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al-amyloidosis

README.md

AL (Immunoglobulin Light Chain) Amyloidosis — QSP Model

Mechanistic Map

Disease Overview

AL amyloidosis (immunoglobulin light chain amyloidosis) is a systemic disease caused by a clonal plasma cell dyscrasia in which misfolded monoclonal free light chains (FLC) polymerize into amyloid fibrils and deposit in organs—primarily the heart, kidneys, liver, and peripheral nerves—causing progressive multi-organ failure.

Feature Details
Incidence ~10 per million/year (~4,000 new US cases/year)
Median Age at Diagnosis ~63 years
Light Chain Type λ (lambda) more common than κ (kappa) in AL
Most Affected Organs Heart (>75%), Kidney (>50%), Liver (~20%), Nerves (~15%)
Most Common Cause of Death Cardiac arrhythmia / sudden cardiac death
Key Prognostic Factor Mayo 2012 Stage (NT-proBNP + hs-TnT + dFLC + eGFR)

Mechanistic Map Clusters

Cluster Description
① Plasma Cell Biology HSC → MGUS → SMM → clonal PC expansion, CD38 expression
② Light Chain Production Monoclonal FLC (λ/κ), dFLC, misfolding, UPR, oligomers
③ Amyloid Fibril Formation Nucleation, elongation, seeding (autocatalytic), SAP/GAG binding
④ Cardiac Amyloidosis LV thickening, diastolic dysfunction, NT-proBNP, hs-TnT, NYHA HF
⑤ Renal Amyloidosis Glomerular amyloid, proteinuria, eGFR decline, nephrotic syndrome
⑥ Hepatic & Neuropathic Hepatomegaly, ALP, autonomic/peripheral neuropathy, macroglossia
⑦ BM Microenvironment Stromal IL-6, APRIL/BAFF, NF-κB, IRF4/BLIMP-1, MCL-1
⑧ Daratumumab PK TMDD 2-CMT model, CD38 receptor dynamics, Q1W→Q2W→Q4W schedule
⑨ CyBorD PK Bortezomib 1-CMT + proteasome binding; CY active metabolite; DEX
⑩ Pharmacodynamics ADCC/CDC/ADCP, PC killing, hematologic + organ response
⑪ Staging & Biomarkers Mayo 2012 (4-stage), RF thresholds, ECOG PS
⑫ Immune Effectors NK cells, CD8 T cells, Treg, PD-1/PD-L1, NK fratricide by Dara
⑬ Clinical Endpoints OS, EFS, PFS, TTR, cardiac death, QoL, hospitalization
⑭ Safety Monitor IRR, cytopenias, neuropathy, DVT/PE, hyperglycemia, REMS

Drug Summary

Drug Class Target Key Dose
Daratumumab Anti-CD38 mAb CD38 on PCs 16 mg/kg IV QW×8→Q2W×16→Q4W
Bortezomib Proteasome inhibitor 20S proteasome 1.3 mg/m² SC D1,8,15,22
Cyclophosphamide Alkylating agent DNA (via 4-OH-CY) 300 mg/m² PO D1,8,15,22
Dexamethasone Glucocorticoid GR-mediated apoptosis 20-40 mg PO D1,8,15,22
Melphalan Alkylating agent DNA cross-linking 0.15-0.25 mg/kg PO D1-4 (maintenance)

Model Specifications

mrgsolve ODE Model (al_mrgsolve_model.R)

  • 20 ODE compartments across 2 modules:
    • PK (12 compartments): Daratumumab C1, C2, RC (TMDD complex), CD38 receptor; BTZ plasma + proteasome complex; CY gut depot + active metabolite; DEX gut depot + plasma; MEL gut + plasma
    • Disease PD (8 compartments): Plasma cell pool, dFLC, cardiac amyloid, renal amyloid, NT-proBNP, hs-TnT, eGFR, NK cells
  • 7 treatment scenarios:
    1. Untreated (natural history)
    2. Daratumumab monotherapy
    3. CyBorD (3-drug)
    4. Dara-CyBorD (ANDROMEDA regimen)
    5. VCD (bortezomib + CY + high-dose DEX)
    6. Melphalan + Dexamethasone (MDex)
    7. Dara-CyBorD in CYP2C19 poor metabolizer

Shiny App (al_shiny_app.R)

8 interactive tabs:

  1. Patient Profile — Mayo 2012 staging, disease overview, drug mechanisms
  2. PK Profiles — Daratumumab (TMDD), bortezomib-proteasome complex, CY, DEX
  3. Hematologic PD — Plasma cell pool, dFLC, NK cells, response classification
  4. Organ Biomarkers — NT-proBNP, hs-TnT, eGFR, 24h proteinuria
  5. Clinical Endpoints — Cardiac/renal amyloid burden, organ response flags
  6. Scenario Comparison — Multi-arm dFLC/NT-proBNP/eGFR comparison + Day 180 table
  7. Biomarker Staging — Mayo 2012 stage evolution, risk factor status gauges
  8. Safety Monitor — IRR, NK depletion, DDI table, REMS schedule

References (al_references.md)

50 references across 10 sections: Landmark Trials · Pathophysiology · Cardiac Amyloidosis · Biomarkers/Staging · Daratumumab PK/PD · Bortezomib · Renal Amyloidosis · QSP Modeling · Guidelines · Drug Combination

Calibration

Clinical Trial Regimen CR Rate Cardiac Organ Response Reference
ANDROMEDA Dara+CyBorD 53.3% ~42% NEJM 2021
ANDROMEDA CyBorD alone 18.1% ~22% NEJM 2021
MDex Melphalan+Dex ~33% ~26% Blood 2004
CyBorD Bortezomib+CY+DEX ~29% ~18% Blood 2012

Response Criteria

Category Hematologic Cardiac Organ Renal Organ
Response dFLC ≥50% reduction NT-proBNP ≥30% + ≥300 pg/mL reduction Proteinuria ≥30% reduction
VGPR dFLC <40 mg/L or >90% reduction — —
CR dFLC <40 mg/L — —
sCR CR + normal FLC ratio + negative BMPC — —

How to Run

# Run mrgsolve model
source("al_mrgsolve_model.R")

# Launch Shiny app
shiny::runApp("al_shiny_app.R")

# Render mechanistic map
# dot -Tsvg al_qsp_model.dot -o al_qsp_model.svg
# dot -Tpng -Gdpi=150 -Gsplines=line al_qsp_model.dot -o al_qsp_model.png

Files

File Description
al_qsp_model.dot Graphviz mechanistic map source (14 clusters, 100+ nodes)
al_qsp_model.svg Vector mechanistic map (scalable)
al_qsp_model.png Raster mechanistic map (150 dpi)
al_mrgsolve_model.R mrgsolve ODE model (20 compartments, 7 scenarios)
al_shiny_app.R Interactive Shiny dashboard (8 tabs)
al_references.md 50 PubMed-linked references (10 sections)