PLASMA CELL DYSCRASIAS

1
PLASMA CELL DYSCRASIAS
CLASSIFICATION

• Monoclonal gammopathy of uncertain significance
  (MGUS)
• Idiopathic
• Associated with other diseases (autoimmune,
  infectious, non-heme cancer, etc)
• Plasma cell or lymphoid malignancy
• Waldenstrom's macroglobulinemia
• Other lymphoproliferative disorders
• Smoldering multiple myeloma
• Multiple myeloma

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MOLECULAR PATHOGENESIS OF MYELOMA
Lancet 2004363875
3
MULTIPLE MYELOMA
Definition

• Increased numbers of abnormal or immature plasma
  cells in the bone marrow, or localized
  plasmacytoma
• Monoclonal protein in blood or urine
• Some patients are nonsecretors
• Lytic bone lesions
• Not all patients have lytic bone disease

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MULTIPLE MYELOMA
EPIDEMIOLOGY

• Incidence in US approx 3 cases/100,000/yr
• 98 of cases gt 40 yrs old
• Risk factors
• genetic
• radiation exposure
• ? chemical exposure

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MULTIPLE MYELOMA
Serum and urine protein electrophoresis
Free light chain
Monoclonal IgG
Serum
Urine
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Multiple myeloma (IgG kappa)
IgG 2080 Anemia, leukopenia Lytic bone
lesions 10 marrow plasma cells
7
Multiple myeloma (IgA)
IgA 1010 (nl 70-140) IgG 165 (nl 695-2190) IgM
14 (nl 60-265) Anemia, thrombocytopenia 16
marrow plasma cells
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MGUS
Ifix monoclonal IgG kappa No proteinuria IgA 234
(50-540) IgG 1840 (600-1600) IgM 85
(40-250) Normal CBC
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Waldenstrom macroglobulinemia with hyperviscosity
syndrome
Anemia, fatigue, retinopathy, bleeding
disorder IgA 125 (70-440) IgG 724
(695-2190) IgM 5130 (60-265) Serum viscosity
3.6 Marrow lt5 plasmacytoid B-lymphocytes
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Waldenstrom macroglobulinemia
Mild fatigue IgM 8460, serum viscosity 2.7 Hgb
12, WBC 3700, platelets 143,000 Marrow 50
plasmacytoid B-lymphocytes
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Kappa light chain myeloma with cardiac amyloidosis
Serum (hypogammaglobulinemia)
Urine (kappa light chain)
Always check the urine!
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MULTIPLE MYELOMA BONE MARROW ASPIRATE
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MYELOMA CYTOGENETICS
t(414)
del (13)
Lancet 2004363875
14
MULTIPLE MYELOMA
DIAGNOSIS

• Monoclonal paraprotein
• Intact immunoglobulin in serum (SPEP)
• Light chains in serum or urine (IEP)
• Marrow plasmacytosis (gt 20 - may be patchy)
• Lytic bone lesions
• Plasmacytoma

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MULTIPLE MYELOMA
CLINICAL MANIFESTATIONS

• Anemia progressing to pancytopenia
• Bone pain/destruction
• Hypercalcemia
• Humoral immune defect
• Local effects of plasmacytomas
• Systemic effects of paraprotein

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MONOCLONAL GAMMOPATHY
COMPLICATIONS

• Hyperviscosity (IgM gtgt IgA gt IgG)
• Renal dysfunction (light chains)
• Glomerular
• Tubular
• Neuropathy
• Other organ damage (rare)
• Cryoglobulinemia (types I and II)
• Amyloidosis

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MULTIPLE MYELOMA
Cast nephropathy
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CRYOGLOBULINEMIA IN IgM GAMMOPATHY
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MULTIPLE MYELOMA

• Demographics

Mayo Clin Proc 20037821
20
MULTIPLE MYELOMA
Presenting features (1027 pts)
Mayo Clin Proc 20037821
Bone pain
58
Fatigue
32
Weight loss
24
Paresthesias
5
Fever
0.7
ECOG PS gt2
10
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MULTIPLE MYELOMA
Preexisting conditions and risk factors
Mayo Clin Proc 20037821
Cancer in 1st degree relative
42
Myeloma in 1st degree relative
2
Hx of plasma cell proliferative disorder
34
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MULTIPLE MYELOMA

• Pre-existing plasma cell disorders

Mayo Clin Proc 20037821
23
MULTIPLE MYELOMA
Physical findings
Mayo Clin Proc 20037821
Palpable liver
4
Palpable spleen
1
Lymphadenopathy
1
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MULTIPLE MYELOMA
Hematologic findings at presentation
Mayo Clin Proc 20037821
Hgb lt 12
73
Hgb lt 8
7
ESR gt 20
84
ESR gt 100
33
WBC lt 4000
20
WBC lt 2000
1
Plts lt 100K
5
Plts gt 500K
2
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MULTIPLE MYELOMA

• Laboratory findings

Mayo Clin Proc 20037821
26
MULTIPLE MYELOMA
Serum and urine proteins
Mayo Clin Proc 20037821
Monoclonal band on SPEP in 82 3 non-secretory
at presentation
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MULTIPLE MYELOMA
Types of monoclonal proteins
Mayo Clin Proc 20037821
28
MULTIPLE MYELOMA
Radiographic findings at presentation
Mayo Clin Proc 20037821
29
MULTIPLE MYELOMA
Survival
Mayo Clin Proc 20037821
30
MULTIPLE MYELOMA
Prognostic factors
Mayo Clin Proc 20037821





Most important factors in multivariate analysis
31
Adapted from Greipp et al, Blood 2003102190a
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Adverse cytogenetics in myeloma

• del13 or del13q
• t(414
• del17p

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MULTIPLE MYELOMA
INDICATIONS FOR TREATMENT

• Symptomatic disease
• Bone destruction
• Anemia
• Organ dysfunction
• Hypercalcemia
• Increasing paraprotein or ß2-microglobulin level

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Treatment mnemonic

• Calcium increased
• Renal dysfunction
• Anemia
• Bone lesions

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MULTIPLE MYELOMA
TREATMENT

• Initial treatment
• Thalidomide or lenalidomide dexamethasone
• Bortezomib dexamethasone
• Bortezomib lenalidomide dexamethasone
• Melphalan prednisone lenalidomide/thalidomide
• Autologous SCT prolongs survival
• Refractory disease
• High dose cyclophosphamide
• Platinum-based regimen
• Bisphosphonates as adjunctive Rx
• Allogeneic transplant role?

36
Overall and progression-free survival in multiple
myeloma standard chemotherapy vs high-dose
chemotherapy with stem cell rescue NEJM
20033481875
37
Blood 2010116679-686
38
N Engl J Med 1996334488-93
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Lancet 2004363875
40
How do thalidomide related drugs work?
Science 2014343256