Diagnosis and Treatment of

Multiple Myeloma

Mark B. Juckett MD
Division of Hematology
University of Wisconsin
December 11, 2002
 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
Cancer Mortality Wisconsin
White males, ages 50-74
Wisconsin Cancer Mortality
Black males, ages 50-74
Age specific Mortality by Race
Myeloma Mortality by State

75,075 total deaths 1970 1994

White males
Myeloma Mortality by State

75,075 total deaths 1970 1994

Black males
Regional Mortality Rate
Myeloma 1970-1994
 Age-adjusted Incidence per
100,000
Male Female

White 6.2 4.1

Black 11.8 10.0

 Etiology
Familial clustering
African Americans
Radiation
Agriculture, Benzene, Radiation, Sheet
metal work
Chronic inflammatory disorders
 Normal B cell Development
Pre B cell
IgM

B cell Follicles

Bone
Marrow Travel

Lymph Node
B cell finds meaning
meaning

B cell activation
Germinal Center
Formation
 Plasma Cells travel
back to bone marrow

Memory B cell

Activated B cell

Plasma Cell
Properties of Plasma Cells
Proliferate
Secrete Immunoglobulins
Make space
Influence bone turnover
Secrete Inflammatory
mediators
 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
Presenting Symptoms and Signs
Symptoms Signs
Back Pain Lytic lesions
Fatigue Anemia, pancytopenia
Anorexia Hypercalcemia
Recurrent infection Renal insufficiency
Constipation Monoclonal proteins
Somulence Organomegaly
Fracture Bone tumors
Neuropathy Hypogammaglobulins
 Initial Diagnostic Workup
H&P Bone Marrow Biopsy
CBC 24-hour urine
BUN/creat, lytes UPEP/immunofix
Calcium/albumin Beta2-microglobulin
Quant Ig Skeletal survey
SPEP/immunofix
Lytic Bone Lesions in Myeloma

Important for diagnosis

Treatment of impending fracture
Protein Electrophoresis
Serum or Urine
 Staging
Greater than 20% plasma cells

Stage I (All) Stage III (Any)

Hgb > 10 g/dl Hgb < 10 g/dl
Normal calcium Hypercalcemia
Normal bones or Solitary Multiple lytic lesions
plasmacytoma High M-protein
Low M-protein IgG > 7 g/dl
IgG < 5 g/dl IgA > 5 g/dl
IgA < 3 g/dl Light chains > 12 g/24 h
Light chains < 4 g/24 h

Stage II not fitting I or III

 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
 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
 Treatment
Solitary 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
 Treatment
Smoldering 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
 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
 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
 Treatment
Stage 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
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
 Randomized Trials
Comparing Standard vs. High-dose chemotherapy

Chemotherapy High-dose
Chemotherapy
CR rate 5 11% 22 30%

Event-free 18 30 mos 24 42 mos

Survival
Overall 44 64 mos 57 72 mos
Survival
High-dose Chemotherapy
for Myeloma

5 yr OS
Convential chemo 12%
High Dose 52%

No Cure

Attal NEJM
335:91, 1996
 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
 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?
 Non-myeloablative SCT
Immuno
suppression Stem cells
only

Manipulate the Immune response to

maximize Graft vs. Disease
 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
 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
 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
 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
 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
 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
 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)