Rajkumar SV, et al. Blood. 2005;106:812-817.

Plasma cell disorders

MGUS
Solitary plasmacytoma (bone or extramedullary)
Multiple myeloma
Amyloidosis
Waldenstrom macroglobulinemia

Criteria for Diagnosis of Myeloma
MGUS
< 3 g/dL M spike
< 10% PC
Active MM
3 g M spike
OR: 10% PC
No anemia, no bone lesions;
normal calcium and
kidney function
Anemia, bone lesions,
high calcium, or
abnormal kidney function
(CRAB criteria) + amyloidosis,
recurrent bacterial infections
Smoldering MM
10% PC
M spike +
AND AND
Rajkumar SV, et al. Blood. 2005;106:812-817.
Risk of Progression of MGUS
1148 patients with MGUS followed for 8982
person-yrs
Median follow-up: 15 yrs
7.6% of patients experienced progression during
observation
Cumulative probability of progression ~ 1% per yr
At 10 yrs: 9%
At 20 yrs: 20%
At 25 yrs: 30%
Multiple myeloma
malignant proliferation of plasma cells derived by only one
clone
3800 new cases every
year in the UK
Incidence:
6/100,000/year
Age at diagnosis: 60-70
Multiple myeloma
etiology and pathogenesis
Radiation, farmers, petroleum worker. More
common in blacks.
Errors in IgH switch recombination t(11;14),
t(4;14), myc ras p53, BRAF gene sometimes
involved. Critical role of IL6, IGF-1, VEGF.
Theory of clonal tides.
Role of microenvironment.
Epidemiology of Multiple Myeloma
~ 20,180 new cases and 10,650 deaths from
multiple myeloma are expected in the United
States in 2010
Slightly more common in men than in women
Incidence in blacks is ~ twice than that in whites
Median age at diagnosis is 69 yrs for men and 71
yrs for women
75% of men are older than 70 yrs of age
79% of women are older than 70 yrs of age
Cancer facts and figures 2010. American Cancer Society; 2010. Altekruse SF, et al, eds. SEER cancer
statistics review, 1975-2007. National Cancer Institute. NCCN practice guidelines. 2011.
Distribution of Monoclonal Proteins
in Multiple Myeloma
M protein found in serum and/or urine or both
at time of diagnosis in 97% of patients (3% are
nonsecretory)
Of the 3% with nonsecretory myeloma with
negative serum and urine immunofixation,
60% will have detectable serum free light
chains on the serum free light chain assay
Kyle RA ,et al. Mayo Clin Proc. 2003;78:21-33. IMWG. Br J Haematol. 2003;121:749-757.
Jacobson Jl, et al. Br J Haematol. 2003;122:441-450.
Clinical features
Bone lesions bone pain,
bone fractures, spinal cord
compression
Bone marrow involvement
Anemia
Kidney failure
Hypercalcemia
Infections

M component 70-75%
Light chain only 20 -22 %
2-3 % non secretory
Major Symptoms at Diagnosis
Bone pain: 58%
Fatigue: 32%
Weight loss: 24%
Paresthesias: 5%
11% are asymptomatic or have only mild
symptoms at diagnosis
Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33.
Clinical Features at Presentation
M serum protein (93%)
Lytic bone lesions (67%)
Increased plasma cells in the bone marrow (96%)
Anemia (normochromic normocytic) (73%)
Hypercalcemia (corrected calcium 11 mg/dL)
(13%)
Renal failure, serum creatinine 2.0 mg/dL (19%)
Infection
Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33.
Initial Diagnostic Evaluation
History and physical examination
Blood workup
CBC with differential and platelet
counts
BUN, creatinine
Electrolytes, calcium, albumin, LDH
Serum quantitative immunoglobulins
Serum protein electrophoresis
and immunofixation

2
-microglobulin
Serum free light chain assay
proBNP
Urine
24-hr protein
Protein electrophoresis
Immunofixation
electrophoresis
Other
Skeletal survey
Unilateral bone marrow
aspirate and biopsy evaluation
with immunohistochemistry
and/or bone marrow flow
cytometry, cytogenetics, and
FISH
MRI (spine, pelvis) as indicated
NCCN practice guidelines. 2011.

Categories of Myeloma
Classification Characteristics Management
Indolent MM Presence of serum/urine M protein
Bone marrow plasmacytosis
Mild anemia or few small dubious bone lesions
(skull)
Absence of symptoms
Monitoring every
3 mos, with treatment
beginning at disease
progression
Symptomatic MM Presence of serum/urine M protein
Bone marrow plasmacytosis
Anemia, renal failure, hypercalcemia, or
lytic bone lesions
Patients with primary systematic amyloidosis and
bone marrow plasma cells 30% are considered
to have both MM and amyloidosis
Immediate treatment
IMWG. Br J Haematol. 2003;121:749-757.
Durie-Salmon Staging System for
Myeloma
Subclassification Criteria
A Normal renal function (serum creatinine level < 2.0 mg/dL)
B Abnormal renal function (serum creatinine level 2.0 mg/dL)
Durie B, et al. Cancer. 1975;36:842-854. IMWG. Br J Haematol. 2003;121:749-757.
Stage Criteria Myeloma Cell Mass
(x 10
12
cells/m
2
)
I All of the following:
Hemoglobin > 10 g/dL
Serum calcium level 12 mg/dL (normal)
Normal bone or solitary plasmacytoma on x-ray
Low M component production rate: IgG < 5 g/dL; IgA < 3 g/dL;
Bence-Jones protein < 4 g/24 hrs
< 0.6 (low)
II Not fitting stage I or III 0.6-1.2 (intermediate)
III 1 or more of the following:
Hemoglobin < 8.5 g/dL
Serum calcium level > 12 mg/dL
Multiple lytic bone lesions on x-ray
High M-component production rate: IgG > 7 g/dL; IgA > 5 g/dL;
Bence-Jones protein > 12 g/24 hrs
> 1.2 (high)
International Staging System for
Symptomatic Myeloma
Stage Criteria
1
2
-M < 3.5 mg/dL and
ALB 3.5 g/dL
2 Not stage 1 or 3
3
2
-M 5.5 mg/dL
Greipp PR, et al. J Clin Oncol. 2005;23:3412-3420.
Major Adverse Prognostic Factors
Karyotypic deletion 13 or hypodiploidy
High plasma cell labeling index
Molecular genetics: t(4;14), t(14;16), cr 1 or
17p-
High LDH,
2
-microglobulin
Increased circulating plasma cells
Plasmablastic morphology
Low albumin
IMWG Classification of Active MM
High Risk (25%)
FISH
Del 17p
t(4;14)*
t(14;16)
Cytogenetic deletion 13q
Cytogenetic
hypodiploidy
PCLI 3%
Standard Risk (75%)*
All others, including:
Hyperdiploidy
t(11;14)
t(6;14)
Dispenzieri A, et al. Mayo Clin Proc. 2007;82:323-341. Fonseca R, et al. Leukemia. 2009;23:2210-2221.
*Patients with t(4;14),
2
-M < 4 mg/L and Hb 10 g/dL may have intermediate-risk disease.
Initial Therapy Considerations
Ensure patient does not have smoldering MM
(asymptomatic MM) since no treatment proven
effective, although clinical trials are ongoing
Approach to therapy for MM is based on whether
a patient is a transplantation candidate
Patients seeking care within the VHA system
typically present with more comorbidities than in
other settings
Consider clinical trials if available
Improving CR rates is a key goal of current trials
Treatment
Combination chemotherapy
Steroids
Cyclophosphamide
Thalidomide
Anthracycline

High-dose chemotherapy with SC rescue

Radiotherapy
Bisphosphonates
EPO
Surgery (kyphoplasty)

New drugs
Bortezomib
Lenalidomide
Criteria for Transplantation
Younger than 70 yrs of age
High performance score
Acceptable function
Major organs
Neuropsychiatric
Acceptable social circumstances
Caregiver
Absence of drug/alcohol addiction
VHA clinical guidance for the initial management of adults with MM. August 2009.
Clearly not transplantation
candidate based on age, performance
score, AND/OR comorbidity
MPT, MPV,
or clinical trial
Potential transplantation
candidate
VDT x 4 cycles
Stem cell harvest
Initial Approach to Treatment of
MM
Current Frontline Options
Conventional chemotherapy
Survival 3 yrs
Transplantation
Prolongs survival 5 -7 yrs
Novel agents targeting stromal interactions
and associated signaling pathways have shown
promise
Chng WJ, et al. Cancer Control. 2005;12:91-104.
Rajkumar SV, et al. Blood. 2005;106:812-817.
Waldenstrom macroglobulinemia
Lymphoplasmacytoid lymphoma
IgM production
Hyperviscosity
Bone marrow infiltration, non bone lesions, no renal
failure
Positive Coombs test, cryoglobulins

Sign and Symptoms
Fatigue, dizziness, visual disturbance, peripheral
neuropathy, infections, adenopathies, epato-
splenomegaly

Rajkumar SV, et al. Blood. 2005;106:812-817.
Solitary plasmacytoma
Bone or upper respiratory tract
M component production
Normal bone marrow


Sign and Symptoms
Local or compression symptoms, bone pain,
neuologic signs