Paraproteinaemias. Multiple myeloma. Amyloidosis. Part 2 Dr Paraproteinaemias. Multiple myeloma. Amyloidosis. Part 2 Dr. Gábor Mikala

Waldenström Macroglobulinemia Uncontrolled proliferation of lymphoplasmacytes producing IgM Median age 63 years Presents with weakness, fatigue, epistaxis, blurred vision Bone pain and lytic bone lesions are uncommon (<5%) 25% have hepatomegaly, splenomegaly and lymphadenopathy Hyperviscosity is common

Mayo Clin Proc, Sept 2010

Hyperviscosity syndrome bleeding (nasal and gums) blurred vision dizziness, headaches, ataxia congestive heart failure retinal vein engorgement, and papilledema rarely occurs with serum viscosity <4 centipoises (cp) (normal 1.8 cp) IgM pentamer

Macroglobulinemia: Principles of Therapy Observation in patients with asymptomatic disease. Active drugs for therapy Alkylating agents: Chlorambucil, Cytoxan MAbs: Rituximab Purine analogues: Fludarabine, Cladribine BCR inhibitors (ibrutinib) Bendamustine Steroids Bortezomib Thalidomide analogues

Plasma Cell Disorders Manifest Due to Clonal Immunoglobulin AL Amyloid Light chain deposition dz Neuropathy Cryoglobulinemia Acquired vWD

What is amyloid (amylin : starch-like)? Def : Homogeneous, Pink, extracellular , pathologic material.

Nature of Amyloid Physical Nature : non branching protein fibrils 7.5 -10 nm in diameter. Beta pleated sheet. Chemical nature : 95% Protein Fibril

Primary systemic amyloidosis Disease name Type of amyloid in the tissue Precursor Multiple Myeloma AL Ig lambda (or kappa chains)

Secondary systemic amyloidosis Disease name Type of amyloid in the tissue Chronic inflammatory disease. AA Hemodialysis associated amyloidosis in chronic renal failure. A-beta 2 micro globulin. (Aβ2- micro globulin) Rheumatoid arthritis

Special stain and amyloid Lugol’s iodine : Brown in gross specimen of heart.

Special stain and amyloid Congo red ( normal light) Brick red Congo red ( polarized light) Apple green birefringence

Amyloidosis of kidney ; amyloid deposit in the mesangium of the glomerular tuft

Amyloid in heart : name the stain and viewing light

Clinical manifestation Kidney Nephrotic syndrome, protenuria, renal failure Tongue , GIT Macroglossia, malabsorpton Heart Cardiomegaly, heart failure Bone marrow involvement in Multiple Myeloma. Fracture/ Multiple myeloma

Clinical Settings Where Ig Deposition Diseases (Including AL Amyloid) Should Be Suspected In Pts With Monoclonal Ig Congestive Heart Failure Neuropathy (including autonomic neuropathy) Nephrotic syndrome, Renal Failure Malabsorption Hepatosplenomegaly Carpal tunnel syndrome – especiall if bilateral Macroglossia Unexplained constitutional symptoms „Racoon-eye” palpebral suffusions

Diagnostic Approach in Suspected AL Amyloid

Principles of Management in AL Amyloid Therapeutic approach guided by age, organ involvement. Cardiac involvement and dysfunction as a major predictor. Therapy directed at the underlying clonal plasma cells. Melphalan Steroids Proteasome Inhibitors (bortezomib) Thalidomide/lenalidomide Experimental therapy directed at the amyloid

Conclusion Plasma cell dyscrasias are a heterogeneous group of disorders. Clinical presentation may be due to the clone itself or the properties of the secreted Ig. Therapy largely directed (if indicated) at reducing the underlying clone.