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

MOLECULAR PATHOGENESIS OF MYELOMA
Lancet 2004;363:875
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
MULTIPLE MYELOMA
EPIDEMIOLOGY
• Incidence in US approx 3 cases/100,000/yr
• 98% of cases > 40 yrs old
• Risk factors:
genetic
 radiation exposure
 ? chemical exposure

MULTIPLE MYELOMA
Serum and urine protein electrophoresis
Monoclonal IgG
Serum
Urine
Free light chain
Multiple myeloma (IgG kappa)
IgG 2080
Anemia, leukopenia
Lytic bone lesions
10% marrow plasma cells
Multiple myeloma (IgA)
IgA 1010 (nl 70-140)
IgG 165 (nl 695-2190)
IgM 14 (nl 60-265)
Anemia, thrombocytopenia
16% marrow plasma cells
MGUS
Ifix: monoclonal IgG kappa
No proteinuria
IgA 234 (50-540)
IgG 1840 (600-1600)
IgM 85 (40-250)
Normal CBC
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: <5% plasmacytoid B-lymphocytes
Waldenstrom macroglobulinemia
Mild fatigue
IgM 8460, serum viscosity 2.7
Hgb 12, WBC 3700, platelets 143,000
Marrow: 50% plasmacytoid B-lymphocytes
Kappa light chain myeloma with cardiac
amyloidosis
Serum (hypogammaglobulinemia)
Urine (kappa light chain)
Always check the urine!
MULTIPLE MYELOMA – BONE MARROW ASPIRATE
MYELOMA CYTOGENETICS
t(4;14)
del (13)
Lancet 2004;363:875
MULTIPLE MYELOMA
DIAGNOSIS
• Monoclonal paraprotein


Intact immunoglobulin in serum (SPEP)
Light chains in serum or urine (IEP)
• Marrow plasmacytosis (> 20% - may be patchy)
• Lytic bone lesions
• Plasmacytoma
MULTIPLE MYELOMA
CLINICAL MANIFESTATIONS
• Anemia progressing to pancytopenia
• Bone pain/destruction
• Hypercalcemia
• Humoral immune defect
• Local effects of plasmacytomas
• Systemic effects of paraprotein
MONOCLONAL GAMMOPATHY
COMPLICATIONS
• Hyperviscosity (IgM >> IgA > IgG)
• Renal dysfunction (light chains)
Glomerular
 Tubular
Neuropathy
Other organ damage (rare)
Cryoglobulinemia (types I and II)
Amyloidosis

•
•
•
•
MULTIPLE MYELOMA
Cast nephropathy
CRYOGLOBULINEMIA IN IgM GAMMOPATHY
Brit J Haematol 2004; 124:565
MULTIPLE MYELOMA
Demographics
Mayo Clin Proc 2003;78:21
MULTIPLE MYELOMA
Presenting features (1027 pts)
Mayo Clin Proc 2003;78:21
Bone pain
58%
Fatigue
32%
Weight loss
24%
Paresthesias
5%
Fever
0.7%
ECOG PS >2
10%
MULTIPLE MYELOMA
Preexisting conditions and risk factors
Mayo Clin Proc 2003;78:21
Cancer in 1st degree
relative
42%
Myeloma in 1st degree
relative
2%
Hx of plasma cell
proliferative disorder
34%
MULTIPLE MYELOMA
Pre-existing plasma cell disorders
Mayo Clin Proc 2003;78:21
MULTIPLE MYELOMA
Physical findings
Mayo Clin Proc 2003;78:21
Palpable liver
4%
Palpable spleen
1%
Lymphadenopathy
1%
MULTIPLE MYELOMA
Hematologic findings at presentation
Mayo Clin Proc 2003;78:21
Hgb < 12
73%
Hgb < 8
7%
ESR > 20
84%
ESR > 100
33%
WBC < 4000
20%
WBC < 2000
1%
Plts < 100K
5%
Plts > 500K
2%
MULTIPLE MYELOMA
Laboratory findings
Mayo Clin Proc 2003;78:21
MULTIPLE MYELOMA
Serum and urine proteins
Mayo Clin Proc 2003;78:21
Monoclonal band on SPEP in 82%
3% non-secretory at presentation
MULTIPLE MYELOMA
Types of monoclonal proteins
Mayo Clin Proc 2003;78:21
MULTIPLE MYELOMA
Radiographic findings at presentation
Mayo Clin Proc 2003;78:21
MULTIPLE MYELOMA
Survival
Mayo Clin Proc 2003;78:21
MULTIPLE MYELOMA
Prognostic factors
Mayo Clin Proc 2003;78:21
*
*
*
*
*
* Most important factors in multivariate analysis
*Adapted from Greipp et al, Blood 2003;102:190a
Adverse cytogenetics in myeloma
del13 or del13q
t(4;14
del17p
MULTIPLE MYELOMA
INDICATIONS FOR TREATMENT
• Symptomatic disease
• Bone destruction
• Anemia
• Organ dysfunction
• Hypercalcemia
• Increasing paraprotein
microglobulin level
or ß2-
Treatment mnemonic
• Calcium increased
• Renal dysfunction
• Anemia
• Bone lesions
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?
Overall and progressionfree survival in multiple
myeloma: standard
chemotherapy vs highdose chemotherapy with
stem cell rescue
NEJM 2003;348:1875
Blood 2010;116:679-686
N Engl J Med 1996;334:488-93
Lancet 2004;363:875
How do thalidomide & related drugs work?
Science 2014;343:256