Post on 27-Nov-2015
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Multiple Myeloma and
Related Disorders
Kumar Rajagopalan
Outline
• Biology• Plasma Cell Dyscrasia
– MGUS– Plasmacytoma
• Multiple myeloma– Smoldering– POEMS
• Waldenstrom’s Macroglobulinemia• Amyloidosis
The Continuum of Plasma Cell Disorders
Normal MGUS Indolent Multiple Myeloma Myeloma
Myeloma, Malpas et al. 2004
• The hallmark of plasma cell disorders is the presence of a paraprotein in the serum and/or urine.
Paraproteinemias
• Normal immunoglobulin pattern – Polyclonal reflects progeny of different
plasma cells
• Paraproteinemia– Monoclonal immunoglobulin band in sera
reflects synthesis from single plasma cell clone
SPEP
Polyclonal Gammopathy
MonoclonalGammopathy
Normal Immunoelectrophoresis
Presentation of Plasma Cell Disorders
• Increased protein on a routine chemistry panel
• Anemia
• Bone pain
• Renal dysfunction
• Hypercalcemia
Pathophysiology: Monoclonal B-Cells/Plasma Cell Dyscrasia
• Marrow replacement– Cytopenias– Constitutional symptoms
• Decreased quantitative immunoglobulins– Infections
• Lytic bone lesions– Fractures– Hypercalcemia
• Extramedullary involvement– Plasmacytomas– Organomegaly
Pathophysiology: Monoclonal Immunoglobulin Proteins
• Heavy chains or Light chains in serum, urine, kidney or other tissues– Renal insufficiency– Neurologic disease– Hyperviscosity– Cold Agglutinin disease– AL Amyloidosis– POEMS: Polyneuropathy, Organomegaly, Endocrine
disturbances, M-protein, Skin changes
MGUS: Monoclonal Gammopathy of Undetermined
Significance
MGUS
• Diagnosis– Serum M-protein
• Usually IgG or IgA, usually <3 g/dL• Stable over time
– Marrow plasma cells <10%– No lytic bone lesions, unexplained anemia,
hypercalcemia, or renal insufficiency
• Incidence– 1-2% of adults– Increases with age
• 6% aged 62-79 y/o, 14% >90 y/o
NEJM 2002;346:564. Kyle ASH 2002 #384.
MGUS Progression
• 1384 patients at Mayo• MGUS: 1% per year progression
– Relative risk 25x (myeloma), 46x (Waldenstrom’s), 8.4x (amyloid), 2.4x (lymphoma)
• IgM MGUS: 1.5% per year• Predictors
– Size of M-spike (> 2.5 g/dL, 41% at 10 yr)
– Serum albumin
NEJM 2002;346:564
MGUS Progression: 1% per Year
MGUS: Management
• Testing– CBC, calcium, creatinine, SPEP with
immunofixation, quantitative immunoglobulins, 24-hour urine protein (with UPEP and immunofixation if positive)
– If M-protein 2-3 g/dl, add bone marrow and skeletal survey
• F/U– SPEP/H&P repeated in 6 months, then annually
Multiple Myeloma and Related Disorders
• Definition:
A group of diseases that involve malignant proliferation of Ig-secreting cells of B-cell lineage that are usually associated with paraproteinemia or paraproteinuria.
Multiple Myeloma
• US Incidence: 15,000 new cases/year– 1% of malignancies
• US Prevalence: 65,000 cases/year• Double incidence rate in African Americans• Median age 65
– 3% <40 years old
• Unknown cause– Radiation, benzene, solvents, pesticides, insecticides
Etiology
• Etiology is not known.
• Risk factors: Race, sex.
• Increased risk with ionizing radiation and exposure to pesticides like Dioxin.
• Recently viruses like HHV-8 and SV-40, have been linked to myeloma development.
Pathogenesis
• Bone marrow microenvironment very important for proliferation and chemotherapy resistance.
• BM stromal cells produce IL-6, responsible for pathogenesis and progression.
• IL-6 inhibits apoptosis of plasma cells.• IL-6 contributes to bone loss by stimulating
osteoclasts and inhibiting bone formation.• Interaction with extracellular matrix proteins
protect cells from chemo and radiation.
MM: Clinical Features
• Disease of the elderly (7th decade)
• Bone pain – most commonly vertebra and long bones– lytic lesions– fractures
Multiple Myeloma Typical “Punched Out” Lesions
Multiple Myeloma
Multiple Myeloma Diagnosis(1 major+1 minor or 3 minor)
• Major Criteria– Plasmacytoma on
tissue biopsy
– 30% Marrow plasmacytosis
– M-protein• 3.5 g/dL IgG
• 2 g/dL IgA
• 1g/24 hr urine Bence Jones
• Minor Criteria– 10-29% Marrow
plasmacytosis
– M-protein• Less than major
– Lytic bone lesions
– Low immunoglobuins• IgM <50 mg/dL
• IgA <100 mg/dL
• IgG <600 mg/dL
Kyle, Mayo Clin Proc, 2003.
Newly Diagnosed Multiple Myeloma: 1985-1998
• N=1027• Median age: 66 years• Median survival: 33 months
– Did not improve 1985 through 1998
• Multivariate analysis– Age, plasma cell labeling index,
thrombocytopenia, serum albumin, creatinine (log value)
Kyle, Mayo Clin Proc, 2003.
Newly Diagnosed Multiple Myeloma: 1985-1998
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Ca Cr >2 Anemia Skel Surv UPEP SPEP
Myeloma Diagnostic Work-Up
• SPEP and UPEP (24 collection) with immunofixation– 3% nonsecretory: check serum free light chains
• Skeletal survey (not a bone scan)• Quantitative serum immunoglobulins (IgA, IgG,
IgM)• Bone Marrow Aspirate and Biopsy
• Other tests (calcium, creatinine, beta-2 microglobulin, CRP, albumin, plasma cell labeling index, etc, etc) are only for staging/prognosis
M-Protein Tests
• Urine Dipstick not sensitive to Bence Jones proteins, need sulfosalicylic acid (SSA)
• Screening (SPEP/UPEP)– Gamma-globulins
• Polyclonal gammopathy: liver disease, connective tissue disease, chronic infection, others
• Hypogammaglobulinemia: Immunodeficiency, nephrotic syndrome (amyloidosis), myeloma/CLL
• Monoclonality– Immunofixation with monospecific antibodies– Immunoelectrophoresis– Immunoassay for serum free light chains (Mayo Clinic)
Myeloma Prognostic Work-Up
• Hemoglobin• Calcium• Serum creatinine• Beta-2 microglobulin• Albumin• Bone Marrow cytogenetics
– FISH chromosome 13 and 11?
• C-reactive protein??• Plasma cell labeling index??• Serum IL-6??
Myeloma Renal Disease
• “Myeloma kidney”– Normal glomerular function
– Concentrated light chains precipitate in tubules
– Monoclonal light chains seen in UPEP with immunofixation
• Glomerular lesions– Deposits of amyloid or light chain deposition disease
– Nonselective leakage of all serum proteins
– UPEP preponderance of albumin
Renal Manifestations
Amyloidosis
Light chain Deposition
Pierre Ronco JNEPHROL 2000; 13 (suppl. 3):
Myeloma Kidney Cast Formation
Pathology
Myeloma: Durie-Salmon Staging
Stage I• Hemoglobin >10 g/dL
• Normal calcium
• No lytic bone lesions
• Low M-protein
– IgG <5 g/dL
– IgA <3 g/dL
– Bence Jones <4 g/24h
Stage II (not Stage I/III)
Stage III• Hemoglobin <8.5• Calcium >12 (adjusted)• >3 lytic bone lesions• High M-protein
– IgG >7 g/dL– IgA >5 g/dL– Bence Jones >12 g/24h
A) Creatinine <2B) Creatinine >2
Myeloma: Median Survival
Durie-Salmon stage
Stage I 60 months
Stage II 40 months
Stage III 15 months
International Myeloma Working Group Staging System
Stage 2Microglobulin Albumin
I < 3.5 > 3.5
II <3.5
3.5 – 5.5
<3.5
any
III
> 5.5
any
Kyle, Mayo Clin Proc, 2003.
Therapy of Newly Diagnosed Multiple Myeloma: 1985-1998
Myeloma: Therapy Principles
• Observation for stage I• Incurable despite conventional chemotherapy and
high-dose therapy• Bisphosphonates• Chemotherapy
– Conventional– High-dose with stem cell rescue– New agents
• Graft-versus-myeloma
Myeloma: Therapy
• Alkylating agents– Melphalan: low-dose oral to high-dose myeloablative
• Steroids– Alone (pulse Dexamethasone) or combination (M&P, VAD,
Thal/Dex)
• Cyclophosphamide• Thalidomide and the IMiD’s• Bortezomib (Velcade): proteosome inhibitor• Graft-versus-myeloma effect
– Mini-allogeneic transplantation
• Interferon: maintenance
Therapy of Multiple Myeloma
• Chemotherapy– pulse dexamethasone
– pulse dexamethasone+ thalidomide
– pulse dexamethasone +lenalidomide (revlimid)
– pulse dexamethasone + bortezimib (velcade)
– melphalan+prednisone + imid (not transplant candidate)
• Autologous stem cell transplant• Radiation
Kyle, R. A. et al. N Engl J Med 2004;351:1860-1873
Major Classes of Drugs Used in the Treatment of Myeloma
NEJM 2003; 348: 1875.
Autologous Transplantation
Myeloma: Supportive Therapy
• Bisphosphonates– Phase III: monthly pamidronate (JCO 1998;16:593)
• Skeletal-related events 38% versus 51%, p=0.015• Median survival 21 versus 14 months
• Compression fractures: vertebroplasty• DVT risk: steroids, steroids + thalidomide• Hypercalcemia• Renal insufficiency: ?Plasmapheresis• Infections• Anemia: Eyrthropoietins
Myeloma Bone Marrow Microenvironment
• Interactions– Myeloma cell adhesion molecules react with
stroma– Release of osteoclast activating factors (IL-1B,
IL-6, TNFB)– Vascular endothelial growth factor (VEGF)
secreted by myeloma cells
• Myeloma Bone Disease
New Agents
JCO 2002;20:1625.
Smoldering Myeloma
• Serum M-protein >3 g/dL
• Marrow plasma cells >10%
• No lytic bone lesions, unexplained anemia, hypercalcemia, or renal insufficiency
• Evolve to overt multiple myeloma– 3.3% per year– Greatest for IgA
Plasmacytoma
Extramedullary Plasmacytoma
• ~3% of plasma cell neoplasms• Isolated plasma cell tumors of soft tissues
– Upper respiratory tract common
• Uninvolved marrow, negative skeletal survey
• M-protein present ~25% cases– Disappears following treatment
• Curable with local radiation therapy
Solitary Plasmacytoma of Bone
• ~3% of plasma cell neoplasms• One isolated bony lesion of plasma cells• Uninvolved marrow <5% plasma cells• M-protein present ~25% cases
– Disappears following treatment
• Curable with local radiation therapy– Median OS 10 years– Multiple myeloma develops in 50-60%
Osteosclerotic Myeloma (POEMS)
• Polyneuropathy– Sensorimotor peripheral neuropathy in 75%
• Organomegaly– Lymphadenopathy, hepatomegaly, splenomegaly
• Endocrinopathy– Adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic
• M-Protein• Skin changes
– Hyperpigmentation, hypertrichosis, plethora, hemangiomata, white nails
Osteosclerotic Myeloma
Lymphoplasmacytic Lymphoma (Waldenstrom’s Macroglobulinemia)• Malignant proliferation of plasmacytoid
lymphocytes secreting IgM M-protein• 1400 cases/year• Organomegaly/Peripheral neuropathies• Cryoglobulinemia
– Type I: Raynaud’s phenomenon, cold urticaria, etc.– Type II: Purpura, arthralgias, renal failure, mononeuritis
• IgM tissue infiltration/AL amyloidosis• Coagulation abnormalities
Hyperviscosity
• Usually IgM >5 g/dL, viscosity >4.0• Eyes
– “Sausage link” conjunctival and retinal veins– Retinal hemorrhages, Papilledema
• CNS– Ataxia, nystagmus, vertigo, confusion, altered consciousness
• Increased intravascular volume– Dilutional anemia– Risk congestive heart failure with transfusion
• Therapy: plasmapheresis/chemotherapy
Waldenstrom’s Macroglobulinemia: Therapy
• Plasmapheresis for hyperviscosity
• 2-Chlorodeoxyadenosine (2-CdA, cladribine)
• Fludarabine
• Rituximab
• Other myeloma-like therapies
Monoclonal IgM: DDx
• MGUS• Multiple myeloma• Waldenstrom’s• CLL• Chronic cold agglutinin disease
– No evidence of neoplasia– Hemolytic anemia aggravated by cold exposure– 90% have kappa light chains
Amyloidosis
• Extracellular tissue deposition of low molecular weight fibrils– Beta-pleated sheets, bind Congo red
• Precursor proteins involved– Monoclonal immunoglobulin light chains: Primary (AL)
Amyloidosis– Serum amyloid A protein: Reactive or Secondary (AA)
Amyloidosis– Beta-2 microglobulin: Dialysis (DA) Amyloidosis– Transthyretin, apolipoprotein A-I, Alzheimer amyloid
precursor protein, prion protein, Prolactin, Atrial natriuretic protein, Procalcitonin, Insulin, Keratin…
Amyloidosis: Presentation
• Nephrotic syndrome• Refractory CHF, Arrhythmia, Heart block• Orthostatic hypotension, Peripheral neuropathy• Bleeding diathesis (Raccoon eyes)
– Factor X deficiency, liver disease
• GI bleeding, Gastroparesis/Dysmotility, Malabsorption
• Macroglossia, Shoulder pad sign, Carpal tunnel syndrome, Organomegaly
• Skin thickening/waxy, easy bruising
Amyloidosis
Amyloidosis: Work-up
• Biopsy– Involved organs or bone marrow– Fat pad, salivary glands, rectal mucosa: 50-70%
success for diagnosis
• Echocardiography suggestive– Speckled myocardium– Interventricular septal thickening
• Distinguish from hereditary forms (10%)• Evaluate for myeloma (rare)
AL Amyloidosis: Course
• Rare progression to multiple myeloma (0.4%)• Poor long-term prognosis
– Cardiac, renal, hepatic failure, and infection– Prognostic factors: circulating plasma cells, high beta-2
microglobulin, marrow plasmacytosis >10%, dominant cardiac involvement
– High B2M, marrow plasmacytosis: median survival• 0: 54 months• 1: 19 months• 2: 13.5 months
Dhodapkar, Blood 2004;104:3520. Skinner, Annals 2004;140:85
AL Amyloidosis: Therapy
• Chemotherapy– Dexamethasone with
Dex/IFN maintenance
• High-dose melphalan with Auto transplantation– Risky with cardiac, renal,
GI involvement
Summary
• Spectrum of mature B-cell neoplasms/plasma cell dyscrasias
• Clinical manifestations:– Tumor growth, marrow and tissue infiltration
– M-protein accumulation or infiltration
– Immune dysfunction
– Kidney and bone disease
• Therapy not curative, but increasingly effective