Plasma Cell Disorders
Learning objectives
- LO 1Review how immunoglobulins are normally produced.
- LO 2Classify plasma cell neoplasms and tell the subtypes apart.
- LO 3Explain the M protein and how it is used for diagnosis.
- LO 4Describe multiple myeloma: definition, causes, imaging, morphology and markers, presentation, labs and cytogenetics, prognosis and treatment.
- LO 5Describe Waldenström macroglobulinemia: clinical and marrow findings, diagnostic tests, and how it differs from other lymphomas and plasma cell disorders.
MAPThe precursor ladder: size of the clone, then damage
LO 1Normal immunoglobulin production
Q1. How does a B cell become an Ig-secreting plasma cell?
- Naïve B cell meets antigen → germinal center with T follicular helper cells (CD4+, PD-1+)
- Proliferation, somatic hypermutation, class switching
- → memory B cell or long-lived plasma cell that homes to the marrow
- Plasma cell = terminally differentiated B cell: eccentric "clock-face" nucleus, blue cytoplasm, pale perinuclear hof (Golgi)
Plasma cells
- Eccentric nucleus, hof
Ig structure
- 2 heavy + 2 light chains
Q2. How is an immunoglobulin built?
- 2 identical heavy + 2 identical light chains; variable + constant regions
- Light chain = κ or λ, never both
- Each clone makes one heavy + one light chain for life, plus a slight excess of light chains (small amounts normally in urine)
| Heavy chain | Class | Form |
|---|---|---|
| γ | IgG | Monomer (most myelomas) |
| α | IgA | Dimer (can thicken blood) |
| μ | IgM | Pentamer → hyperviscosity (Waldenström) |
| δ, ε | IgD, IgE | Monomers (rare myelomas) |
Q3. What is the difference between polyclonal and monoclonal?
Polyclonal (normal / reactive)
- Thousands of clones → broad γ band
- Both κ and λ plasma cells (~2:1)
Monoclonal (neoplasm)
- One clone → one product (M protein) → tall narrow spike
- Light-chain restriction: far more κ than λ (or vice versa)
Reactive: κ
- κ cells present
Reactive: λ
- λ cells also present → polyclonal
Myeloma: κ
- Sheets of κ+ cells
Myeloma: λ
- λ negative → κ-restricted
In-house exam
Plasma cells with κ and λ = reactive (polyclonal). Mostly κ (or λ) = monoclonal → neoplasm.
Analogy — the choir
Normal immunity is thousands of voices (a broad hum). In myeloma one singer grabs the microphone: one loud note (M spike) while the rest go quiet (↓ normal Igs → infections).
LO 2Classifying plasma cell neoplasms
Q1. What does the WHO classification include?
| Category | Entities |
|---|---|
| Precursors | Non-IgM MGUS (→ myeloma or AL amyloid, ~1%/y) · IgM MGUS (→ Waldenström, ~1.5%/y) |
| Plasma cell myeloma | Multiple myeloma |
| Myeloma variants | Smoldering · non-secretory · plasma cell leukemia |
| Plasmacytoma | Solitary plasmacytoma of bone · extraosseous |
| Ig deposition diseases | Primary (AL) amyloidosis · light/heavy chain deposition disease |
| Paraneoplastic | POEMS · TEMPI · AESOP |
| B-cell lymphoma with plasma cell differentiation | Lymphoplasmacytic lymphoma (Waldenström) · heavy chain diseases |
Q2. How do MGUS, smoldering and active myeloma differ?
| MGUS | Smoldering | Multiple myeloma | |
|---|---|---|---|
| Serum M protein | <3 g/dL | ≥3 g/dL (or urine M >500 mg/24 h) | Any (usually high) |
| Clonal marrow PCs | <10% | 10–59% | ≥10% or plasmacytoma |
| CRAB / SLiM | None | None | ≥1 present |
| Course | ~1%/y (≈20% over 10–15 y) | Higher risk; ~10-y survival | Treat |
- MGUS: ~3% of adults over 50; most myelomas start here
- MGUS risk factors: abnormal FLC ratio, IgA or IgM type, M protein >1.5 g/dL (all 3 → 50–60% progression at 20 y; none → 5%)
Trap
Smoldering myeloma carries a higher progression risk than MGUS, not lower. And ≥10% clonal plasma cells alone isn't myeloma: WHO also needs a myeloma-defining event, otherwise it's smoldering.
Q3. What are the other plasma cell disorders?
| Disorder | Key features |
|---|---|
| Solitary plasmacytoma | One mass of clonal plasma cells, marrow normal, no CRAB. Bone (thoracic vertebra) → ~50% progress to myeloma; extraosseous (head/neck 90%) → ~15%. Treat with radiation |
| AL amyloidosis | Misfolded light chains (usually λ) deposit: nephrotic syndrome, restrictive cardiomyopathy, macroglossia, neuropathy, periorbital purpura; Congo red apple-green birefringence |
| POEMS | Polyneuropathy · Organomegaly · Endocrinopathy · M protein (usually λ) · Skin changes; ↑ VEGF; sclerotic bone lesions |
| Light-chain myeloma | ~20%: only light chains → no serum spike, Bence Jones proteinuria, worse kidneys |
| Non-secretory / plasma cell leukemia | Rare variants; PCL is aggressive |
In-house exam
Know POEMS: polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes.
Step 1
AL (light chain) vs AA amyloid: AA follows chronic inflammation and has no M protein. Both: Congo red, apple-green birefringence under polarized light.
ApplyLO 2 application questions
A1A 48-year-old has an IgG κ spike of 2.1 g/dL, 4% marrow plasma cells and normal calcium, creatinine, hemoglobin and bones. Diagnosis?
A2A new patient has 65% clonal marrow plasma cells but normal calcium, creatinine, hemoglobin and bones. Smoldering or active?
LO 3The M protein and how to find it
Q1. Which tests find and type the M protein?
| Test | What it does | Key point |
|---|---|---|
| Serum protein electrophoresis (SPEP) | Proteins separate: albumin, α1, α2, β, γ; a monoclonal protein runs to one spot → M spike | Screens + quantifies; use serum (no fibrinogen peak) |
| Immunofixation | Antisera to γ, α, μ, κ, λ | Types the spike (e.g., IgG κ) |
| 24-h urine electrophoresis | Detects free light chains = Bence Jones protein | Often only light chains in urine |
| Serum free light chains | Free κ and λ | Abnormal κ:λ = clonal; involved/uninvolved >100 = myeloma-defining |
Normal SPEP
- Albumin + small humps
M spike
- Albumin + narrow γ spike
In-house exam
Abnormal SPEP shows two peaks: albumin + the M spike.
Step 1 — workup order
SPEP (find) → immunofixation (type) → UPEP/FLC (light chains) → marrow biopsy (% clonal PCs, FISH) → skeletal imaging. Classic labs: ↑ total protein with normal/↓ albumin (protein gap), rouleaux, ↑ ESR, low anion gap.
Trap — no serum spike ≠ no myeloma
Light-chain myeloma (~20%) makes only light chains, which are filtered into urine: SPEP shows hypogammaglobulinemia. Urine dipstick detects albumin, not light chains; use UPEP or serum FLC.
LO 4Multiple myeloma
Q1. What is myeloma, who gets it and why?
- Marrow-based, multifocal neoplasm of clonal plasma cells with end-organ damage
- Median age 70; men; ~2× more common in Black patients; ~1% of cancers, 15% of heme cancers
- Risks: pesticides, asbestos, petroleum, radiation, chronic antigen stimulation
- Post-germinal center B → plasma cell; grows on IL-6 and IL-10 (high IL-6 = poor prognosis)
- M protein: IgG 55%, IgA 20%, light chain ~20%, IgD 2%, non-secretory 1%; κ > λ
Q2. Why do bones, blood and kidneys fail?
Memory tool — CRAB
Calcium ↑ · Renal failure · Anemia · Bone lesions (+ infection).
Trap — bone scan and ALP
Pure bone destruction with suppressed osteoblasts → bone scan negative, alkaline phosphatase usually normal. Use X-ray, CT, MRI or PET.
Q3. What does myeloma look like on imaging and in the marrow?
- X-ray: punched-out lytic lesions (skull, ribs, vertebrae) in ~80%; fractures
- Marrow: ≥10% clonal plasma cells in sheets/clusters; binucleate cells; Mott cells / Russell bodies; high N:C ratio = worse
- Blood: rouleaux (high Ig neutralizes RBC charge) and ↑ ESR
- Markers: CD38, CD138, cytoplasmic Ig; CD19, CD27, CD81 lost; CD56+; CD45 dim
Punched-out skull
- Lytic lesions, no sclerotic rim
Myeloma marrow
- Sheets of plasma cells
Rouleaux
- RBCs stacked like coins
Mott cell
- Cytoplasmic Ig globules (Russell bodies)
In-house exam
- Punched-out skull lesions → myeloma
- Myeloma cells: CD38, CD138, cytoplasmic Ig; no CD19, CD27, CD81
- Rouleaux = high Ig
- ≥10% clonal plasma cells (+ a defining event)
Q4. How does myeloma present?
- Bone pain, pathologic fractures (vertebra), cord compression
- Anemia, fatigue
- Recurrent infections (encapsulated bacteria)
- Hypercalcemia: confusion, weakness, constipation
- Renal failure: cast nephropathy (light chains + Tamm-Horsfall), hypercalcemia, amyloid
- Physical exam often normal
Step 1
Kidney biopsy with large fractured casts in distal tubules and giant cells → myeloma cast nephropathy. Heavy albuminuria in myeloma → think AL amyloid.
Q5. What are the diagnostic criteria, lab tests and cytogenetics?
WHO: clonal marrow PCs ≥10% (or biopsy-proven plasmacytoma) + ≥1 of:
CRAB
- Hypercalcemia
- Renal insufficiency
- Anemia
- ≥1 bone lesion (X-ray, CT, PET/CT)
SLiM
- Sixty: ≥60% clonal PCs
- Light chain ratio >100
- MRI: >1 focal lesion
| Risk | Abnormality | Partner |
|---|---|---|
| Favorable | Hyperdiploidy | Odd-numbered trisomies |
| Favorable | t(11;14), t(6;14) | Cyclin D1, D3 |
| Unfavorable | t(4;14), t(14;16), t(14;20) | FGFR3/MMSET, c-MAF, MAFB → cyclin D2 |
| Unfavorable | del(17p13) | TP53 |
| Unfavorable | del 13 / monosomy 13 (~50%); hypodiploidy; 1p del, 1q21 gain | — |
- Abnormalities seen in ~30% by karyotype but ~90% by FISH (plasma cells divide slowly)
- IGH (14q32) translocations 55–70%; KRAS/NRAS 30–40%
Memory tool
"SLiM CRAB": any of these = treat. Cyclin D1/D3 good, D2 bad; "4-16-20 are bad numbers."
In-house exam
Most common myeloma chromosome change: monosomy / partial deletion of 13.
Trap
t(11;14) is favorable in myeloma but defines mantle cell lymphoma.
Q6. What predicts outcome?
| ISS stage | Criteria | Median survival |
|---|---|---|
| I | β2-microglobulin <3.5 mg/L + albumin ≥3.5 g/dL | 62 mo |
| II | Neither I nor III | 44 mo |
| III | β2-microglobulin ≥5.5 mg/L | 29 mo |
- Poor prognosis: high stage, low Hb, high Ca, renal dysfunction, extensive lytic lesions, plasmablastic morphology, high-risk FISH, ↑ IL-6, circulating plasma cells, minimal residual disease
- Incurable; death from infection, renal failure
- MRD monitoring, least → most sensitive: morphology → flow → FISH → molecular (PCR/NGS)
Q7. How is myeloma treated?
| Class | Examples · mechanism |
|---|---|
| Traditional | Melphalan + prednisone (oral) |
| Proteasome inhibitors | Bortezomib: misfolded Ig piles up → ER stress, apoptosis; ↓ NF-κB. Neuropathy, zoster |
| IMiDs | Thalidomide, lenalidomide: anti-angiogenic, immune; teratogenic, VTE |
| Antibodies | Daratumumab (anti-CD38) · elotuzumab (anti-SLAMF7) |
| Bone | Bisphosphonates, denosumab (inhibit resorption) |
| Transplant | Autologous stem cell transplant after conditioning, usually younger/fit patients |
Step 1
Plasma cells make huge amounts of protein, so blocking the proteasome kills them first. Daratumumab can make myeloma cells look CD38-negative on flow.
ApplyLO 4 application questions
A1A 61-year-old man has 5 months of back pain, pneumococcal pneumonia, creatinine 3.7 and punched-out skull lesions. What will the marrow show?
A2A 70-year-old with back pain and creatinine 2.9 has no serum M spike. What's the likely diagnosis and test?
LO 5Waldenström macroglobulinemia
Q1. What are the clinical and pathologic features?
- Lymphoplasmacytic lymphoma + IgM M protein; median age 63, men; precursor = IgM MGUS; hepatitis C association
- B lymphocytes → plasmacytoid lymphocytes → plasma cells; MYD88 L265P (~90%; → NF-κB); CXCR4 predicts response
- Fatigue, weight loss; marrow failure (anemia, infection, bleeding); nodes, spleen
- Hyperviscosity (10–30%): blurred vision, "sausage-link" retinal veins, headache, stroke, mucosal bleeding, neuropathy
- Cryoglobulinemia (Raynaud), cold agglutinins; Bing-Neel (CNS)
- No lytic lesions, no hypercalcemia
High yield — why IgM thickens blood
IgM is a pentamer (~900 kDa) that stays in vessels → sludging, rouleaux, hyperviscosity. Treat urgently with plasmapheresis.
Q2. What does the marrow show?
- Mix of small lymphocytes, plasmacytoid lymphocytes and plasma cells
- Dutcher bodies (intranuclear Ig inclusions)
- Increased mast cells
Lymphoplasmacytic infiltrate
- Lymphocytes → plasma cells
Plasmacytoid cells
- Lymphocytes with plasma cell features
Mast cell
- ↑ in Waldenström marrow
In-house exam
Mast cells in a lymphoplasmacytic infiltrate → lymphoplasmacytic lymphoma. Dutcher bodies → Waldenström; Russell bodies → myeloma.
Q3. Which tests make the diagnosis?
- SPEP → IgM on immunofixation (usually κ)
- Marrow, nodes, blood: lymphoplasmacytic cells; CD19, CD20+, surface IgM; CD5−, CD10−
- MYD88 L265P testing
- Marked rouleaux, ↑ ESR; serum viscosity; keep samples warm (cryoglobulins)
IgM spike
- Typed by immunofixation
Q4. How is Waldenström different from myeloma and other lymphomas?
| Waldenström | Myeloma | |
|---|---|---|
| M protein | IgM | IgG > IgA, light chain |
| Cells | Lymphocytes → plasmacytoid → plasma cells | Pure plasma cells |
| Markers | CD20+, sIgM | CD38, CD138; CD19/20− |
| Bone | No lytic lesions, no hypercalcemia | Lytic lesions, hypercalcemia |
| Nodes / spleen | Yes | Unusual |
| Inclusions | Dutcher bodies, mast cells | Russell bodies / Mott cells |
| Mutation | MYD88 L265P | Not MYD88 |
| Both | M spike, anemia, rouleaux, possible hyperviscosity | |
- vs CLL (CD5/CD23+), mantle (CD5, cyclin D1), follicular (CD10)
- Course: indolent, median ~4–7 y; rarely → DLBCL; poor: age, cytopenias, neuropathy, weight loss
- Treatment: alkylators or steroids ± rituximab, BTK inhibitors; hyperviscosity → plasmapheresis
In-house exam
M spike with no lytic lesions or hypercalcemia → Waldenström, not myeloma.
Memory tool
Waldenström = "thick blood, no holes": IgM pentamer, CD20, Dutcher bodies, mast cells.
ApplyLO 5 application question
A1A 67-year-old man has blurred vision, nosebleeds, lymphadenopathy and sausage-link retinal veins; skeletal survey is normal. Diagnosis, mutation and urgent treatment?
IDImage ID
Image 1 — electrophoresis
Image 2 — X-ray
Image 3 — smear
Image 4 — cell
Image 5 — IHC
Image 6 — cell
MCQExam-style questions
1A marrow biopsy shows increased plasma cells; IHC shows both κ- and λ-positive cells in about a 2:1 ratio. Interpretation?
2A 69-year-old woman has back pain, a T10 compression fracture and multiple lytic lesions. Marrow aspirate shows plasma cells. Which lab finding is most likely?
3Which immunophenotype fits myeloma cells?
4A 66-year-old has an IgG spike of 3.8 g/dL and 22% marrow plasma cells; calcium, creatinine, hemoglobin and MRI are normal; FLC ratio is 20. Diagnosis?
5Which mediator from marrow stroma drives osteoclast activation and lytic lesions in myeloma?
6A patient with confusion, constipation and calcium of 13.8 mg/dL has rouleaux on the smear. Most likely underlying disease?
7Which is the most common cytogenetic abnormality in myeloma?
8Two myeloma patients have FISH results: A has t(11;14); B has t(4;14) and del(17p). Which statement is correct?
9A patient has polyneuropathy, hepatosplenomegaly, hypothyroidism, a λ M protein and skin hyperpigmentation. Diagnosis?
10A myeloma patient develops heavy albuminuria, macroglossia and a stiff, restrictive heart. Biopsy will show:
11A 67-year-old has blurred vision, epistaxis, lymphadenopathy, an IgM spike and a normal skeletal survey. Which finding is expected in the marrow?
12Which mutation is found in ~90% of Waldenström but not in myeloma?
13Bortezomib kills myeloma cells mainly by:
!Source notes
| Item | Lecture | Step 1 / standard references |
|---|---|---|
| Marrow PC threshold | ">10%" | WHO: ≥10% |
| Hypercalcemia at diagnosis | ~10% | ~25–30% |
| ISS albumin unit | "3.5 mg/L" | 3.5 g/dL |
| Myeloma median survival | ~3 years | ~6–10 years with modern therapy |
| Waldenström median survival | 4–7 years | ~8–10+ years |
| Hyperviscosity threshold | IgM >3 g/dL | Usually >4 g/dL |
| MRD sensitivity order | FISH above flow | Flow more sensitive than FISH; NGS most sensitive |
| Transplant age | <65 | Based on fitness (up to ~70–75) |
| Inclusions | Intranuclear and cytoplasmic Ig grouped as "Mott cell" | Mott/Russell = cytoplasmic (myeloma); Dutcher = intranuclear (Waldenström) |
| MGUS vs smoldering risk | One note says MGUS progresses more | Smoldering carries the higher risk |