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.
• 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

  • 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)

  • 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)
  • 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.
    • 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)

Asymptomatic Myeloma

• Risk of progressing is 73% at 15y.  (median time 5years)

   

   

• Asymptomatic Myeloma One of: M-protein level ≥3g/dL (convert!) (<3g/dL = MGUS) OR by ≥10% plasma cells on bone marrow exam.   AND Absence of Myeloma-related end-organ damage.

• Can also follow kappa:lambda light chain ratio (measure of light chain prouction by myeloma)

  • Predictive of disease progression.  normally kappa = lambda. 

     

Monoclonal Gammopathy of Undetermined Significance (MGUS)

• Typically found incidentally on protein electrophoresis.

• MGUS Definition: M-protein level of <3g/dL (more is indicative of myeloma) Bone Marrow Biopsy: <10% plasma cells No evidence of kidney failure, anemia, bone disease or any other organ damage

•  

  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)

• 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:

  • 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

• Difference between Waldenstrom's and MM is cell of origin
• • 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.

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:

  • 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. 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.

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  • 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
• 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).