocytopenia); VTE (requires thromboprophylaxis); teratogenicity (strict pregnancy prevention programme); fatigue; diarrhoea; secondary malignancies (rare)
Dexamethasone — "d"	Corticosteroid	Direct lymphocytotoxicity to myeloma cells; anti-inflammatory; reduces cytokine production (especially IL-6, the major myeloma growth factor); synergistic with PI and IMiD	Hyperglycaemia; insomnia; mood disturbance; immunosuppression; osteoporosis; proximal myopathy; gastritis
Daratumumab (Darzalex) — "Dara"	Anti-CD38 monoclonal antibody	CD38 is highly expressed on myeloma cells. Daratumumab binds CD38 → induces cell death via ADCC, CDC, and phagocytosis; also modulates the immune microenvironment	Infusion reactions (first dose); neutropenia; infections; interferes with blood bank crossmatching (must notify blood bank)

"For the triplet and quadruplet induction therapy for MM patients, what is the core backbone of drugs? → 1× proteasome inhibitor (Bortezomib), 1× immunomodulatory drug (Lenalidomide), 1× steroid (Dexamethasone)" ^[1]

High Yield — Dara-VRd is the Current Standard of Care

The GRIFFIN and PERSEUS trials have established Dara-VRd (daratumumab + bortezomib + lenalidomide + dexamethasone) as the preferred quadruplet induction for transplant-eligible patients. For transplant-ineligible patients, Dara-VRd or Dara-Rd (daratumumab + lenalidomide + dexamethasone) is increasingly used. The older VRd triplet remains the minimum backbone when daratumumab is not available.

"Eligible: 4 cycles of triple therapy → high dose Melphalan + autologous HSCT" ^[22]

Step	Details
Induction	4–6 cycles of Dara-VRd (or VRd if daratumumab unavailable)
Stem cell harvest	Peripheral blood stem cell collection via apheresis after G-CSF mobilisation (± plerixafor). Must harvest BEFORE prolonged lenalidomide exposure (lenalidomide impairs stem cell mobilisation)
Conditioning	High-dose melphalan (200 mg/m²) — an alkylating agent that ablates residual marrow disease
Autologous HSCT	Infusion of previously collected patient's own stem cells to rescue bone marrow after high-dose chemotherapy
Consolidation	Additional 2 cycles of induction-type regimen post-transplant (optional, centre-dependent)
Maintenance	Lenalidomide monotherapy ≥ 2 years ^[22] (many centres continue until progression or intolerance)

Why Autologous and Not Allogeneic HSCT?

"Autologous HSCT is not curative but provides prolonged control of disease" ^[14]. It uses the patient's OWN stem cells — no graft-versus-host disease (GVHD), lower treatment-related mortality (~1–2%). However, the graft is not "clean" (may contain residual myeloma cells), so relapse is inevitable.

"Allogeneic HSCT is curative for multiple myeloma but the procedure-related mortality is high and is reserved only for young patients with HLA-compatible donors" ^[14]. Allogeneic HSCT provides a graft-versus-myeloma (GvM) effect from donor immune cells, which can eradicate residual disease. However, GVHD and infection risk lead to 10–30% treatment-related mortality — unacceptable for most patients.

"Ineligible: 8–12 cycles of triple therapy" ^[22]

Step	Details
Induction	8–12 cycles of Dara-VRd or VRd (or Dara-Rd for frail patients unable to tolerate bortezomib)
Maintenance	Lenalidomide monotherapy ≥ 2 years ^[22] (often indefinite until progression)

Note: the older regimen of melphalan + prednisolone (MP) ^[14] is rarely used now as first-line but may still appear in older exam stems. It has been superseded by VRd/Dara-VRd.

"Consolidation & maintenance therapy (lenalidomide monotherapy): ≥ 2 years" ^[22]

Drug: Lenalidomide (low dose, oral, continuous)
Purpose: Suppress residual disease and prolong remission
Duration: ≥ 2 years; many centres continue until progression or intolerance
Monitoring: Regular CBC (risk of neutropenia), SPE/sFLC every 2–3 months to monitor response
For high-risk cytogenetics [del(17p), t(4;14)]: bortezomib-based maintenance may be added to lenalidomide

Myeloma will almost inevitably relapse. Treatment of relapsed disease uses agents with different mechanisms or retreats with previously effective drugs if relapse occurred after a long remission.

"Relapse / refractory: Anti-CD38 (daratumumab, isatuximab), SLAMF7 (elotuzumab)" ^[22]

Agent Class	Examples	Mechanism	Notes
Anti-CD38 monoclonal antibodies	Daratumumab, isatuximab	Target CD38 on myeloma cells → ADCC, CDC, phagocytosis	"Monoclonal antibodies → saved for refractory cases" ^[1]. First-line for relapse if not used in induction. Now increasingly used upfront
Anti-SLAMF7 mAb	Elotuzumab	Targets SLAMF7 (CS1) on myeloma and NK cells → enhances NK-cell killing of myeloma	Used in combination with lenalidomide/dexamethasone
Second-generation PIs	Carfilzomib, ixazomib	"Constant evolution: bortezomib → carfilzomib → ixazomib" ^[1]. Irreversible (carfilzomib) or oral (ixazomib) proteasome inhibition	Carfilzomib: more potent but cardiotoxicity risk; Ixazomib: "oral form of bortezomib" ^[1], convenient
Second-generation IMiDs	Pomalidomide	Similar to lenalidomide but effective in lenalidomide-refractory disease	Combined with dexamethasone ± other agents
Anti-BCMA therapies	Belantamab mafodotin (ADC), teclistamab (BiTE), idecabtagene vicleucel / ciltacabtagene autoleucel (CAR-T)	BCMA (B-cell maturation antigen) is highly expressed on myeloma cells. "Immunotherapy against BCMA: Antibody-drug conjugate (ADC), Bi-specific T-cell engager (BiTE), CAR-T" ^[22]	CAR-T: patient's T cells engineered to express anti-BCMA chimeric antigen receptor → dramatic responses in heavily pre-treated patients; risk of CRS and neurotoxicity
XPO1 inhibitor	Selinexor	"Nuclear cytoplasmic transport receptor inhibitor" ^[1] — blocks exportin-1 (XPO1), trapping tumour suppressors (p53, p21) in the nucleus → apoptosis	Last-line; GI side effects common
BCL-2 inhibitor	Venetoclax	"BCL-2 inhibitors: venetoclax" ^[1] — inhibits anti-apoptotic protein BCL-2 → restores apoptosis. Particularly effective in t(11;14) myeloma (overexpresses BCL-2)	Tumour lysis risk; used in selected patients

D. Management of Specific Scenarios

High-dose dexamethasone immediately (reduces oedema around cord)
Urgent MRI whole spine to confirm and localise
Urgent radiotherapy (most common definitive treatment) ± surgical decompression (if spinal instability or neurological deterioration despite RT)
Commence definitive chemotherapy

"Myeloma kidney is an emergency, must act immediately to save the kidney" ^[1]
Aggressive IV hydration to maintain high urine output
Avoid nephrotoxins (NSAIDs, contrast, aminoglycosides)
Commence chemotherapy immediately (bortezomib-based regimens preferred — renally safe, rapid FLC reduction)
Consider high-cut-off haemodialysis to remove free light chains (if available)
Dialysis for standard AKI indications

No treatment required — observation only ^[1]
Annual follow-up: SPEP, sFLC, CBC, RFT, calcium
Patient education: report new bone pain, fatigue, infections
"Most important differential diagnosis of MGUS? → AL amyloidosis" ^[1] — if suggestive symptoms (nephrotic syndrome, cardiomyopathy, neuropathy), investigate actively

No treatment required — observation ± clinical trial ^[1]^[14]
Closer monitoring than MGUS: every 3–6 months with SPEP, sFLC, CBC, RFT, calcium
High-risk SMM patients may be offered early treatment in clinical trials (e.g., lenalidomide + dexamethasone showed benefit in QUIREDEX trial), but this remains controversial outside trials

Response to treatment is assessed using changes in M-protein, sFLC, and BM plasma cell percentage:

Response Category	Definition
Complete Response (CR)	Negative immunofixation of serum and urine; < 5% BM plasma cells; no soft tissue plasmacytomas
Stringent CR (sCR)	CR + normal sFLC ratio + absence of clonal cells by immunohistochemistry or flow cytometry
VGPR	≥ 90% reduction in serum M-protein + urine M-protein < 100 mg/24h
Partial Response (PR)	≥ 50% reduction in serum M-protein + ≥ 90% reduction in 24h urine M-protein
Minimal Residual Disease (MRD) negativity	No detectable myeloma by next-generation flow cytometry or next-generation sequencing (sensitivity 10⁻⁵) — emerging as the deepest and most prognostically significant endpoint

Drug Class	Mechanism (First Principles)	Key Side Effects	Examples
Proteasome inhibitors	Block 26S proteasome → misfolded proteins accumulate → ER stress → apoptosis (myeloma cells especially vulnerable as heavy Ig producers)	Peripheral neuropathy, thrombocytopenia, GI, VZV reactivation	Bortezomib, carfilzomib, ixazomib
IMiDs	Bind cereblon → degrade Ikaros/Aiolos → myeloma cell death + immune enhancement (T/NK cell activation)	VTE, myelosuppression, teratogenicity, secondary malignancy	Thalidomide, lenalidomide, pomalidomide
Corticosteroids	Direct lymphocytotoxicity; ↓ IL-6; anti-inflammatory; synergistic with other agents	Hyperglycaemia, infection, osteoporosis, insomnia, myopathy	Dexamethasone, prednisolone
Anti-CD38 mAb	Target CD38 → ADCC, CDC, phagocytosis, immunomodulation	Infusion reactions, neutropenia, interference with blood typing	Daratumumab, isatuximab
Anti-BCMA	Target BCMA on myeloma cells → ADC delivers cytotoxin, BiTE redirects T cells, CAR-T provides sustained killing	CRS (CAR-T), keratopathy (belantamab), infections	Belantamab, teclistamab, ide-cel, cilta-cel
Alkylating agents	Cross-link DNA → prevent replication → cell death	Myelosuppression, secondary malignancy (MDS/AML)	Melphalan (conditioning), cyclophosphamide
Bisphosphonates	Inhibit osteoclast activity via farnesyl pyrophosphate synthase inhibition → ↓ bone resorption	ONJ, nephrotoxicity, hypocalcaemia	Zoledronic acid, pamidronate
Anti-RANKL mAb	Bind RANKL → prevent osteoclast activation	Hypocalcaemia (ensure vitamin D replete), ONJ	Denosumab

High Yield Summary — Management of Multiple Myeloma

Only active MM needs treatment — MGUS and SMM are monitored
First decision: transplant eligible (< 70, fit) vs ineligible (≥ 70 or comorbid)
Induction backbone: Dara-VRd (daratumumab + bortezomib + lenalidomide + dexamethasone) is current standard quadruplet
Transplant-eligible: 4–6 cycles induction → stem cell harvest → high-dose melphalan → autologous HSCT → maintenance
Transplant-ineligible: 8–12 cycles induction → maintenance
Maintenance: lenalidomide monotherapy ≥ 2 years
Autologous HSCT is NOT curative but prolongs remission; allogeneic HSCT is potentially curative but high mortality
Supportive care: TLS prophylaxis (hydration + allopurinol; check HLA-B*5801), bisphosphonates/denosumab for bone disease, hydration for renal protection, infection prophylaxis, thromboprophylaxis on IMiDs
Bisphosphonates contraindicated if eGFR < 35 → use denosumab instead
Relapse: Anti-CD38 (daratumumab), second-gen PI/IMiD, anti-BCMA therapies (CAR-T, BiTEs, ADCs)
Cast nephropathy is a medical emergency — immediate hydration + chemotherapy (bortezomib-based) ± high-cut-off dialysis
Spinal cord compression — emergency dexamethasone + urgent RT ± surgical decompression

Active Recall - Management of Multiple Myeloma

References

^[1] Senior notes: Block A - An old man with bone pain and anaemia: multiple myeloma; monoclonal gammopathy.pdf (pp. 25, 27) ^[2] Senior notes: Ryan Ho Haemtology.pdf (pp. 105–107) ^[3] Lecture slides: GC 030. An old man with bone pain and anaemia.pdf (p. 23) ^[14] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp. 1476, 1481) ^[22] Senior notes: Maksim Medicine Notes.pdf (pp. 180–181) ^[25] Senior notes: Block A - High white cell count: acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (p. 9) ^[26] Senior notes: Block A - Confused and dehydrated: hypercalcaemia; hypocalcaemia.pdf (p. 12)

Complications of Multiple Myeloma

Myeloma complications arise from four interconnected pathophysiological pillars: (1) bone destruction, (2) bone marrow failure, (3) paraprotein/light chain-mediated organ damage, and (4) immune dysfunction. Some of these are "defining" features of the disease (i.e., the CRAB criteria themselves), while others emerge during the disease course or as a consequence of treatment. We discuss each systematically from first principles.

"Complications of Myeloma" — a dedicated GC 030 lecture slide ^[3]

Listed in the lecture and notes ^[14]:

Complications: Renal failure, Bone destruction, Bone marrow failure, Bacterial infection, Hypercalcaemia, Hyperviscosity syndrome ^[14]

1. Bone Complications

Mechanism: Myeloma causes purely osteolytic bone destruction through ↑RANKL:OPG ratio + ↑DKK1 → osteoclast activation + osteoblast suppression → cortical and trabecular bone is eroded without compensatory new bone formation → structural failure
Sites: Axial skeleton predominates (vertebral bodies, ribs, pelvis, skull, proximal long bones) — these sites contain the most active red marrow, which is where myeloma cells preferentially home
Consequences:
- Vertebral compression fractures → back pain, loss of height, progressive kyphosis
- Long bone fractures from trivial trauma (pathological fractures)
- Rib fractures → pleuritic pain, impaired ventilation
- Chronic pain requiring long-term analgesia

High Yield — Bone Scans Are Negative

Reminder: because osteoblasts are suppressed, technetium-99m bone scans will be negative despite extensive bone destruction. This is a defining feature and perennial exam topic.

This is the most feared orthopaedic complication and is commonly examined ^[14]^[27]^[28].

Mechanism: Vertebral body collapse → posterior extrusion of bony fragments into the spinal canal → mechanical compression of the spinal cord. Alternatively, an extramedullary plasmacytoma (myeloma growing outside the marrow space) can directly compress the cord ^[1]

"Of all the fractures, spinal ones probably the most concerning. Any posterior extrusion of fragment into the canal will definitely cause neurological compromise." ^[1]

Clinical presentation: "Progressive bilateral lower limb weakness, urinary and bowel incontinence, mild paraplegia with increased tone and brisk reflexes in the lower limbs, plantar responses extensor bilaterally" ^[14]
- Back pain (usually the first sign — 90%) → motor weakness (UMN pattern below level) → sensory level → sphincter dysfunction (late sign)
- "Pre-treatment neurological function is the strongest predictor of post-treatment neurological function" ^[28]
Sites: thoracic (70%) > lumbosacral (20%) > cervical (10%) ^[28]
Management:
- "Start dexamethasone 10 mg IV bolus then 4 mg IV q6h" ^[28] — reduces peri-tumoural oedema, buys time
- "Urgent MRI of the whole spine" ^[28] — to detect multiple levels of involvement (33% have multilevel disease)
- "Urgent decompression spinal surgery or radiotherapy" ^[14] — surgery if spinal instability or neurological deterioration; RT if stable or unfavourable prognosis
- "Give corticosteroids and RT for these patients to reduce swelling" ^[1]

Exam Favourite — Spinal Cord Compression Case

The classic exam stem from GC 030 / Felix Lai Case 1 ^[14]: A 70-year-old woman on chemotherapy for myeloma develops progressive bilateral lower limb weakness with UMN signs and sphincter disturbance. Immediate management: dexamethasone IV + urgent whole-spine MRI + consult orthopaedics/oncology for urgent decompression ± RT.

Occurs in ~30% at diagnosis; can recur during disease progression
Mechanism: Osteoclast activation → excessive calcium release from bone into blood. Compounded by renal impairment (↓ calcium excretion) and dehydration (↓ dilutional effect)
"Local osteolysis due to local active factors — IL-6, TNF-β" ^[5] — this is NOT PTHrP-mediated (unlike solid tumours)
Clinical features: confusion, drowsiness, constipation, nausea, polyuria (nephrogenic DI from hypercalcaemia), dehydration, shortened QT on ECG, cardiac arrhythmias
Vicious cycle: hypercalcaemia → polyuria → dehydration → ↓ GFR → worsens hypercalcaemia AND renal failure
Management: IV hydration → bisphosphonate/denosumab → treat underlying myeloma (see Management section)

"Is renal involvement common as a complication of myeloma? → Yes. At least 50% of patients with newly diagnosed myeloma will have renal involvement of varying degrees." ^[1]

"Why is renal failure common in multiple myeloma?" — a classic SAQ ^[14]. Multiple mechanisms contribute:

Mechanism	Pathophysiology	Clinical Notes
Cast nephropathy (most common)	"Predominant cause of kidney injury in myeloma, known as myeloma kidney" ^[1]. Free light chains are filtered by the glomerulus → exceed proximal tubular reabsorptive capacity → combine with Tamm-Horsfall protein in distal tubules → form obstructing waxy casts → tubulointerstitial nephritis → tubular rupture	This is a medical emergency ^[6]. "Myeloma kidney is an emergency, must act immediately to save the kidney" ^[1]. Presents as AKI with proteinuria; urine dipstick may be negative
Hypercalcaemia	"Secondary to bone resorption" ^[1] → nephrogenic DI → dehydration → pre-renal AKI + nephrocalcinosis → intrinsic renal damage	Correct calcium urgently; IV hydration is first step
Dehydration	"Due to hypercalcaemia" ^[1] → reduced oral intake (nausea, confusion) → pre-renal AKI	Aggressive hydration critical
AL amyloidosis	Misfolded light chains deposit as amyloid fibrils in glomerular basement membrane and mesangium → nephrotic syndrome (heavy proteinuria, oedema, hypoalbuminaemia)	"Rare" as cause of renal failure in myeloma ^[1], but important; "Amyloidosis (accumulation of FLC): present with nephrotic syndrome (require renal Bx)" ^[22]; Congo red stain positive
Light chain deposition disease (LCDD)	Non-amyloid light chain deposits in GBM → nodular glomerulosclerosis	Congo red negative; different from amyloidosis
Direct myeloma deposition	"Rare" ^[1] — tumour cells infiltrate renal parenchyma	Very uncommon
Drug-induced	"Drug-induced e.g. NSAID, bisphosphonate, chemoTx" ^[22] — patients often take NSAIDs for bone pain before diagnosis; zoledronic acid nephrotoxicity; contrast nephropathy from imaging	Always avoid NSAIDs in myeloma — one of the most important practical points
Fanconi syndrome	Light chain proximal tubulopathy → impaired proximal tubular function → glycosuria, aminoaciduria, phosphaturia, type II RTA	Rare but recognised
Hyperuricaemia	High cell turnover → urate crystal deposition in tubules	Urate nephropathy; prophylax with allopurinol/febuxostat
Recurrent UTI	Immunoparesis + ↓ neutrophils → impaired defence against urinary pathogens	Contributes to progressive renal damage

"Light chain multiple myeloma has the worst prognosis for the kidneys" ^[1] — because free light chains are small enough to be freely filtered by the glomerulus, whereas intact immunoglobulins are too large

3. Bone Marrow Failure

Prevalence: ~70% at diagnosis; the most common haematological abnormality
Mechanism: Marrow infiltration by malignant plasma cells → physical "crowding out" of normal erythroid precursors; cytokine suppression of erythropoiesis (IL-6, TNF-α); renal impairment → ↓ EPO production; hepcidin elevation (anaemia of chronic disease component)
Clinical features: Fatigue, pallor, dyspnoea on exertion, tachycardia
Normocytic normochromic (NcNc) pattern ^[22]
Management: treat underlying myeloma; transfusion for symptomatic anaemia; ESAs

"Anaemia (NcNc) / bleeding tendency: BM infiltration + acquired vWD" ^[22]
Mechanisms:
- Thrombocytopenia from marrow infiltration (plasma cells crowd out megakaryocytes)
- Acquired von Willebrand disease — paraprotein binds to vWF → impaired platelet adhesion
- Paraprotein coating platelets → impaired platelet aggregation
- Paraprotein interference with coagulation factors → prolonged clotting times
- Hyperviscosity → endothelial damage, impaired microvascular flow
Clinical features: Mucosal bleeding (epistaxis, gum bleeding), ecchymoses, purpura, GI bleeding

Marrow infiltration reduces granulocyte production → leukopenia (~20%) ^[2]
Exacerbated by chemotherapy → severe treatment-related neutropenia
Contributes to infection susceptibility

"Recurrent infections: immunoparesis (↓↓ other Ig)" ^[22]

Mechanism: Immunoparesis — the malignant clone suppresses production of normal polyclonal immunoglobulins → "↓ opsonisation of encapsulated organisms by Ig production" ^[2] → humoral immune deficiency. Compounded by neutropenia (marrow infiltration + chemotherapy), T-cell dysfunction (from steroids and IMiDs), and mucosal barrier disruption
Timing and organism pattern:
- Early disease / first 3 months of treatment: Encapsulated bacteria — Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus (these rely on opsonisation by antibodies for clearance)
- Later / post-chemotherapy: Gram-negative bacteria, fungi (Candida, Aspergillus), viral reactivation (VZV, CMV, HBV)
- On specific therapies: VZV reactivation with bortezomib (requires aciclovir prophylaxis); PJP with prolonged steroids (requires cotrimoxazole prophylaxis); HBV reactivation with rituximab/anti-CD38 (requires entecavir prophylaxis)
Clinical significance: Infections are the single most common cause of death in myeloma patients — more common than disease progression itself in many series

"Hyperviscosity syndrome: rare cf. WM" ^[22]

Prevalence: 2–5% of myeloma patients (much more common in Waldenström macroglobulinaemia where the IgM pentamer greatly increases viscosity)
Mechanism: Very high concentrations of circulating M-protein → ↑ serum viscosity → sludging of blood in microvasculature → impaired tissue perfusion
More common with IgA myeloma (IgA tends to polymerise) or when M-protein levels are extremely high (> 5 g/dL)
Clinical features:
- Neurological: headache, confusion, somnolence, dizziness, visual disturbance (blurred vision, diplopia) → coma if severe
- Ophthalmological: dilated, segmented, tortuous "sausage-link" retinal veins ± retinal haemorrhages, papilloedema
- Bleeding: mucosal (epistaxis, gum bleeding) — paradoxical, because viscosity impairs platelet function and damages endothelium
- Cardiac: high-output heart failure from expanded plasma volume
Diagnosis: Serum viscosity measurement (normal ~1.5 cP; symptomatic typically ≥ 4 cP)
Management: Emergency plasmapheresis (plasma exchange) to rapidly reduce circulating paraprotein + commence definitive chemotherapy

"AL amyloidosis possibly arising as a complication of myeloma in 10% of cases" ^[7]

Mechanism: Monoclonal free light chains (especially λ) misfold into β-pleated sheet fibrils → deposit extracellularly in various organs → progressive organ dysfunction
"Amyloidosis affects the whole body" ^[7]
Organ involvement:
- Heart: Restrictive cardiomyopathy → diastolic dysfunction → heart failure (low-voltage ECG + thickened walls on echo — a characteristic mismatch). "Cardiac failure: 2° to amyloidosis / anaemia / hyperviscosity" ^[22]
- Kidney: Glomerular amyloid deposition → nephrotic syndrome (massive proteinuria, oedema, hypoalbuminaemia). "Loss of globulin → infection; loss of antithrombin → thrombosis; hyperlipidaemia" ^[7] — classic nephrotic syndrome complications
- Nerve: "Sensory ± motor neuropathy: usually 2° to amyloidosis" ^[22]. Also "autonomic neuropathy, postural hypotension caused by amyloidosis" ^[7]
- Liver: Hepatomegaly with raised ALP; rarely causes hepatic failure
- Tongue: Macroglossia (pathognomonic)
- Skin: Periorbital purpura ("raccoon eyes") — amyloid infiltrates vessel walls → fragile vessels
- GI: Malabsorption, GI bleeding, pseudo-obstruction
Diagnosis: "Congo red stain, salmon pink colour → indicative of amyloid deposition" ^[7]; "electron microscopy to show non-branching fibrils in the extracellular compartment" ^[7]. Apple-green birefringence under polarised light
Prognosis: Cardiac involvement is the major determinant of survival; "albumin anything lower than 30 is critical, have to work fast" ^[7]

AL Amyloidosis — Don't Miss It

AL amyloidosis can present without meeting full myeloma criteria (MGUS-level paraprotein with organ damage). "Most important differential diagnosis of MGUS? → AL amyloidosis — especially if the patient has suggestive symptoms" ^[1]. Whenever a patient with paraprotein develops nephrotic syndrome, cardiomyopathy, neuropathy, or macroglossia, investigate for amyloidosis.

These are iatrogenic complications that arise from the therapies used to treat myeloma:

Treatment	Complication	Mechanism	Prevention / Management
Bortezomib	Peripheral neuropathy ^[22]	Axonal damage by proteasome inhibition in neurons; dose-cumulative	SC > IV administration (lower neuropathy rate); dose reduction or switch to carfilzomib
Bortezomib	VZV reactivation	T-cell immunosuppression	Aciclovir prophylaxis throughout treatment
Lenalidomide / Thalidomide	Venous thromboembolism	IMiDs + dexamethasone are highly thrombogenic (endothelial activation, ↓ thrombomodulin)	Aspirin (standard risk); LMWH (high risk — prior VTE, immobility, obesity)
Lenalidomide	Secondary malignancy (MDS/AML)	Mutagenic effect on haematopoietic stem cells	Rare (~2–5% at 5 years); monitor CBC; balanced against major survival benefit
Thalidomide	Teratogenicity	Disrupts angiogenesis in fetal limb buds	Strict pregnancy prevention programme (REMS/T-STEP)
Dexamethasone	Hyperglycaemia, infection, osteoporosis, myopathy, insomnia, psychosis	Well-known steroid effects	Monitor glucose; PPI cover; dose reduction in elderly
High-dose melphalan + ASCT	Prolonged pancytopenia, mucositis, infections	Marrow ablation	Supportive care in transplant unit; G-CSF; prophylactic antimicrobials
Bisphosphonates (zoledronic acid)	Osteonecrosis of the jaw (ONJ)	Suppression of bone turnover in jaw (high remodelling rate due to dental stress) → avascular necrosis	Dental review before starting; avoid invasive dental procedures during treatment
Anti-CD38 (daratumumab)	Interference with blood bank crossmatching	Daratumumab binds CD38 on reagent RBCs → false-positive indirect antiglobulin test	Notify blood bank; use dithiothreitol-treated RBCs or anti-CD38 neutralising agent
Anti-BCMA CAR-T	Cytokine release syndrome (CRS), neurotoxicity (ICANS)	Massive T-cell activation → cytokine storm	Tocilizumab (anti-IL-6R) for CRS; steroids for ICANS

8. Other Complications

"Circulating plasma cells > 2 × 10⁹/L or > 20% WCC → indicative of plasma cell leukaemia" ^[2]
Can be primary (de novo) or secondary (transformation from pre-existing myeloma — ominous sign)
Aggressive disease with very poor prognosis; extramedullary involvement common
Managed with intensive chemotherapy ± ASCT if eligible

Myeloma cells spreading beyond the bone marrow into soft tissues (liver, spleen, pleura, skin, CNS)
"Extramedullary plasmacytoma — a fancy term to describe the presence of myeloma in non-bone marrow locations" ^[1]
Indicates aggressive, advanced disease; associated with high-risk cytogenetics
Responds to local RT + systemic chemotherapy

"Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein (osteosclerotic myeloma) and Skin changes" ^[2]
A distinct paraneoplastic syndrome associated with a λ light chain–secreting plasma cell clone
Notable because the bone lesions are osteosclerotic (NOT lytic — opposite of typical myeloma)
Treated differently from standard myeloma

Late complication of prior alkylating agents (melphalan) or lenalidomide maintenance
Typically therapy-related MDS → AML; poor prognosis
Incidence ~2–5% at 5–10 years

Complication	Mechanism	Clinical Features	Management
Pathological fractures	Osteolytic bone destruction	Pain, deformity, immobility	Orthopaedic fixation, RT, bisphosphonates/denosumab
Spinal cord compression	Vertebral collapse / plasmacytoma	Back pain → UMN weakness → sphincter dysfunction	Dexamethasone + urgent MRI + surgery/RT
Hypercalcaemia	Osteoclast activation	Confusion, nausea, polyuria, dehydration	IV hydration + bisphosphonate/denosumab
Renal failure	Cast nephropathy, hypercalcaemia, dehydration, amyloidosis, drugs	AKI, proteinuria, oliguria	Hydration, avoid nephrotoxins, bortezomib-based chemo, dialysis
Anaemia	Marrow infiltration, cytokine suppression, ↓ EPO	Fatigue, pallor, dyspnoea	Transfusion, ESA, treat myeloma
Bleeding	Thrombocytopenia, acquired vWD, paraprotein effects	Mucosal bleeding, purpura	Platelet transfusion, treat myeloma
Infections	Immunoparesis, neutropenia	Pneumonia, sepsis, UTI	Antibiotics, vaccination, IVIG, aciclovir/PJP prophylaxis
Hyperviscosity	High M-protein concentration	Visual disturbance, confusion, bleeding, sausage-link retinal veins	Emergency plasmapheresis
AL amyloidosis	Light chain misfolding → fibril deposition	Heart failure, nephrotic syndrome, neuropathy, macroglossia	Treat underlying clone; daratumumab-based regimens
Peripheral neuropathy	Amyloid deposition / bortezomib toxicity	Numbness, tingling, weakness	Dose modification, switch agent
VTE	IMiD + steroid thrombogenicity	DVT, PE	Aspirin or LMWH prophylaxis
Plasma cell leukaemia	Clonal evolution → circulating plasma cells	Aggressive disease, extramedullary	Intensive chemo ± ASCT

High Yield Summary — Complications of Multiple Myeloma

Infections are the #1 cause of death — from immunoparesis (↓ normal Ig) + neutropenia + treatment-related immunosuppression
Renal failure (SAQ favourite): multiple mechanisms — cast nephropathy (MC, medical emergency), hypercalcaemia, dehydration, amyloidosis, NSAIDs, hyperuricaemia, Fanconi syndrome, recurrent UTI
Light chain myeloma has the worst renal prognosis — free light chains freely filtered by glomerulus
Spinal cord compression is the most feared bone complication — back pain → UMN weakness → sphincter dysfunction; manage with dexamethasone + urgent MRI + surgery/RT
AL amyloidosis occurs in ~10% — heart, kidney, nerve, liver, tongue, skin; Congo red positive; must screen MGUS patients with suggestive symptoms
Hyperviscosity is rare in myeloma (cf. WM) — manage with emergency plasmapheresis
Treatment complications: bortezomib → neuropathy + VZV; IMiDs → VTE + teratogenicity; bisphosphonates → ONJ; steroids → hyperglycaemia/infection; melphalan → secondary MDS/AML
Bone scan negative because osteoblasts suppressed — a defining and commonly examined feature
Plasma cell leukaemia (circulating plasma cells > 2 × 10⁹/L) indicates very aggressive disease

Active Recall - Complications of Multiple Myeloma

References

^[1] Senior notes: Block A - An old man with bone pain and anaemia: multiple myeloma; monoclonal gammopathy.pdf (pp. 19–21) ^[2] Senior notes: Ryan Ho Haemtology.pdf (pp. 105–106) ^[3] Lecture slides: GC 030. An old man with bone pain and anaemia.pdf (p. 25) ^[5] Senior notes: Ryan Ho Chemical Path.pdf (p. 23) ^[6] Senior notes: Block A – Nephrology Data Interpretation.pdf (p. 5) ^[7] Senior notes: Block A - Hematology Data Interpretation.pdf (p. 1) ^[14] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp. 1479, 1481) ^[22] Senior notes: Maksim Medicine Notes.pdf (pp. 180–181) ^[27] Senior notes: Ryan Ho Neurology.pdf (p. 170) ^[28] Lecture slides: Handbook of Internal Medicine 2024.pdf (p. 366, Metastatic Spinal Cord Compression)

High Yield Summary

Multiple Myeloma — Key Points for Exams:

Definition: BM-based neoplasm of clonal plasma cells (≥10% BM) with monoclonal protein production and end-organ damage (CRAB)
Epidemiology: Median age ~70, M > F, rare < 50; ~17% of haematological malignancies
Spectrum: MGUS (1%/yr) → SMM (10%/yr first 5y) → Active MM — only active MM needs treatment
CRAB: Calcium ↑, Renal insufficiency, Anaemia, Bone lytic lesions
Pathophysiology of bone disease: ↑RANKL:OPG ratio + ↑DKK1 → osteoclast activation + osteoblast suppression → purely lytic lesions → bone scan negative (no osteoblastic activity)
Renal damage: Cast nephropathy (most common — light chain precipitation in tubules), hypercalcaemia, amyloidosis
Immunoparesis: Suppression of normal Ig → recurrent infections (leading cause of death)
Key lab clues: Raised ESR, reversed A:G ratio, normocytic anaemia, raised calcium, raised creatinine, M-spike on SPEP
Paraprotein + immunoparesis = think myeloma
High-risk cytogenetics: del(17p), t(4;14), t(14;16)
AL amyloidosis can complicate myeloma in ~10% of cases
Bone scans are NEGATIVE in myeloma — use skeletal survey/LDCT/PET-CT instead

High Yield Summary — Differential Diagnosis of Myeloma

Bone pain DDx: Bone metastases (blastic or lytic — check for known primary), 1° HPT, osteoporosis (normal ALP, no paraprotein), osteomalacia (raised ALP, low vit D), Paget's (very high ALP, mixed lytic/sclerotic)
Hypercalcaemia DDx: 90% is malignancy + 1° HPT → distinguish by PTH level (suppressed in myeloma, elevated in HPT)
AKI DDx: Cast nephropathy is a medical emergency; distinguish from diabetic nephropathy, drug-induced AKI, amyloidosis
Paraprotein DDx: MGUS vs SMM vs active MM — distinguish by BM plasma cell %, M-protein level, and presence of CRAB/MDE
Key discriminator: The triad of raised globulin (paraprotein) + lytic bone lesions + normocytic anaemia essentially clinches myeloma; no other condition reliably produces all three
Don't forget: Light chain myeloma, non-secretory myeloma, and IgD myeloma can present with panimmunoparesis without a visible M-spike on SPE — check serum free light chains and UPE
Pepper-pot skull (HPT) ≠ raindrop skull (myeloma) — common exam pitfall

High Yield Summary — Diagnostics

IMWG 2014 criteria: BM plasma cells ≥ 10% + myeloma-defining event (CRAB or SLiM)
SLiM-CRAB: Sixty (≥ 60% BM PC), Light chain ratio > 100, MRI focal lesions ≥ 1 + Calcium, Renal, Anaemia, Bone
Paraprotein workup: SPE + immunofixation + serum FLC + UPE + immunofixation — all four are mandatory at diagnosis
50% of light chain myeloma is SPE-negative but UPE-positive — never skip urine studies
Urine dipstick is negative — it detects albumin, not light chains
BM biopsy: ≥ 10% clonal plasma cells; immunophenotyping (CD138, κ/λ); FISH for cytogenetics
Skeletal imaging: WBLDCT or PET-CT or WB-MRI preferred; skeletal survey if unavailable
NEVER order a Tc-99m bone scan — osteoblasts suppressed → false negative
ALP is typically normal — osteoblasts suppressed (distinguishes from metastases/Paget's)
R-ISS staging: β2-microglobulin + albumin + LDH + FISH cytogenetics — check before treatment starts
Rouleaux ≠ myeloma diagnostic — it indicates raised proteins (non-specific) but should prompt SPE

High Yield Summary — Management of Multiple Myeloma

Only active MM needs treatment — MGUS and SMM are monitored
First decision: transplant eligible (< 70, fit) vs ineligible (≥ 70 or comorbid)
Induction backbone: Dara-VRd (daratumumab + bortezomib + lenalidomide + dexamethasone) is current standard quadruplet
Transplant-eligible: 4–6 cycles induction → stem cell harvest → high-dose melphalan → autologous HSCT → maintenance
Transplant-ineligible: 8–12 cycles induction → maintenance
Maintenance: lenalidomide monotherapy ≥ 2 years
Autologous HSCT is NOT curative but prolongs remission; allogeneic HSCT is potentially curative but high mortality
Supportive care: TLS prophylaxis (hydration + allopurinol; check HLA-B*5801), bisphosphonates/denosumab for bone disease, hydration for renal protection, infection prophylaxis, thromboprophylaxis on IMiDs
Bisphosphonates contraindicated if eGFR < 35 → use denosumab instead
Relapse: Anti-CD38 (daratumumab), second-gen PI/IMiD, anti-BCMA therapies (CAR-T, BiTEs, ADCs)
Cast nephropathy is a medical emergency — immediate hydration + chemotherapy (bortezomib-based) ± high-cut-off dialysis
Spinal cord compression — emergency dexamethasone + urgent RT ± surgical decompression

High Yield Summary — Complications of Multiple Myeloma

Infections are the #1 cause of death — from immunoparesis (↓ normal Ig) + neutropenia + treatment-related immunosuppression
Renal failure (SAQ favourite): multiple mechanisms — cast nephropathy (MC, medical emergency), hypercalcaemia, dehydration, amyloidosis, NSAIDs, hyperuricaemia, Fanconi syndrome, recurrent UTI
Light chain myeloma has the worst renal prognosis — free light chains freely filtered by glomerulus
Spinal cord compression is the most feared bone complication — back pain → UMN weakness → sphincter dysfunction; manage with dexamethasone + urgent MRI + surgery/RT
AL amyloidosis occurs in ~10% — heart, kidney, nerve, liver, tongue, skin; Congo red positive; must screen MGUS patients with suggestive symptoms
Hyperviscosity is rare in myeloma (cf. WM) — manage with emergency plasmapheresis
Treatment complications: bortezomib → neuropathy + VZV; IMiDs → VTE + teratogenicity; bisphosphonates → ONJ; steroids → hyperglycaemia/infection; melphalan → secondary MDS/AML
Bone scan negative because osteoblasts suppressed — a defining and commonly examined feature
Plasma cell leukaemia (circulating plasma cells > 2 × 10⁹/L) indicates very aggressive disease

Multiple Myeloma

Definition

Epidemiology

Global

Demographics

Hong Kong Context

Risk Factors

Anatomy and Function — Normal Plasma Cell Biology

The Normal Plasma Cell

Bone Marrow Microenvironment

Aetiology and Pathophysiology

Aetiology

Pathogenesis — The Multi-Hit Model

Stage 1: Establishment of MGUS [2]

Stage 2: Progression into Myeloma [2]

Stage 3: Changes in BM Microenvironment [2]

Pathophysiology of End-Organ Damage

1. Purely Osteolytic Bone Lesions [2]

2. Hypercalcaemia [2][5]

3. Renal Dysfunction [2][4]

4. Anaemia

5. Immunodeficiency / Immunoparesis

6. Hyperviscosity

Classification

By Immunoglobulin Type Secreted

By Light Chain Type

Staging — Revised International Staging System (R-ISS, 2015)

The Pre-Malignant Spectrum

High-Risk Cytogenetics (for exam purposes)

Clinical Features

Overview

Symptoms

1. Bone Pain (most common presenting symptom, ~70%)

2. Fatigue and Weakness (due to anaemia)

3. Symptoms of Hypercalcaemia ("Bones, stones, abdominal groans, psychiatric overtones") [9]

4. Recurrent Infections

5. Symptoms of Renal Impairment

6. Bleeding Tendency

7. Symptoms of Hyperviscosity (uncommon, ~2–5% of myeloma, more common in IgA or very high tumour burden)

8. Neuropathy

9. Constitutional Symptoms

Signs

General Examination

Musculoskeletal

Neurological

Abdominal

Skin

Eyes (Fundoscopy)

Mouth

Cardiovascular

Summary Table: Clinical Features Linked to Pathophysiology

Key Laboratory Clues That Should Raise Suspicion for Myeloma

Related Conditions in the Plasma Cell Neoplasm Spectrum

MGUS (Monoclonal Gammopathy of Undetermined Significance) [1][12]

Smouldering Myeloma (SMM)

AL Amyloidosis [7]

Waldenström Macroglobulinaemia (WM)

Active Recall - Multiple Myeloma (Definition, Epidemiology, Pathophysiology, Clinical Features)

References

Approach to Differential Diagnosis — Organising Framework

1. Differential Diagnosis of Bone Pain in the Elderly

2. Differential Diagnosis of Normocytic Normochromic Anaemia

3. Differential Diagnosis of Hypercalcaemia

4. Differential Diagnosis of Acute Kidney Injury / Chronic Kidney Disease

5. Differential Diagnosis of Paraprotein / Monoclonal Gammopathy

6. Differential Diagnosis of Recurrent Infections / Immunodeficiency

7. Differential Diagnosis by Presentation Cluster — The Classic Exam Scenario

Summary Table — Differential Diagnosis of Multiple Myeloma by Presentation

Active Recall - Differential Diagnosis of Multiple Myeloma

Diagnostic Criteria — IMWG 2014 (Updated)

Why were the SLiM criteria added in 2014?

Comparison Table: MGUS vs Smouldering Myeloma vs Active Myeloma

Diagnostic Algorithm

Investigation Modalities — Detailed Breakdown

A. Initial Blood Tests (Screening / Baseline)

B. Detection of Monoclonal Protein (The "Paraprotein Workup")

C. Bone Marrow Examination

D. Skeletal Imaging

E. Renal Investigations

F. Prognostic / Staging Investigations