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 Wisconsin White males, ages 50-74

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

5. Age specific Mortality by Race

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

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

8. Regional Mortality Rate Myeloma 1970-1994

9. Age-adjusted Incidence per 100,000 MaleFemale White6.24.1 Black11.810.0

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

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

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

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

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. 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

17. 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

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

19. Protein Electrophoresis Serum or Urine

20. Staging Greater 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

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. 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

24. 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

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. 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

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 ChemotherapyHigh-dose Chemotherapy CR rate5 – 11%22 – 30% Event-free Survival 18 – 30 mos24 – 42 mos Overall Survival 44 – 64 mos57 – 72 mos

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

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)