Multiple Myeloma & Plasma Cell Dyscrasias

Plasma cell dyscrasias are clonal proliferations of terminally differentiated B-cells (plasma cells) that secrete a single, structurally homogeneous immunoglobulin or fragment — the monoclonal (M) protein. They span a clinical spectrum from the benign, premalignant MGUS through smouldering myeloma to symptomatic multiple myeloma, plasmacytoma, Waldenström macroglobulinaemia and primary amyloidosis. For NEET PG, the cluster of M-spike on SPEP, Bence Jones proteinuria, marrow plasmacytosis, lytic ("punched-out") bone lesions and rouleaux is the recurring MCQ skeleton.

Definition & Classification

A monoclonal gammopathy is the presence of an M-protein produced by a single clone of plasma cells/lymphoplasmacytic cells. The M-protein may be an intact immunoglobulin (most commonly IgG > IgA), a free light chain only (light-chain myeloma), or rarely IgD/IgE, or no detectable protein (non-secretory myeloma).

Disorder	Key clone	M-protein	Marrow plasma cells	Hallmark
MGUS	Plasma cell	< 3 g/dL	< 10%	Asymptomatic, no CRAB
Smouldering (asymptomatic) myeloma	Plasma cell	≥ 3 g/dL	10–60%	No CRAB / no myeloma-defining event
Multiple myeloma	Plasma cell	Usually present	≥ 10% (often >30%)	CRAB or biomarker present
Solitary plasmacytoma	Plasma cell	± small	Single focus (bone/soft tissue)	One lesion, normal marrow
Waldenström macroglobulinaemia	Lymphoplasmacytic	IgM	Lymphoplasmacytic infiltrate	Hyperviscosity, MYD88 mutation
Primary (AL) amyloidosis	Plasma cell	Light chains (λ > κ)	Often < 10%	Organ amyloid deposition
Heavy-chain disease	B-cell	Incomplete heavy chain only	Variable	α (commonest), γ, μ types

High-yield: IgG is the commonest M-protein in multiple myeloma; IgM monoclonal protein points to Waldenström macroglobulinaemia, not myeloma.

Etiology & Pathophysiology

Myeloma arises from a post-germinal-centre plasma cell that has undergone somatic hypermutation and class switching. Nearly all myeloma is preceded by MGUS, which progresses at ~1% per year. Two oncogenic pathways predominate:

1. Primary IgH translocations at chromosome 14q32 — t(11;14) (cyclin D1), t(4;14) (FGFR3/MMSET, adverse), t(14;16) (c-MAF, adverse).
2. Hyperdiploidy — trisomies of odd-numbered chromosomes, generally favourable.

Disease progression accrues secondary hits: del(17p) (loss of TP53, poor prognosis), MYC rearrangements, and RAS/NF-κB activation. Risk factors include older age (median ~65–70 yrs), male sex, African ancestry, and radiation exposure.

Bone disease is central. Malignant plasma cells secrete RANK-ligand and inhibit osteoprotegerin (OPG), driving osteoclast activation; they also secrete the Wnt-inhibitor Dickkopf-1 (DKK-1), suppressing osteoblasts. The result is uncoupled, purely lytic bone destruction → "punched-out" lesions, hypercalcaemia and pathological fractures, without a compensatory osteoblastic (sclerotic) reaction — which is why a bone scan is typically negative and a skeletal survey/low-dose CT is preferred.

Renal injury ("myeloma kidney" / cast nephropathy): filtered free light chains bind Tamm-Horsfall (uromodulin) protein in the distal tubule forming obstructing casts. Hypercalcaemia, hyperuricaemia, dehydration, NSAIDs and amyloid all contribute.

Infection is the leading cause of death: normal immunoglobulin production is suppressed (immunoparesis) and neutropenia from marrow infiltration/therapy adds to it. Encapsulated organisms (Streptococcus pneumoniae, Haemophilus) early; gram-negatives later.

High-yield: Lytic lesions are mediated by RANKL ↑ / OPG ↓ (osteoclast activation) and DKK-1 (osteoblast suppression) → bone scan negative, skeletal survey/PET-CT/MRI positive.

Clinical Features — the CRAB criteria

Symptoms are remembered by CRAB (myeloma-defining when attributable to the clone):

• C — hyperCalcaemia (>11 mg/dL or >1 mg/dL above ULN): constipation, confusion, polyuria, stones, bone pain.
• R — Renal insufficiency (creatinine >2 mg/dL or CrCl <40 mL/min).
• A — Anaemia (Hb <10 g/dL or >2 g/dL below normal) — normocytic normochromic; fatigue, pallor.
• B — Bone lesions (≥1 lytic lesion on imaging): bone pain (back, ribs), pathological fracture, cord compression.

Other features: recurrent infections, bleeding (M-protein coats platelets/coagulation factors), neuropathy (amyloid, hyperviscosity, POEMS), and the rouleaux-driven raised ESR. Hyperviscosity (headache, visual blurring, mucosal bleeding, altered sensorium) is far commoner in Waldenström (large pentameric IgM) than in myeloma.

High-yield: The most common presenting symptom of multiple myeloma is bone pain (especially back); the leading cause of death is infection; the commonest cause of renal failure is light-chain cast nephropathy.

Diagnosis & Investigation of Choice

The diagnostic workhorse is serum protein electrophoresis (SPEP) which shows a sharp, narrow-based M-spike in the γ (or β) region, contrasting with the broad-based polyclonal hump of reactive states. Confirm clonality and isotype by immunofixation electrophoresis (IFE) — the most sensitive qualitative test for identifying the M-protein type. Quantify involved/uninvolved chains with the serum free light chain (sFLC) assay; an abnormal κ:λ ratio (normal 0.26–1.65) is a sensitive marker and one of the myeloma-defining biomarkers.

Diagnostic stepwise approach:

Suspect myeloma (bone pain + anaemia + ↑ESR/↑Ca²⁺/renal failure) → SPEP + serum IFE + sFLC → 24-h urine for Bence Jones protein (urine PEP + IFE) → bone marrow aspiration & biopsy (clonal plasma cells %) → skeletal imaging (low-dose whole-body CT / PET-CT / whole-body MRI) → cytogenetics (FISH) for risk stratification.

Test	Finding in myeloma	Exam pearl
SPEP	Tall narrow M-spike	Quantifies M-protein burden
Serum IFE	Identifies heavy + light chain class	Most sensitive qualitative test
Urine (Bence Jones)	Free light chains	Detected by IFE, NOT routine dipstick (dipstick reads albumin)
sFLC ratio	κ:λ markedly abnormal	Best for light-chain & non-secretory disease
Marrow	Clonal plasma cells ≥10%	"Flame cells", "Mott cells", Russell/Dutcher bodies
Peripheral smear	Rouleaux ("stacked coins")	High protein → ↑ESR
Skeletal survey/CT	Lytic "punched-out" lesions	Bone scan negative
β2-microglobulin + albumin	Staging	Basis of R-ISS

High-yield: Bence Jones protein is detected by urine immunofixation / heat test (precipitates at 40–60°C, redissolves on boiling, reprecipitates on cooling) — the standard urine dipstick is negative because it only detects albumin.

IMWG diagnostic criteria (2014 update)

Multiple myeloma = clonal marrow plasma cells ≥ 10% (or biopsy-proven plasmacytoma) PLUS ≥ 1 of:

• Any CRAB feature attributable to the clone, or
• A myeloma-defining biomarker (SLiM):
  • S — Sixty: clonal marrow plasma cells ≥ 60%
  • Li — involved:uninvolved sFLC ratio ≥ 100 (involved ≥ 100 mg/L)
  • M — > 1 focal lesion ≥ 5 mm on MRI

High-yield mnemonic: CRAB + SLiM defines symptomatic myeloma needing treatment. The SLiM biomarkers identify high-risk smouldering patients who progress almost universally, so they are now treated as myeloma even without end-organ damage.

Staging — Revised International Staging System (R-ISS)

Stage	Criteria	Median survival (approx)
I	β2-microglobulin < 3.5 mg/L and albumin ≥ 3.5 g/dL, normal LDH, no high-risk FISH	Best
II	Neither I nor III	Intermediate
III	β2-microglobulin ≥ 5.5 mg/L and (high LDH or high-risk FISH: del17p, t(4;14), t(14;16))	Worst

High-yield: β2-microglobulin reflects tumour burden and renal function and is the single most important prognostic lab; high-risk cytogenetics are del(17p), t(4;14), t(14;16).

Management / Drug of Choice

Treatment depends on transplant eligibility. The modern backbone is a triplet/quadruplet combining a proteasome inhibitor (bortezomib), an immunomodulatory drug (lenalidomide) and dexamethasone, increasingly with an anti-CD38 monoclonal antibody (daratumumab).

Transplant-eligible (fit, < 65–70 yrs): Induction with VRd (bortezomib + lenalidomide + dexamethasone) or Dara-VRd → autologous stem cell transplant (high-dose melphalan conditioning) → lenalidomide maintenance.

Transplant-ineligible: VRd-lite or Dara-Rd, then maintenance.

Supportive care is heavily examined:

• Bone disease: monthly IV bisphosphonates (zoledronic acid / pamidronate) or denosumab (RANKL inhibitor; preferred in renal impairment) — reduce skeletal events and hypercalcaemia. Watch for osteonecrosis of the jaw.
• Hypercalcaemia: IV normal saline hydration + bisphosphonate ± calcitonin; steroids.
• Renal: hydration, avoid NSAIDs/contrast, treat the clone; plasmapheresis is not standard for cast nephropathy.
• Infection: vaccination, prophylaxis; consider IVIG in recurrent infection.
• Hyperviscosity (esp. Waldenström): urgent plasmapheresis.
• Anaemia: erythropoietin; transfusion as needed.
• Cord compression: MRI + dexamethasone + radiotherapy/surgery.

Newer agents for relapse: carfilzomib, ixazomib, pomalidomide, isatuximab, selinexor, belantamab, and BCMA-directed CAR-T / bispecific antibodies (teclistamab).

High-yield: Bortezomib (proteasome inhibitor) is renally safe and a preferred backbone in renal impairment; its classic toxicity is peripheral neuropathy (and reactivation of varicella-zoster → give acyclovir prophylaxis). Thalidomide/lenalidomide are teratogenic and prothrombotic (give VTE prophylaxis).

Complications

• Pathological fractures, vertebral collapse, spinal cord compression.
• Acute & chronic kidney disease (cast nephropathy, amyloid, Fanconi syndrome from light chains).
• Hypercalcaemic crisis.
• Recurrent bacterial infections (commonest cause of death).
• Hyperviscosity syndrome.
• AL amyloidosis — nephrotic syndrome, restrictive cardiomyopathy, macroglossia, periorbital purpura, carpal tunnel; Congo red → apple-green birefringence under polarised light.
• Bleeding diathesis.
• Transformation to plasma cell leukaemia (≥ 20% / >2 ×10⁹/L circulating plasma cells) — aggressive.

Key Differentials

Feature	Multiple myeloma	Waldenström	MGUS	Bone metastasis
M-protein	IgG/IgA	IgM	< 3 g/dL	None
Marrow	Plasma cells ≥10%	Lymphoplasmacytic	< 10%	Tumour cells
Bone lesions	Lytic, no sclerosis	Rare	Absent	Lytic ± sclerotic
Bone scan	Often negative	—	—	Usually positive
Hyperviscosity	Uncommon	Common	Absent	—
Lymphadenopathy/HSM	Rare	Common	Absent	—

Other mimics: reactive plasmacytosis (infection, connective tissue disease — polyclonal), POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, M-protein, Skin changes — often sclerotic lesions), and chronic kidney disease anaemia.

High-yield: A polyclonal increase in gammaglobulins (broad-based) suggests reaction/infection/chronic liver disease, NOT a clonal dyscrasia. Only a narrow monoclonal spike counts.

Recently asked / exam angle

• Bence Jones protein classic image-based / heat-test question — precipitates at 40–60°C, dissolves on boiling.
• Rouleaux on peripheral smear with raised ESR → think paraproteinaemia/myeloma.
• "Punched-out lytic lesions in skull with negative bone scan" — pathognomonic stem for myeloma.
• M-protein isotype: IgG in myeloma vs IgM in Waldenström (very frequently paired).
• SLiM-CRAB criteria and the cut-offs (60% plasma cells, sFLC ratio ≥100, >1 MRI lesion).
• Prognostic marker → β2-microglobulin; adverse cytogenetics → del(17p).
• Bortezomib → peripheral neuropathy; thalidomide → teratogenicity & DVT.
• Congo red apple-green birefringence for associated AL amyloidosis; periorbital purpura, macroglossia.
• Inclusion bodies: Russell bodies (cytoplasmic), Dutcher bodies (intranuclear immunoglobulin), "flame cells", "Mott cells (grape cells)".
• MYD88 L265P mutation → Waldenström macroglobulinaemia.

Rapid revision

1. Commonest M-protein in myeloma = IgG; IgM = Waldenström.
2. Diagnostic triad: marrow plasmacytosis ≥10% + M-protein + CRAB/SLiM.
3. Bone lesions are purely lytic (RANKL↑, OPG↓, DKK-1↑) → bone scan negative, use skeletal survey/CT/MRI/PET.
4. Bence Jones protein = free light chains; detected by urine IFE, missed by routine dipstick.
5. Smear shows rouleaux; ESR markedly raised.
6. Best prognostic marker = β2-microglobulin; staging = R-ISS.
7. High-risk FISH = del(17p), t(4;14), t(14;16).
8. Renal failure mainly from light-chain cast nephropathy; commonest cause of death = infection.
9. Backbone therapy = bortezomib + lenalidomide + dexamethasone (VRd) ± daratumumab → autologous SCT if fit (melphalan conditioning).
10. Bone protection = bisphosphonates / denosumab; beware jaw osteonecrosis.
11. Hyperviscosity (Waldenström) → urgent plasmapheresis; bortezomib → peripheral neuropathy + zoster.
12. AL amyloid: Congo red → apple-green birefringence, macroglossia, periorbital purpura, restrictive cardiomyopathy.