Table of contents
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Multiple Myeloma Syndromes
- Proliferation of monoclonal plasma cells leading to a range of symptoms.
- Monoclonal Gammopathy of Undetermined Significance (MGUS)
- Asymptomatic condition manifested ONLY by a laboratory abnoramlity.
- However, patients with MGUS can and will go on to get MM.
- AL Amyloidosis
- Precipitated proteins cause end-organ dysfunction.
- Plasma Cells Malignancies
- Multiple Myeloma
- Walderstroms Macroglobulinemia.
- Monoclonal Gammopathy of Undetermined Significance (MGUS)
Plasma Cell Malignancies
Multiple Myeloma
- Malignancy of plasma cells involving bone and bone marrow.
- Mean age of dx: 70 (Backs >> Whites).
- Monoclonal M protein (intact or part of IgG), or light chains
- Typically a heavy chain and Kappa or Lambda light chain. (light chains freely cleared by kidney)
- 16% there are only free light chains. (rarely no immunoglobulin).
- Symptomatic myeloma is different from asymptomatic. (treatment is different).
- Symptoms:
- 58% have bone pain due to lytic lesions.
- Motor weakness (para-protein affecting nerve/muscle)
- Neurologic Dysfunction - spinal cord compression (bladder, weakness etc..) EMERGENCY!
- Retropulsed bone fragments from vertebral body compression or plasmacytoma directly.
- Peripheral Neuropathy - rare, but can occur with myeloma or amyloidosis.
- Pulmonary infection is common (do not make antibodies).
- Cytopenia
- Anemia (70%).
- Leukopenia (20%)
- Thrombocytopenia (5%)
- Compilcations:
- Hypercalcemia (30%)
- Renal Dysfunction (50%)
- -- Cast nephropathy (filtered monoclonal free light chains cause obstructions and intra-tubular precipitation.
- Plasmapheresis considered for light-chain disease, but unclear if help. (reduces light chains by 50%).
- Hypercalcemia (IV fluids and bisphosphonate).
- Kidney disease can be precipitated by CT contrast dye, NSAIDs, and loop diuretics.
- -- Cast nephropathy (filtered monoclonal free light chains cause obstructions and intra-tubular precipitation.
- Diagnostic Tests:
- Blood film: Rulleoux -- Means high protein level, also see with liver disease etc..
- M-Protein Detection:
- Urine light chains (regular dip does not detect light chain protein)
- uPEP - electropheresis and immunofixation.
- Can do urine free light chains, but not as good. 24hr urine is higher sensitivity.
- sPEP - run on gel and look for monoclonal fraction (when immunofix using gel impregnated to various Ig's, and can identify M-protein in almost all of patients).
- sPEP + uPEP can identify M-protein in 97% of pts (3% have non-secretory MM, can detect serum free light chain testing).
- Can monitor M-protein for treatment response
- Bone Involvement:
- Skeletal Survey - plain films of skull, long bones for lytic lesions.
- Bone Scan - Can detect increased osteoblastic activity (most bone metastasis), and only positive in 10% of people. In MM lesions are almost purely osteolytic, order skeletal survey instead!
- DIAGNOSIS
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Diagnosis of Symptomatic Myleoma: (All 3 of:)
- Symptomatic + ≥10% clonal plasma cells on a BM biopsy. (can have up to 8% routinely)
- OR biopsy of tissue with monoclonal plasma cells
- Presence of a clonal M-protein.
- Evidence of myeloma-related end organ damage.
- CRAB mnemonic
- C- HyperCalcemia
- R- Renal insufficiency
- A- Anemia (<100)
- B- Bony lesions (lytic or osteoporisis with compression fracture)
- (MGUS vs. Myeloma: can also use M-protein ≥ 3g/dL for myeloma)
- Symptomatic + ≥10% clonal plasma cells on a BM biopsy. (can have up to 8% routinely)
- Look for end-organ damage.
- Prognostic Features:
- Serum Beta-2-microglobulin Level - activity/response of disease in MM pts. (HLA-type protein antigen)
- Stage 1: <3.5 (Median survival 62mo)
- Stage 3: >5.5 (Median survival 29mo)
- Serum Beta-2-microglobulin Level - activity/response of disease in MM pts. (HLA-type protein antigen)
- Treatment:
- Core therapies:
- Immuno-modulatory drugs: Thalidomide and Lenalidomide.
- Proteosomal Inhibitor: Bortezomib
- Alkylating Agent: Melphalan (DO NOT USE if candidate for autologous HSCT)
- First: Decide if patient is a candidate for autologous hematopoietic stem cell transplant (HSCT)?
- If not a candidate (i.e. old or has ++ comorbidities)
- Melphalan + Prednisone (+/- Thalidomide or Bortezomib)
- If HSCT candidate:
- Bortezomib + Dexamethasone (+/- Thalidomide or Lenalidomide)
- Conditioning therapy: Melphalan (high dose) after harvesting stem cells.
- If not a candidate (i.e. old or has ++ comorbidities)
- Maintenance: Thalidomide +/- steroids. (improves disease free survival after HSCT, unclear if helps survival)
- Relapse: Lenalidomide or Bortezomib.
- Lytic bone disease is a big issue:
- Give bisphosphonates (Pamidronate or Zolendronic acid are ones studied - monthly), can start immediately after diagnosis. Careful with osteonecrosis of jaw (esp if poor dentition, recent dental work. etc..)
- Surgery for unstable fractures (i.e. >50% of shaft diameter).
- Radiation can help palliate bone disease.
- Vaccinate! for encapsulated organisms (Pneumococcus, Flu)
- Core therapies:
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Asymptomatic Myeloma
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Risk of progressing is 73% at 15y. (median time 5years)
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Asymptomatic Myeloma
- One of:
- M-protein level ≥3g/dL (convert!) (<3g/dL = MGUS)
OR - by ≥10% plasma cells on bone marrow exam.
- M-protein level ≥3g/dL (convert!) (<3g/dL = MGUS)
- AND Absence of Myeloma-related end-organ damage.
- One of:
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Can also follow kappa:lambda light chain ratio (measure of light chain prouction by myeloma)
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Predictive of disease progression. normally kappa = lambda.
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Monoclonal Gammopathy of Undetermined Significance (MGUS)
- Typically found incidentally on protein electrophoresis.
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MGUS Definition:
- M-protein level of <3g/dL (more is indicative of myeloma)
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Bone Marrow Biopsy: <10% plasma cells
- No evidence of kidney failure, anemia, bone disease or any other organ damage
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Does not require treatment. (does require workup)
- Incidental M-Protein workup:
- CBC, Calcium, Alb, Creatinine, Urinalysis, sPEP, uPEP + immunofixation, 24hr urine collection,
- quantitative IgG, IgM, IgA, serum free light chain, skeletal survey.
- Bone Marrow biopsy if:
- Findings suspicious for plasma cell dyscrasia requiring tx.
- Non-IgG M-protein
- M-protein level of ≥1.5 g/dL
- Abnormal serum free light chain ratio.
- By age 85 about 7.5% have MGUS (M>F, black>white)
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1%/year progression (lower than asymptomatic myeloma).
- Follow-up: (varies)
- CBC, Caclcium, Creat, sPEP/uPEP + immunofixation, serum free light chains.
- Follow-up generally q6-12mo frequency based on risk. (many RF's)
- MGUS Osteoporosis --> get bone mineral density from time to time.
POEMS Syndrome (Variant of MM)
- Characterized by osteosclerotic myeloma.
- "Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Protein, Skin changes.
- Less aggressive, can be treated with rads if osteosclerotic lesions.
Waldenstrom's Macroglobulinemia.
- It is a Lymphoplasmacytic Lymphoma (unlike MM that is a plasma cell malignancy)
- Characterized by monoclonal IgM antibodies (IgM pentamers = macroglobulin)
- Mean age = 64, M>F, Whites.
- Symptoms:
- Constitutional Symptoms + Lymphadenopathy + Hepatosplenomegaly
- Hyperviscocity syndrome (30%)
- Headaches, blurred vision, dizzy, tinnitus, deafness, mental status changes.
- Fundoscopic: Dilated tortuous retinal veins + retinal hemorrhage.
- Neuro: Peripheral Sensory/Motor Neuropathy (common) (anti-myelin glycoprotein antibody)
- Platelet Dysfunction (mucosal bleeding)
- Cold Agglutinin Disease, Cryoglobulinemia.
- Kidney Disease: Glomerulonephritis
- Labs:
- Serum viscocity is elevated.
- Anemia with rouleaux seen on film (high protein). High level of the IgM M-protein.
- Diagnosis:
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Diagnosis
Symptomatic Waldenstrom's Macroglobulinemia
- 1. Bone Marrow: Lymphoplasmacytic Lymphoma comprising ≥10% of bone marrow.
- 2. High level of IgM M-protein.
- 2. Symptomatic WM
Asymptomatic Waldenstrom's Macroglobulinemia
- 1. Bone Marrow: Lymphoplasmacytic Lymphoma ≥10% of BM.
- 2. High leve of IgM M-protein
- 3. Asymptomatic (no organ dysfunction)
IgM MGUS
- Bone Marrow: Lymphoplasmacytic Lymphoma comprising <10%
- Usually IgM M-protein of <3 g/dL
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- Difference between Waldenstrom's and MM is cell of origin
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- Malignant plasma cell (MM) vs. plasmacytic lymphoma type cell (WM).
- NOTE: IgM myeloma is different.
- Generally low grade lymphoma, make a lot of IgM (pentameric) --> leads to hyperviscocity.
- Decreased blood flow to brain, eye.
- Treatment:
(similar principles as MM, but different drugs.)- Only for symptomatic WM. (asymptomatic don't benefit, just watch closely).
- Hyperviscocity Syndrome:
- Emergency treatment with plasmapheresis.
- Medications:
- Rituximab (Monoclonal Anti-CD20 antibody)
- CD20 found in B-cells, destroys B-cells. Very well tolerated.
- +/- Cytotoxic Chemotherapy: Chlorambucil, cyclophosphamide, fludarabine, etc.. even some myeloma drugs.
- Rituximab (Monoclonal Anti-CD20 antibody)
AL Amyloid
- Tissue deposition of protein fibriles of a beta-pleated sheet configuration --> subsequent end-organ damage.
- In AL Amyloidosis, that protein is light chains. (most common) + other congenital forms.
- Monoclonal light chains more often lambda than kappa.
- Overt myeloma is found in 10% of patients.
- Presentation - organ involvement:
- Kidney: Nephrotic Range Proteinuria + worsening kidney injury.
- Heart: Restrictive cardiomyopathy (cardiomyocyte disfunction)
- Liver: Hepatomegaly.
- Nervous System: Neuropathy - symmetric distal sensory motor neuropathy, carpal tunnel syndrome, autonomic neuropathy (orthostatic hypotension).
- Dermatological: Peri-orbital purpura (easy bruising) and macroglossia.
- GI Tract: Malabsorption/dysmotility
- MSK: Muscle/joints
- Heme: Hemophilia (easy bruising/bleeding): amyloid protein absorbs Factor X, peri-orbital purpura, classically rub clavicles for easy bruising. [Acquired Factor X deficiency]
- Diagnosis:
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Diagnosis of AL Amyloid:
- 1. Tissue biopsy (any tissue that can be involved).
- Typically highest yield is subcutaneous abdominal fat pad biopsy.
- Abdominal fat pad biopsy or BM aspirate 80% sensitive.
- If negative, can biopsy any involved tissue.
- On biopsy see amorphous eosinophilic material that demonstrates apple-green biofiringence when stained with congo red dye under polarized light.
- Other tests:
- Immunoflurescence, or immunohistochemistry, or direct protein sequencing can confirm deposit is composed of clonal light chains.
- Other tests:
- Typically highest yield is subcutaneous abdominal fat pad biopsy.
- 2. Demonstrate a monoclonal plasma cell process:
- sPEP, uPEP, and immunofixation, serum free light chains, and BM biopsy
- (All required to establish a clonal plasma cell process.)
- 3. Evidence that amyloid deposides are composed of clonal light chains.
- 1. Tissue biopsy (any tissue that can be involved).
- After diagnosis, MUST assess cardiac function:
- ECG
- Trans-thoracic Echo:
- Intraventricular septal hypertrophy, restrictive physiology, and perhaps sparkling changes in myocardium (amyloidosis).
- If involved, poor prognosis.
- Check markers: NT-pro-BNP and troponin T used for prognosis)
- Elevation of none: 26.4mo
- Elevation of one: 10.5mo
- Elevation of two: 3.5mo
- Check markers: NT-pro-BNP and troponin T used for prognosis)
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- Treatment:
- Isn't great...
- Typically chemo: Melphalan + dexamethasone to erradicate clonal plasma cells responsible for producing the light chains.
- Autologous HSCT can be considered in younger healthy patients.
- On the horizon: newer myeloma agents such as bortezomib and thalidomide (trials ongoing).
- Isn't great...
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