Transcript Plasma Cell Disorders Monoclonal Gammopathies Kristi McIntyre M.D.
Plasma Cell Disorders
Monoclonal Gammopathies
Kristi McIntyre M.D.
Texas Oncology
2004
A Cluster of Malignant Plasmablasts Bataille, R. et al. N Engl J Med 1997;336:1657-1664
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
Patient Profile
• 61 year old female presented with rash to dermatologists in 2001. SPEP revealed 0.2 IgGlambda M-protein. Asymptomatic otherwise.
2
Breast ca
M-protein 1 2001 2002 2003 2004
MGUS
Denotes presence of an M-protein in a patient without a plasma cell or lymphoproliferative disorder
•M-protein < 3g/dL • < 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
MGUS
Monoclonal Gammopathy of Undetermined Significance •1
% of adults in US
•
3% of adults over age 70 years
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11% of adults over age 80 years
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14% of adults over age 90 years
MGUS
MGUS can progress to monoclonal disease:
IgA or IgG Multiple Myeloma Primary Amyloidosis or related plasma cell disorder IgM NHL CLL Waldentroms macroglobulinemia
MGUS
• 1,384 patients MGUS
Heavy chain IgG : 70% IgM :15% IgA :12% Light chain Kappa : 61% Lambda : 39% Concentration of uninvolved immunoglobulins reduced in 39% Kyle, R. A. et al. N Engl J Med 2002;346:564-569
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 2002;346:564-569
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 2002;346:564-569
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 2002;346:564-569
Risk of progression to serious disease 1% per year
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 2002;346:564-569
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
MGUS
Management: •
Periodic monitoring of serum protein electrophoresis
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Interval of monitoring based on initial M-protein level
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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)
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
SPEP
Multiple Myeloma
3-4 % patients have no serum or urine M-protein “non-secretory myeloma”
Multiple Myeloma
Patient Profile
• Skeletal survey : diffuse osteoporosis • Bone marrow : 48% atypical plasma cells • L2 biopsy: plasmacytoma
Multiple Myeloma
Diagnostic definition:
Minimal criteria for diagnosis include a bone marrow containing > 10% plasma cells (or plasmacytoma) plus at least one of the following:
•
M-protein in serum >3 g/dL
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M-protein in urine
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Lytic bone lesions
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
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%
Multiple Myeloma
MRI scan:
MRI scans of spine are an excellent assessment of bone marrow and myelomatous involvement.
>95% of patients with multiple myeloma have MRI abnormalities:
Diffuse involvement of bone marrow Focal bone marrow lesions Heterogeneous bone marrow
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
The Role of Wnt-Signaling Antagonist DKK1 on the development of Osteolytic Lesions in Multiple Myeloma
Gene expression analysis
NEJM Tian,E Dec 2003
Multiple Myeloma
Bone disease: mechanism for osteolytic lesions
BM microenvironment Myeloma cell overexpress DKK1 osteoblast Osteoclasts Tian,EDec 2003 NEJM
Multiple Myeloma
Oncologic emergency Spinal cord compression occurs in 5 % of patients with multiple myeloma
Managed with urgent: 1. Corticosteroids 2.neurosurgical intervention (laminectomy or anterior decompression) + radiation therapy to preserve neurological function 3. Radiation therapy alone
Multiple Myeloma
Normochromic /normocytic anemia occurs in 75% patients at diagnosis
Multiple Myeloma
Renal disease •
Serum creatinine increased in > 50% at diagnosis
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Creatinine >2g/dL in 20% of patients
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Renal failure may be presenting manifestation
Major causes: •
Myeloma cast nephropathy
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Hypercalcemia
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Amyloidosis
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Radiocontrast dye in a patient with myeloma
Multiple Myeloma
Multiple Myeloma
Multiple Myeloma
Prognosticators: •
Serum beta2 microglobulin small protein synthesized by all nucleated cells;light chain moiety of HLA antigen
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LDH reflects cell turnover
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C-reactive protein reflects IL-6 levels
Multiple Myeloma
• Cytogenetics
Abnormalities associated with chromosome 13 carry a particularly unfavorable prognosis & respond poorly to therapy
Multiple Myeloma
Management
MGUS SMM Multiple myeloma
SMM –smoldering multiple myeloma : M-protein >3g/dl ,bone marrow plasma cells >10%, but asymptomatic with no organ related problems
SMM requires no intervention but close surveillance to assess stability
Multiple Myeloma
•
Treatment:Bisphosphonates: Pamidronate given monthly IV has been demonstrated to significantly reduce skeletal events in patients with Multiple Myeloma.
Skeletal events Pamidronate* 21% Placebo 41%
Also reduces bone pain
Multiple Myeloma
Management
Multiple Myeloma Age <70 Transplant eligible Age > 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
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,H:Br J Cancer 1995
Multiple Myeloma
Thalidomide •
old drug 1950’s for sedation & pregnancy induced nausea/vomiting
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Withdrawn 1961-tetratogenic causing phocomelia
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Deformities later found to be due to inhibition of developing fetal limbs vessels (anti-angiogenic)
IMiDs (immunomodulatory agent )with antiangiogenic properties
Multiple Myeloma
Thalidomide & dexamethasone •
Myeloma patients with refractory disease underwent clinical trials producing 50% response rate (CR =PR )
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Median survival from start of therapy 38 months
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Relatively minor side effects and taken orally
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Major clinical trials now testing thalidomide /Dex as induction regimen
Multiple Myeloma
Proteosome inhibitors (Velcade) FDA approval May 2003
Interferes with intracellular pathway that degrades proteins regulating cell cycle, apoptosis,angiogenesis
Multiple Myeloma
•
Autologous transplantation
– recommended for advanced stage myeloma after induction therapy = age <70, 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
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)
Poems(osteosclerotic myeloma)
Treatment : 5000cGy to osteosclerotic bone lesion
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 fracture”bone survey otherwise negative: MRI spine negative.
Lab: BM : <10% plasma cells SPEP 0.52% IgGkappa UPEP -negative
DX : Solitary Plasmacytoma left humerus
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