multiple myeloma and related disorders€¦ · myeloma[1] active myeloma m protein < 3 g/dl...
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Multiple
Myeloma and
Related
Disorders
Zsolt Nagy
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Outline
• Biology
• Plasma Cell Dyscrasia
– MGUS
– Plasmacytoma
• Multiple myeloma
– Smoldering
– POEMS
• Waldenstrom’s Macroglobulinemia
• Amyloidosis
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Classification of Monoclonal Gammopathies
• Monoclonal Gammopathy of Undetermined Significance "Benign"/idiopathic
Associated with other diseases (autoimmune, infectious, non-heme cancer, etc)
• Plasma cell or lymphoid malignancy Waldenstrom's macroglobulinemia
Other lymphoproliferative disorders
Multiple Myeloma
Smolderimg Multiple Myeloma
Plasma cell leukemia
IgD myeloma
POEMS
• Plasmacytoma
• Heavy Chain disease
• Amyloidosis
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The Continuum of Plasma Cell Disorders
Normal MGUS Indolent Multiple
Myeloma Myeloma
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Myeloma, Malpas et al. 2004
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• The hallmark of plasma cell disorders is the
presence of a paraprotein in the serum
and/or urine.
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Paraproteinemias
• Normal immunoglobulin pattern
– Polyclonal reflects progeny of different
plasma cells
• Paraproteinemia
– Monoclonal immunoglobulin band in sera
reflects synthesis from single plasma cell
clone
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SPEP
Polyclonal
Gammopathy
Monoclonal
Gammopathy
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Normal Immunoelectrophoresis
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Presentation of Plasma Cell Disorders
• Increased protein on a routine chemistry
panel
• Anemia
• Bone pain
• Renal dysfunction
• Hypercalcemia
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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
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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
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Solitary or extramedullary plasmacytoma
3% (27)
Chronic lymphocytic leukaemia 2% (21)
Waldenström’s macroglobulinaemia 2% (20)
MGUS 56% (578)
Multiple Myeloma 18%
(185)
Lymphoma 5% (50)
Amyloidosis (AL) 10%
(106)
Smouldering myeloma 4% (39)
RA Kyle in: Myeloma Biology & Management, 1995
M-protein at the Mayo Clinic
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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
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Other diseases associated
with M-protein
• Autoimmune diseases (RA, SLE, scleroderma)
• Skin diseases (pyoderma gangraenosum)
• Liver disease (cirrhosis)
• Infectious diseases (m.tuberculosis, Hep C,HIV)
• …………..
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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
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NEJM 2002;346:564
MGUS Progression: 1% per Year
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Diagnostic work-up MGUS
LAB
• CBC
• Serum Ca/alb and creatinin
• Serum protein electrophoresis (EF) and immunofixation (IF)
• Quantification of immunoglobulins
• 24-hour urine albumin, EF +IF
Skeletal X rays
Bm aspirate/biopsy if– M-protein > 15 g/l
– IgA or IgM M-protein
– Abnormal free light chain ratio
CT thorax/abdomen if IgM paraprotein (m.Waldenstrom)
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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
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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.
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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
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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.
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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.
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MM: Clinical Features
• Disease of the elderly (7th decade)
• Bone pain
– most commonly vertebra and long bones
– lytic lesions
– fractures
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Myeloma: Clinical Features
• Bone pain: often with loss of height
• Constitutional: weakness, fatigue, and weight loss
• Anemia
• Renal disease: renal tubular dysfunction
• Infections: neutropenia/hypogammaglobulinemia
• Hypercalcemia: myeloma cells secrete osteoclast-activating
factors
• Hyperviscosity: 2% with myeloma; 50% with
macroglobulinemia
• Neurologic dysfunction: spinal cord or nerve root compression
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Major Symptoms at Diagnosis
• Bone pain: 58%
• Fatigue: 32%
• Weight loss: 24%
• Paresthesias: 5%
Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33.
11% of patients are asymptomatic or have only mild symptoms at diagnosis
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Multiple Myeloma
Typical “Punched Out” Lesions
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Multiple Myeloma
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Diagnostic Criteria for Myeloma
1. IMWG. Br J Haematol. 2003;121:749-757. 2. Kyle RA, et al. N Engl J Med. 2002;346:564-569.3. Durie BG, et al. Hematol J. 2003;4:379-398.
Patient Criteria MGUS[1,2] Smoldering
Myeloma[1]
Active Myeloma
M protein < 3 g/dL spike ≥ 3 g/dL spike
and/or
In serum
and/or urine[2]
Monoclonal
plasma cells in
bone marrow, %
< 10 ≥ 10 ≥ 10[2]
End-organ
damage
None None ≥ 1 CRAB*
feature[3]
*C: Calcium elevation (> 11.5 mg/L or ULN)R: Renal dysfunction (serum creatinine > 2 mg/dL)A: Anemia (Hb < 10 g/dL or 2 g < normal)B: Bone disease (lytic lesions or osteoporosis)
Only patients with symptomatic MM should be treated
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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
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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)
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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
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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
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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)
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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??
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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
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Renal Manifestations
Amyloidosis
Light chain Deposition
Pierre Ronco JNEPHROL 2000; 13 (suppl. 3):
Myeloma Kidney Cast Formation
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Pathology
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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 <2
B) Creatinine >2
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Myeloma: Median Survival
Durie-Salmon stage
Stage I 60 months
Stage II 40 months
Stage III 15 months
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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
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Kyle, Mayo Clin Proc, 2003.
Therapy of Newly Diagnosed
Multiple Myeloma: 1985-1998
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clinicaloptions.com/oncology
Multiple Myeloma in Session: Basics of Multiple Myeloma
No Improvement in Therapy for Patients
With Myeloma in 30 Yrs Until . . . Prospective, randomized study
of autologous bone marrow transplantation plus chemotherapy
74 patients in high-dose group received autologous transplantation
Attal M, et al. N Engl J Med. 1996;335:91-97.
Type of Response Patients, n
Conventional
Dose
(N = 100)
High
Dose
(N = 100)
CR 5 22
Very good PR 9 16
PR 43 43
MR 18 7
PD 25 12
100
75
50
25
0
OS
(%
)
0 15 30 45 60
Mos
Conventional
dose
High dose
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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
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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
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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
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Kyle, R. A. et al. N Engl J Med 2004;351:1860-1873
Major Classes of Drugs Used in the Treatment of Myeloma
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NEJM 2003; 348: 1875.
Autologous Transplantation
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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
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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
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New Agents
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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
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Plasmacytoma
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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
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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%
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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
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Osteosclerotic Myeloma
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Ghobrial et al, Lancet Oncol 2004, Treon et al, Blood 2009
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• 30-50% of patients:
deletion 6q by FISH
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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
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Consensus recommendations of the 4th
International WM meeting
• First Line therapy:
– Combination therapy
• (RCD or CPR; Cytoxan+nucleoside analogues+R; R-CHOP, R-CVP)
– Rituximab single agent
– Nucleoside analogues
– Alkylators
• Salvage therapy:
– Re-use therapies
– Bortezomib
– Thalidomide+steroids
– Alemtuzumab
– AHSCT
Dimopoulos, JCO 2009, Treon et al Clin
Lymph and Myeloma 2009
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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
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Waldenstrom’s
Macroglobulinemia: Therapy
• Plasmapheresis for hyperviscosity
• 2-Chlorodeoxyadenosine (2-CdA,
cladribine)
• Fludarabine
• Rituximab
• Other myeloma-like therapies
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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
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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…
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The Past
1854 Virchow: Amyloid
1922 Bennhold: Congo red
1959 Cohen & CalkinsFibrillar structure
1968 Eanes & Glennercross- pleated struct.
X-ray diffraction pattern
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The Beginning of AL Amyloidosis
1931 Magnus-Levy (Mount Sinai Hospital, New York)
Bence Jones protein is "Mother Substance”
1961 Kyle & Bayrd
Abnormal plasma cells in all
1964 Osserman
Bence Jones protein
1971 Glenner
Fibril & Bence Jones protein were the same
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Merlini & Bellotti NEJM 2003
localized Amyloidosis
~30 proteins
systemic Amyloidosis
Amyloidosis: Protein Misfolding Diseases
Sipe et al, 2012
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proteotoxicity
Misfolded FLC
structural damage
λ1*
1Merlini & Stone, Blood. 2006;
λ6**
*Perfetti et al, Blood. 2012; **Comenzo et al, Br J Haematol. 1999
Small dangerous clone1
(BMPC 7%)
53% LC only 75% l
Amyloid fibrils
Early detection of amyloid heart involvement is vital
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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
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Amyloidosis
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Merlini et al, Blood 2013 121: 5124-5130
Diagnosis of Amyloidosis
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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)
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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
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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
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LDex12,13Dex5-71990 2000 2010MP1 ASCT2-4 MDex8,9 TDex10
%
B14 CyBorD15,16
1. Kyle, et al. NEJM 1997
2. Comenzo, et al. Blood 1996
3. Gertz, et al. Leuk Lymphoma 2010
4. Cibeira, et al. Blood 2011
5. Gertz, et al. Am J Hematol 1999
6. Merlini, et al. Br J Haematol 2001
7. Dhodapkar, et al. Blood 2004
8. Palladini, et al. Blood 2004
9. Jaccard, et al. NEJM 2007
10. Palladini, et al. Blood 2005
11. Wechalekar, et al. Blood 2007
12. Sanchorawala, et al. Blood 2007
13. Dispenzieri, et al. Blood 2007
14. Reece, et al. Blood 2011
15. Mikhael, et al. Blood 2012
16. Venner, et al. Blood 2012
Survival at 5 years
1131 AL patients
Pavia Center
CTD11
Therapy Development in AL Amyloidosis
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aCR Negative s. & u.IFE, normal FLR
VGPR dFLC <40 mg/L
PR dFLC decrease 50%
NR other
New Criteria for Response to Treatment in Immunoglobulin Light Chain Amyloidosis
Based on Free Light Chain Measurement and Cardiac Biomarkers: Impact on Survival
Outcomes. Palladini et al, J Clin Oncol. 2012;30:4541-9
0 12 24 36 48
Time (months)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pro
po
rtio
n s
urv
ivin
g
NT-proBNP progression (at least 300 ng/L and 30% increase), 169 patients
NT-proBNP stable, 108 patients
NT-proBNP response (at least 300 ng/L and 30% decrease), 100 patients
p<0.001
p<0.001
New cardiac response criteria
reduction of NT-proBNP >30% and
>300 ng/L
Renal response criteria under
validation19
NT-proBNP
0 12 24 36 48
Time (months)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients, 3.6 deaths/100 py)
VGPR (233 patients, 9.6 deaths/100 py)
PR (140 patients, 23.7 deaths/100 py)
NR (179 patients, 47.2 deaths/100 py)
p=0.01
p<0.001
p<0.001
FLC
Renal insufficiency and IMiDs may alter
NT-proBNP metabolism
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o Treatment endpoint: at least VGPR
o Hematologic and cardiac response should be assessed
frequently, every 1-2 cycles (or three months after ASCT)
o Rapid switch if no response
o Therapy can be continued for 1-2 cycles beyond best
response for consolidation
Therapy is Highly Individualized and Must be Risk-adapted Based
on Cardiac Biomarkers and Response-tailored
<VGPR Bortez if unexposed and no severe neuropathy
Len, Pom1, Benda2 in resist. to alkyl/bortez/thal
Len requires monitoring renal function
New drugs, such as Ixazomib3
1Dispenzieri et al, Blood 2012;119 :5397-404 -2Merlini et al, Blood. 2012;120(21) Abstr 4057 - 3Merlini et al,
Blood 2012;120(21) Abstr 731
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Treatment Selection is Based on Cardiac Biomarkers
Merlini et al, Blood 2013 121: 5124-5130
1
1Gertz et al, Bone Marrow Transplant. 2013;48:557-612Wechalekar et al, Blood 2013;121:3420-7
2
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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