Diagnosis and Treatment of Multiple Myeloma

1. Diagnosis and Treatment of Multiple Myeloma Mark B. Juckett MD Division of Hematology University of Wisconsin December 11, 2002

2. 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

3. Cancer Mortality WisconsinWhite males, ages 50-74

4. Wisconsin Cancer Mortality Black males, ages 50-74

5. Age specific Mortality by Race

6. Myeloma Mortality by State 75,075 total deaths 1970 –1994 White males

7. Myeloma Mortality by State 75,075 total deaths 1970 –1994 Black males

8. Regional Mortality RateMyeloma 1970-1994

9. Age-adjusted Incidence per 100,000

10. Etiology • Familial clustering • African Americans • Radiation • Agriculture, Benzene, Radiation, Sheet metal work • Chronic inflammatory disorders

11. Pre B cell IgM B cell Follicles Bone Marrow Lymph Node Normal B cell Development Travel

12. “meaning” B cell activation Germinal Center Formation B cell finds “meaning”

13. Memory B cell “Activated B cell” Plasma Cell Plasma Cells travel back to bone marrow

14. Properties of Plasma Cells • Proliferate • Secrete Immunoglobulins • “Make space” • Influence bone turnover • Secrete Inflammatory mediators

15. 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

16. 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 Presenting Symptoms and Signs

17. H&P CBC BUN/creat, lytes Calcium/albumin Quant Ig SPEP/immunofix Bone Marrow Biopsy 24-hour urine UPEP/immunofix Beta2-microglobulin Skeletal survey Initial Diagnostic Workup

18. Lytic Bone Lesions in Myeloma • Important for diagnosis • Treatment of impending fracture

19. Protein ElectrophoresisSerum or Urine

20. 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 StagingGreater than 20% plasma cells • Stage II – not fitting I or III

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. Randomized Trials Comparing Standard vs. High-dose chemotherapy

30. High-dose Chemotherapy for Myeloma • 5 yr OS • Convential chemo 12% • High Dose 52% • No Cure Attal NEJM 335:91, 1996

31. 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

32. 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?

33. Non-myeloablative SCT Immuno suppression only Stem cells Manipulate the Immune response to maximize Graft vs. Disease

34. 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

35. 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

36. 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

37. 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

38. 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

39. 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

40. 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)