diagnosis and treatment of multiple myeloma mark b. juckett md division of hematology university of...
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Diagnosis and Treatment of Multiple Myeloma
Mark B. Juckett MD
Division of Hematology
University of Wisconsin
December 11, 2002
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Introduction
• Multiple myeloma is a clonal plasma cell neoplasm
• Usually accompanied by monoclonal antibody production
• 1% of all cancer
• Median age 65 years
• Incidence higher in African populations
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Cancer Mortality WisconsinWhite males, ages 50-74
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Wisconsin Cancer Mortality Black males, ages 50-74
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Age specific Mortality by Race
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75,075 total deaths 1970 –1994White males
Myeloma Mortality by State
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75,075 total deaths 1970 –1994Black males
Myeloma Mortality by State
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Regional Mortality RateMyeloma 1970-1994
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Age-adjusted Incidence per 100,000
Male Female
White 6.2 4.1
Black 11.8 10.0
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Etiology
• Familial clustering
• African Americans
• Radiation
• Agriculture, Benzene, Radiation, Sheet metal work
• Chronic inflammatory disorders
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Normal B cell Development
Travel
Lymph Node
Follicles
BoneMarrow
Pre B cellIgM
B cell
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B cell finds “meaning”
B cell activation
Germinal CenterFormation
“meaning”
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Plasma Cells travel back to bone marrow
Memory B cell
“Activated B cell”
Plasma Cell
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Properties of Plasma Cells
• Proliferate
• Secrete Immunoglobulins
• “Make space”
• Influence bone turnover
• Secrete Inflammatory mediators
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Clinical Manifestations
• Plasma Cell proliferation– Pancytopenia, bone damage, constitutional
symptoms, anorexia, cachexia, hypercalcemia
• Monoclonal protein production– Renal failure, hyperviscosity, amyloidosis,
hypoalbuminemia, neurologic symptoms
• Immunodeficiency– Infection, autoimmune phenomena
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Presenting Symptoms and Signs
• Symptoms– Back Pain
– Fatigue
– Anorexia
– Recurrent infection
– Constipation
– Somulence
– Fracture
– Neuropathy
• Signs– Lytic lesions
– Anemia, pancytopenia
– Hypercalcemia
– Renal insufficiency
– Monoclonal proteins
– Organomegaly
– Bone tumors
– Hypogammaglobulins
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Initial Diagnostic Workup
• H&P• CBC• BUN/creat, lytes• Calcium/albumin• Quant Ig• SPEP/immunofix
• Bone Marrow Biopsy• 24-hour urine• UPEP/immunofix• Beta2-microglobulin• Skeletal survey
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Lytic Bone Lesions in Myeloma
•Important for diagnosis•Treatment of impending fracture
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Protein ElectrophoresisSerum or Urine
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StagingGreater than 20% plasma cells
• Stage I (All)– Hgb > 10 g/dl
– Normal calcium
– Normal bones or Solitary plasmacytoma
– Low M-protein• IgG < 5 g/dl
• IgA < 3 g/dl
• Light chains < 4 g/24 h
• Stage III (Any)– Hgb < 10 g/dl
– Hypercalcemia
– Multiple lytic lesions
– High M-protein• IgG > 7 g/dl
• IgA > 5 g/dl
• Light chains > 12 g/24 h
•Stage II – not fitting I or III
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Smoldering Myeloma
• Monoclonal gammopathy– IgG > 3.5 g/dl and < 5 g/dl– IgA > 2 g/dl and < 3 g/dl– Urine light chains > 1 g/dl
• Bone Marrow Plasma cells– Greater than 10% and less than 20%
• No anemia, renal insufficiency, hypercalcemia• No lytic lesions or diffuse osteopenia
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NCCN Treatment Guidelines
• National Comprehensive Cancer Network– Group of NCI Cancer Centers
• Evidence based guidelines of appropriate care for general population
• Reviewed annually and updated by panel members
• Available online: www.nccn.org
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TreatmentSolitary Plasmacytoma
• Radiation therapy 45 to 50 Gy
• Follow up– CBC, SPEP, UPEP, chemistry every 3 months– Bone Survey ± CT scan or MRI every 6 mo– Yearly evaluation after one year and no disease
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TreatmentSmoldering or Stage I myeloma
• Counseling and observation• Followup
– CBC, SPEP, UPEP, chemistry every 3 mo
– Bone survey ± Bone marrow biospy every 6 mo
• Clinical trial of thalidomide or other biological therapy
• Progression to Stage II, III disease– Treat accordingly
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Treatment Stage II or III disease
• General Goals of Oncology– Cure to regain normal life– Achieve complete remission to preserve quality
life– Control disease to preserve quality life– Minimize symptoms– Prevent suffering
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Treatment Stage II or III disease
• Combination chemotherapy– Not curative, complete remission uncommon
• Multiple regimens – none yet shown to improve survival over 30 years of study
• Regimen choice depending on goals of therapy
• Supportive care crucial for preservation of function and activity
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TreatmentStage II or III disease
• Goals of initial treatment– Gain control of disease
– Improve organ function
– Maintain activity & function
– Relieve pain, constitutional symptoms
• Chemotherapy regimens differ in toxicity, ability to achieve remission
• Approach differs depending on age, comorbidity, possibility of stem cell transplant
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Stem cell transplant for myeloma
• Rationale– Dose response relationship for remission and
hematologic toxicity– Stem cell transplant minimizes the hematologic
toxicity of high dose chemotherapy– Stem cell transplant has no anti-myeloma effect
per se but allows escalation of chemotherapy
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Randomized Trials Comparing Standard vs. High-dose chemotherapy
Chemotherapy High-dose
Chemotherapy
CR rate 5 – 11% 22 – 30%
Event-free
Survival
18 – 30 mos 24 – 42 mos
Overall
Survival
44 – 64 mos 57 – 72 mos
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High-dose Chemotherapy for Myeloma
Attal NEJM 335:91, 1996
5 yr OS•Convential chemo 12%•High Dose 52%
•No Cure
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Candidates for High-dose chemotherapy
• Who?– Responding patients– Age < 65 yo, possible for age 65 – 75 years– Adequate renal, pulmonary, cardiac function
• When?– Upfront vs. first relapse: Same overall survival,
but better QOL with upfront
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Investigational Approaches
• Thalidomide– Response rate 36% in relapse
• PS-341, Arsenic trioxide, R115777
• Allogeneic transplant– Outpatient treatment with minimal
chemotherapy– Studies suggest long remissions – Cure?
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Non-myeloablative SCT
Immunosuppression
onlyStem cells
Manipulate the Immune response to maximize Graft vs. Disease
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Auto/Allo Transplant for Myeloma
• Auto - improve cytoreduction with less morbidity prior to NST
• Allo NST - use in minimal residual disease state to allow time for “GVM”
• Separate Auto and Allo to reduce TRM
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Auto/Allo NST - Results
• 32 patients (median age 55)
• Previously treated (43% refractory/relapse)
• Mel-200 with PBSCT
• NST - TBI 2Gy, PBSCT, CSA, MMF
• 31/32 received both
• NST - median 0 days hospitalization, neutropenia, thrombocytopenia
Maloney, Blood 98:1822a
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Auto/Allo NST - Results (cont)
• Overall survival 81% (median f/u 423 days)
• Day-100 mortality 6%
• GVHD– Acute 45%– Chronic 55%
• Response Rate 84% (CR 53%, PR 31%)
• 2 Patients have progressed
Maloney, Blood 98:1822a
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Supportive Care
• Prevent Fractures– 85% of patients have lytic bone disease– Biphosphonates – Pamidronate, Zolentronate– Local radiotherapy for critical lytic lesions and
persistent pain
• Anemia– Erythropoietin helpful for anemia patients
• Infection– Prophylactic antibiotics and IV immunoglobulin for
patients with recurrent infection
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Monoclonal Gammopathy
• Increasingly common with age• Associated with many inflammatory conditions• Diagnosis depends on finding M-protein
– But
• No evidence of clinical disease– No lytic lesions
– Plasma cells below 10% in the bone marrow
– Normal blood counts and renal function
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Distinguishing between MGUS and Myeloma
• Rising M-spike• Urinary free light chains• Decreased immunoglobulins• Plasmacytosis greater than 10%• Osteolysis• Hypercalcemia• Spleen or liver involvement• Anemia or pancytopenia• Elevated ESR
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Conclusions
• Myeloma is a cancer of plasma cells• Patients suffer primarily from bone disease,
anemia and renal disease• Conventional treatment is non-curative• Aggressive treatment with high-dose
chemotherapy preserves quality life• Supportive care improves quality life (and
survival)