Plasma Cell

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Plasma Cell

• Disorders

Monoclonal Gammopathies
Kristi McIntyre M.D. Texas Oncology 2004
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Classification of Monoclonal Gammopathies

• Monoclonal Gammopathy of Undetermined
  Significance
• Malignant Monoclonal Gammopathies
  Multiple Myeloma
  
  
  
  Smolderimg Multiple Myeloma
  Plasma
  cell leukemia
  
  IgD myeloma
  
  POEMS
• Plasmacytoma
• Malignant Lymphoproliferative disorders
• Heavy Chain disease
• Amyloidosis

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Patient Profile

• 61 year old female presented with rash to
  dermatologists in 2001. SPEP revealed 0.2
  IgGlambda M-protein. Asymptomatic otherwise.

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Breast ca
M-protein
1
2001
2002
2003
2004
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MGUS

• Denotes presence of an M-protein in a patient
  without a plasma cell or lymphoproliferative
  disorder

• M-protein lt 3g/dL
• lt 10 plasma cells in bone marrow
• No or small amounts of M-protein in urine
• Absence of lytic bone lesions,anemia,hypercalcemia
  or renal insufficiency
• No evidence of B cell lymphoproliferative
  disorder
• Stability of M-protein over time

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MGUS

• Monoclonal Gammopathy of Undetermined Significance

• 1 of adults in US
• 3 of adults over age 70 years
• 11 of adults over age 80 years
• 14 of adults over age 90 years

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MGUS

• MGUS can progress to monoclonal disease

IgA or IgG
IgM
Multiple Myeloma Primary Amyloidosis or related
plasma cell disorder
NHL CLL Waldentroms macroglobulinemia
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MGUS

• 1,384 patients MGUS

Light chain
Heavy chain
IgG 70 IgM 15 IgA 12
Kappa 61 Lambda 39
Concentration of uninvolved immunoglobulins
reduced in 39

• Kyle, R. A. et al. N Engl J Med 2002346564-569

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MGUS

• prognosticators( predictors of progression)

1. Age
2. sex
3. Size of initial M-protein
4. Type of immunoglobulins
5. Hemoglobin
6. of bone marrow plasma cells
7. Reduction of uninvolved imunoglobulins
8. Urinary light chains

Kyle, R. A. et al. N Engl J Med 2002346564-569
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Initial Monoclonal Protein Values in 1384
Residents of Southeastern Minnesota in Whom
Monoclonal Gammopathy of Undetermined
Significance Was Diagnosed from 1960 through 1994
Kyle, R. A. et al. N Engl J Med 2002346564-569
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Probability of Progression among 1384 Residents
of Southeastern Minnesota in Whom Monoclonal
Gammopathy of Undetermined Significance (MGUS)
Was Diagnosed from 1960 through 1994
Kyle, R. A. et al. N Engl J Med 2002346564-569

• Risk of progression to serious disease 1 per
  year

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Patterns of Increase in Monoclonal Protein among
1384 Residents of Southeastern Minnesota in Whom
Monoclonal Gammopathy Was Diagnosed in 1960
through 1994
Kyle, R. A. et al. N Engl J Med 2002346564-569
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MGUS

• The size of the M-protein at the time of
  recognition of MGUS is the most important
  predictor of progression
• IgM IgA monoclonal proteins have a greater risk
  of progression than an IgG M-protein
• Reduction in uninvolved immunoglobulins urine
  protein not significant

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MGUS

• Management

• Periodic monitoring of serum protein
  electrophoresis
• Interval of monitoring based on initial M-protein
  level
• Monitoring should be at least annually LIFELONG

• Risk does not go away with time cumulative
  probability of progression
• ( 10 at 10 years , 25 at 25 years)

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Patient Profile

• 64 year old female hospitalized with severe low
  back pain for 3 weeks. Spine films negative MRI
  scan showed path fracture at L2 . Fatigue x 2
  months

ESR 28mm/hr Creat 0.6 Calcium 9.4 SPEP
M-protein IgG kappa 4.8 g/dl
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Multiple Myeloma

• SPEP

3-4 patients have no serum or urine M-protein
non-secretory myeloma
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Multiple Myeloma
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Patient Profile

• Skeletal survey diffuse osteoporosis
• Bone marrow 48 atypical plasma cells
• L2 biopsy plasmacytoma

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Multiple Myeloma

• Diagnostic definition

Minimal criteria for diagnosis include a bone
marrow containing gt 10 plasma cells (or
plasmacytoma) plus at least one of the following

• M-protein in serum gt3 g/dL
• M-protein in urine
• Lytic bone lesions

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Multiple Myeloma

• International Myeloma Working Group

• Presence of an M-protein in serum
• Presence of bone marrow clonal plasma cells
• Presence of related tissue or organ impairment
  (CRAB)

C calcium R renal failure A anemia B
bone lesions
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Multiple Myeloma

• Bone Disease

Conventional radiographs abnormal 80 of patients
who present with multiple myeloma
Osteopenia or osteoporosis 20 Focal lytic bone
57 Pathologic fractures 20 Vertebral body
compression fractures 20
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Multiple Myeloma

• MRI scan

• MRI scans of spine are an excellent assessment
  of bone marrow and myelomatous involvement.
• gt95 of patients with multiple myeloma have MRI
  abnormalities

Diffuse involvement of bone marrow Focal bone
marrow lesions Heterogeneous bone marrow
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Multiple Myeloma
Osteolytic lesions occur through 2 mechanisms via
production of cytokines by myeloma cells adjacent
to bone

• Stimulation of osteoclastic activity

IL-6
Inhibition of osteoblastic activity
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The Role of Wnt-Signaling Antagonist DKK1 on the
development of Osteolytic Lesions in Multiple
Myeloma
Gene expression analysis
NEJM Tian,E Dec 2003
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Multiple Myeloma

• Bone disease mechanism for osteolytic lesions

BM microenvironment Myeloma cell overexpress DKK1
Osteoclasts
osteoblast
Tian,EDec 2003 NEJM
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Multiple Myeloma

• Oncologic emergency

Spinal cord compression occurs in 5 of patients
with multiple myeloma
Managed with urgent 1. Corticosteroids 2.neurosur
gical intervention (laminectomy or anterior
decompression) radiation therapy to preserve
neurological function 3. Radiation therapy alone
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Multiple Myeloma
Normochromic /normocytic anemia occurs in 75
patients at diagnosis
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Multiple Myeloma

• Renal disease

• Serum creatinine increased in gt 50 at diagnosis
• Creatinine gt2g/dL in 20 of patients
• Renal failure may be presenting manifestation

Major causes

• Myeloma cast nephropathy
• Hypercalcemia
• Amyloidosis
• Radiocontrast dye in a patient with myeloma

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Multiple Myeloma
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Multiple Myeloma
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Multiple Myeloma

• Prognosticators

• Serum beta2 microglobulin- small protein
  synthesized by all nucleated cellslight chain
  moiety of HLA antigen
• LDH reflects cell turnover
• C-reactive protein reflects IL-6 levels

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Multiple Myeloma

• Cytogenetics

Abnormalities associated with chromosome 13 carry
a particularly unfavorable prognosis respond
poorly to therapy
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Multiple Myeloma

• Management

MGUS
Multiple myeloma
SMM
SMM smoldering multiple myeloma M-protein
gt3g/dl ,bone marrow plasma cells gt10, but
asymptomatic with no organ related problems
SMM requires no intervention but close
surveillance to assess stability
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Multiple Myeloma

• TreatmentBisphosphonates

Pamidronate given monthly IV has been
demonstrated to significantly reduce skeletal
events in patients with Multiple Myeloma.
Pamidronate
Placebo
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Skeletal events

• Also reduces bone pain

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Multiple Myeloma

• Management

Multiple Myeloma
Age lt70 Transplant eligible
Age gt 70 Transplant ineligible
Melphalan 0.15mg/kg x 7 d Prednisone 20mg po tid
x 7d
MP produces reponse rates of 50-60 median
survival of 2-3 years
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Multiple Myeloma

• Conventional chemotherapy for induction

VAD -Vincristine Adriamycin Dexamethasone
ORR CR
84 27
Modification of this regimen now with
VDD(pegylated lipasomal doxirubicin)
Anderson,HBr J Cancer 1995
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Multiple Myeloma

• Thalidomide

• old drug 1950s for sedation pregnancy induced
  nausea/vomiting
• Withdrawn 1961-tetratogenic causing phocomelia
• Deformities later found to be due to inhibition
  of developing fetal limbs vessels
  (anti-angiogenic)

IMiDs (immunomodulatory agent )with
antiangiogenic properties
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Multiple Myeloma

• Thalidomide dexamethasone

• Myeloma patients with refractory disease
  underwent clinical trials producing 50 response
  rate (CR PR )
• Median survival from start of therapy 38 months
• Relatively minor side effects and taken orally
• Major clinical trials now testing thalidomide
  /Dex as induction regimen

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Multiple Myeloma

• Proteosome inhibitors (Velcade) FDA approval May
  2003

Interferes with intracellular pathway that
degrades proteins regulating cell cycle,
apoptosis,angiogenesis
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Multiple Myeloma

• Autologous transplantation recommended for
  advanced stage myeloma after induction therapy
  age lt70, good PS, normal renal function

Tandem double better than single (41 vs 21 mos OS)

• Allogeneic transplantation-insufficient evidence
  currently nonmyeloblative mini transplants as
  salvage

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Poems(osteosclerotic myeloma)

• Polyneuropathy dominating feature(100),motor
• Organomegaly-hepatosplenomegaly (50)
• Endocrinopathy hypogonadism, hypothyroidism (66)
• Monoclonal gammopathy
• Skin changes hyperpigmentation, hypertrichosis

Sclerotic bone lesions 97 Etiology of symptoms
related to proinflammatory cytokines (VEGF)
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Poems(osteosclerotic myeloma)

• Treatment 5000cGy to osteosclerotic bone lesion

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Patient Profile

• 54 year old high profile male trial attorney
  went skiing with the firm in March 2002. Fell
  fractured left humerus. Saw orthopedic surgeon on
  return to Dallas.Pathologic fracturebone survey
  otherwise negative MRI spine negative.

Lab BM lt10 plasma cells SPEP
0.52 IgGkappa UPEP -negative
DX Solitary Plasmacytoma left humerus
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Solitary plasmacytoma

• Presence of single plasmacytoma without evidence
  of multiple myeloma
• Younger median age at presentation (55yrs)
• 50-60 will convert multiple myeloma within 10
  years
• Treatment tumoricidal radiation to site
  (5000cGy)
• Possible bone marrow collection/storage