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Plasma CellDisorders
Kristi McIntyre M.D.Texas Oncology2004
Monoclonal Gammopathies
Bataille, R. et al. N Engl J Med 1997;336:1657-1664
A Cluster of Malignant Plasmablasts
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.
2001 2002 2003 2004
2
1M-proteinBreast ca
MGUSDenotes 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•11% of adults over age 80 years•14% of adults over age 90 years
MGUS
MGUS can progress to monoclonal disease:
IgA or IgG
Multiple MyelomaPrimary Amyloidosis
or related plasma cell disorder
IgM
NHLCLL
Waldentroms macroglobulinemia
MGUS
• 1,384 patients MGUS
Kyle, R. A. et al. N Engl J Med 2002;346:564-569
IgG : 70%IgM :15%IgA :12%
Heavy chain Light chain
Kappa : 61%Lambda : 39%
Concentration of uninvolved immunoglobulins reduced in 39%
MGUSprognosticators( predictors of progression):
1. Age2. sex3. Size of initial M-protein4. Type of immunoglobulins5. Hemoglobin6. # of bone marrow plasma cells7. Reduction of uninvolved imunoglobulins8. Urinary light chains
Kyle, R. A. et al. N Engl J Med 2002;346:564-569
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
Risk of progression to serious disease 1% per year
Kyle, R. A. et al. N Engl J Med 2002;346:564-569
Patterns of Increase in Monoclonal Protein among 1384 Residents of Southeastern Minnesota in Whom Monoclonal Gammopathy Was Diagnosed in 1960 through 1994
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•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)
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/hrCreat : 0.6Calcium 9.4SPEP : 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:
•M-protein in serum >3 g/dL• M-protein in urine•Lytic bone lesions
Minimal criteria for diagnosis include a bone marrow containing > 10% plasma cells (or plasmacytoma) plus at least one of the following:
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 calciumR renal failureA anemiaB bone lesions
Multiple Myeloma
Bone DiseaseConventional 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 marrowFocal bone marrow lesionsHeterogeneous bone marrow
Multiple Myeloma
Stimulation of osteoclastic activity
Osteolytic lesions occur through 2 mechanisms via production of cytokines by myeloma cells adjacent to bone:
Inhibition of osteoblastic activity
IL-6
NEJM Tian,E Dec 2003
The Role of Wnt-Signaling Antagonist DKK1 on the development of Osteolytic Lesions in Multiple Myeloma
Gene expression analysis
Multiple Myeloma
Bone disease: mechanism for osteolytic lesions
BM microenvironmentMyeloma cell overexpress
DKK1
osteoblast OsteoclastsTian,EDec 2003 NEJM
Multiple MyelomaOncologic emergency
Spinal cord compression occurs in 5 % of patients with multiple myeloma
Managed with urgent:1. Corticosteroids2.neurosurgical intervention (laminectomy or anterior decompression) + radiation therapy to preserve neurological function3. 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•Creatinine >2g/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
Multiple Myeloma
Multiple Myeloma
Multiple Myeloma
Prognosticators:
•Serum beta2 microglobulin- small protein synthesized by all nucleated cells;light chain moiety of HLA antigen•LDH reflects cell turnover•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
SMM –smoldering multiple myeloma : M-protein >3g/dl ,bone marrow plasma cells >10%, but asymptomatic with no organ related problems
MGUSMultiple myelomaSMM
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.
21% 41%Skeletal events
Pamidronate* Placebo
Also reduces bone pain
Multiple Myeloma
ManagementMultiple Myeloma
Age <70Transplant eligible
Age > 70Transplant ineligible
Melphalan 0.15mg/kg x 7 dPrednisone 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
IMiDs (immunomodulatory agent )with antiangiogenic properties
•old drug 1950’s 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)
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
Multiple MyelomaProteosome 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
•Allogeneic transplantation-insufficient evidence currently nonmyeloblative “mini” transplants as salvage
Tandem double better than single (41 vs 21 mos OS)
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