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 WisconsinWhite males, ages 50-74

Wisconsin Cancer Mortality Black males, ages 50-74

Age specific Mortality by Race

75,075 total deaths 1970 –1994White males

Myeloma Mortality by State

75,075 total deaths 1970 –1994Black males

Myeloma Mortality by State

Regional Mortality RateMyeloma 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

Travel

Lymph Node

Follicles

BoneMarrow

Pre B cellIgM

B cell

B cell finds “meaning”

B cell activation

Germinal CenterFormation

“meaning”

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– Back Pain

– Fatigue

– Anorexia

– Recurrent infection

– Constipation

– Somulence

– Fracture

– Neuropathy

• Signs– Lytic lesions

– Anemia, pancytopenia

– Hypercalcemia

– Renal insufficiency

– Monoclonal proteins

– Organomegaly

– Bone tumors

– Hypogammaglobulins

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

Lytic Bone Lesions in Myeloma

•Important for diagnosis•Treatment of impending fracture

Protein ElectrophoresisSerum or Urine

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

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

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

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

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

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

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

Survival

18 – 30 mos 24 – 42 mos

Overall

Survival

44 – 64 mos 57 – 72 mos

High-dose Chemotherapy for Myeloma

Attal NEJM 335:91, 1996

5 yr OS•Convential chemo 12%•High Dose 52%

•No Cure

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

Immunosuppression

onlyStem cells

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)