Plasma Cell Malignancies



    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. 

    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 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)
        • 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 SymptomsLymphadenopathy + 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. 1. Bone Marrow: Lymphoplasmacytic Lymphoma comprising ≥10% of bone marrow.
        2. 2. High level of IgM  M-protein.
        3. 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]
        • amyloid_tongue.jpg    periorbitalpurpura.jpg
    • 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.

      • 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).
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