49 AL Amyloidosis, Waldenstrom Macroglobulinemia & POEMS
Key Points
- AL amyloidosis: misfolded Ig light chains → fibrils → organ deposition; cardiac severity drives prognosis
- WM: IgM + ≥10% LPL in BM; MYD88 L265P (>90%); BTK inhibitors transformative 1st-line
- POEMS: polyneuropathy + M-protein + organomegaly/endocrine/skin + ↑ VEGF; chemo ± ASCT primary tx
49.1 AL Amyloidosis (Light Chain Amyloidosis)
49.1.1 Epidemiology & Pathophysiology
- Incidence: ~8-10/M/yr; median age 60 yrs; ~7% initially misdiagnosed
- Mechanism: clonal PCs → monoclonal light chain (κ/λ) misfolds → β-pleated sheet fibrils → organ dysfunction
- Plasma cell burden often <5% BM; ~80% have monoclonal serum/urine protein
- ~20% pts w/ <5% PCs; clonal restriction on flow cytometry essential
49.1.2 Clinical Presentation
Organ involvement (Table 49-1):
| Organ | Frequency | Presentations |
|---|---|---|
| Heart | 70-80% | DOE, edema, syncope, arrhythmia, cardiac dysfunction |
| Kidneys | 50-65% | Proteinuria, nephrotic syndrome, renal failure |
| Liver | 15-20% | Hepatomegaly, ↑ ALP, hyperbilirubinemia |
| GI tract | 10% | Diarrhea, malabsorption, GI bleed, weight loss |
| PNS | 10-20% | Distal sensory neuropathy, paresthesia, orthostasis |
| Soft tissues | 10-20% | Macroglossia, periorbital bruising, CTS, arthralgia |
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- 10% present w/ nonocardiac organ involvement; cardiac can be silent
- Common triad: DOE + nephrotic proteinuria + weight loss
49.1.3 Diagnosis & Staging
Diagnostic approach:
- Tissue confirmation: biopsy (BM, abd fat, kidney) → Congo red → apple-green birefringence
- Subtyping: mass spectrometry (>98% sens/spec); gold standard
- Monoclonal protein ID: SPEP/UIEP ± serum free light-chain (FLC) assay
- Organ assessment: NT-proBNP/BNP, troponin, Cr; urinalysis; EMG for PN
Staging systems (Table 49-2):
| System | Criteria | Prognosis |
|---|---|---|
| Mayo 2012 | Troponin ≥0.025 ng/mL; NT-proBNP ≥1800 pg/mL; dFLC ≥180 mg/L | Stage I-III; HR 4.1-15.5 |
| European 2013 | NT-proBNP ≥8500 pg/mL; Troponin ≥0.035 μg/L | Stage I-IIIb; HR 4.9-16.8 |
| BU 2019 | Troponin >0.1 ng/mL; BNP >81 & >700 pg/mL | OS: >12yr to <3yr |
| Renal | eGFR <30; UPE >5g/24h | 2yr dialysis risk 0-35% to 66-75% |
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49.1.4 Treatment Approaches
Response assessment (Table 49-3):
| Response | Definition |
|---|---|
| Complete | No M-protein by IFE; dFLC ≤40 mg/L |
| VGPR | dFLC <40 mg/L |
| Partial | dFLC reduction ≥50% |
| Organ response | Cardiac: ↓ NT-proBNP ≤30% w/o ↑ troponin ≤20%; Renal: ↓ proteinuria ≤50% or ↓ Cr ≤25% |
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Initial treatment:
- Proteasome inhibitors (PI) + immunomodulatory (IMiD)
- Bortezomib-based standard (bortezomib, lenalidomide ± dex)
- CyBorD (cyclophosphamide + bortezomib + dex): alternative; median OS 4.9 yr
- Ixazomib + lenalidomide + dex (IRd): oral preferred; ↑ ORR
- ORR 60-80%; median hematologic response 4-6 mo; organ response 18 mo
- ASCT (autologous stem cell transplant)
- Eligibility: <70 yrs, NYHA II, adequate PS
- Improves 8-yr OS; median OS >8 yr
- Consider early evaluation for eligible pts
- Daratumumab (anti-CD38) ± combinations
- Monotherapy: ORR ~42%; newly diagnosed
- Combo regimens (PI + IMiD ± dara): ORR 50-80%; response 6 mo (hematologic), 18 mo (organ)
- Relapsed AL: repeat bortezomib or lenalidomide-based if initial good response; alternatives for refractory
49.2 Waldenstrom Macroglobulinemia
49.2.1 Epidemiology & Pathophysiology
- Incidence: ~3/M/yr; median age 73 yrs; male 2-3:1
- MYD88 L265P present in ~90%; CXCR4 mutations (~50%) → aggressive phenotype
- Etiology: infections, pesticide exposure; genetic predisposition; autoimmune (~20%)
- Pathology: lymphoplasmacytic lymphoma; post-germinal center IgM
49.2.2 Clinical Presentation
- Hyperviscosity: flame hemorrhages, papilledema, neuro impairment (vision, HA)
- Cytopenias: anemia, thrombocytopenia; ↑ infection risk
- Bleeding: epistaxis, mucosal, GI; rare hemolytic anemia
- Systemic: fever, night sweats, fatigue, weight loss
- Lymphadenopathy: splenomegaly, hepatomegaly (less common)
- Diagnosis: serum/urine IgM (>10 g/dL → hyperviscosity risk) + clonal LPL on biopsy
- Immunophenotype: IgM+, CD5+/−, CD10−, CD19+, CD23+/−, FMC7+
- MYD88 mutation: valuable differentiating tool
- Most common: symptomatic hyperviscosity ± constitutional symptoms
49.2.3 Treatment Approaches
Treatment indications (initiate when: symptomatic; asymptomatic → observe):
- Hyperviscosity: urgent plasmapheresis for rapid removal; prevent hemorrhagic complications
- Symptomatic disease: goal = symptom control, prevent organ damage, QOL
- Refractory disease: platelet transfusion w/ caution
- Intensity: dictated by severity, symptoms, preference, comorbidities
- Modality: rituximab & bortezomib-based standard; oral preferred; maintenance possible
- Rituximab: monitor for transient ↑ IgM (“IgM flare”); dex may mitigate
Response criteria: CR, PR, VGPR, SD, PD
| Agent | Mechanism | Efficacy | Notes |
|---|---|---|---|
| Rituximab | Anti-CD20 | ORR 50-80% | IgM flare possible |
| BTK inhibitors | Block Bruton kinase → ↓ B-cell | ORR ~90% (ibrutinib ~96%) | AFib, bleeding risk; long-term tx |
| Bortezomib-based | Proteasome inhibition | ORR 75-90% w/ combo | Peripheral neuropathy; median TTP ~24 mo |
| Ixazomib + lenalidomide + dex | Oral PI + IMiD + corticosteroid | ORR ~95% | Oral route preferred |
| Bendamustine ± rituximab | Combination | High ORR | Early-stage preferred; cumulative neuropathy |
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BTK inhibitors (ibrutinib, acalabrutinib):
- Ibrutinib: ORR ~96%; median PFS >5-6 yr; maximal efficacy at 6 mo
- Acalabrutinib: ↑ selectivity; ↓ AFib vs ibrutinib; median time to next tx ~24 mo
- Side effects: bleeding (↓ platelet agg), AFib, infections; transient ↑ IgM post-initiation
- Survival advantage vs standard tx unclear but sustained responses
Frontline approach: BTK inhibitors emerging as transformative option w/ sustained responses
49.3 POEMS Syndrome
49.3.1 Definition & Epidemiology
POEMS = polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (= Takatsuki/Crow-Fukase syndrome)
- Incidence: rare; 1-2% of chronic PN; median age ~45-50 yr; male 2-3:1
- Recognition: dx rate ↑ w/ awareness & multidisciplinary evaluation
49.3.2 Diagnostic Criteria
Mandatory: Progressive, symmetric, predominantly distal sensory-motor neuropathy + monoclonal PC disorder (M-protein in serum/BM/biopsy)
Major (≥1 required):
- Castleman disease: histopathologic evidence on biopsy
- Sclerotic bone lesions: osteosclerosis ± mixed lytic/sclerotic on plain films; ↑ ALP
- ↑ VEGF: >3x ULN
Minor (≥1 required):
- Organomegaly: hepatomegaly, splenomegaly, lymphadenopathy on imaging
- Endocrinopathy: hypothyroidism, adrenal insufficiency, hypogonadism, DM, thyroid abnormalities
- Skin changes: hyperpigmentation, hypertrichosis, sclerotic changes, hemangiomas
- Edema: peripheral edema from capillary leak, ascites
| Criteria | Details |
|---|---|
| Mandatory | (1) Polyneuropathy: progressive, symmetric, distal sensory-motor; (2) Monoclonal PC disorder |
| Major (≥1) | (1) Castleman disease biopsy; (2) Sclerotic/mixed bone lesions; (3) ↑ VEGF >3x ULN |
| Minor (≥1) | (1) Organomegaly on imaging; (2) Endocrinopathy; (3) Skin changes; (4) Edema |
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49.3.3 Treatment
Initial tx (1-3 isolated bone lesions, no BM involvement):
- High-dose chemo ± ASCT: primary modality
- Response: hematologic, VEGF ↓, FDG-PET response, clinical (PN, anasarca improvement)
- Drugs: bortezomib, lenalidomide, melphalan, thalidomide
- Estimated OS ~67%, event-free survival ~76%
- Median follow-up 45 mo: 5-yr OS ~74%, PFS ~75%
- Systemic chemo for polyneuropathy progression
- PN improvement lags other symptoms (years for full resolution)
- Organomegaly, papilledema, skin changes respond faster
- Sclerotic lesions, dFLC, VEGF levels improve
- Daratumumab: monotherapy or w/ lenalidomide/thalidomide/dex; case series show promise
49.4 Clinical Pearls
AL amyloidosis: cardiac severity drives prognosis & urgency; early ASCT evaluation recommended; PI-based standard; hematologic ≠ organ response (distinct time courses)
WM: BTK inhibitors transformative 1st-line w/ sustained responses; MYD88 L265P >90%; IgM flare w/ rituximab doesn’t require interruption; asymptomatic → observe
POEMS: high suspicion + multidisciplinary evaluation essential; mandatory + major criteria critical; chemo ± ASCT primary; early tx improves long-term outcomes