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)