1. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria MULTIPLE MYELOMA

2. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria MULTIPLE MYELOMA Median age at diagnosis, 65 years MM accounts for 1 - 2 % of all malignant diseases

3. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria MGUS (55%) Multiple Myeloma (18%) Amyloidosis AL (12%) Lymphoprolif. Diseases (3%) Smoldering Myeloma (3%) Solitary Plasmacytoma (2%) M.Waldenström (2%) Others (5%) MULTIPLE MYELOMA Monoclonal Gammopathies n= 882 Adapted from Kyle RA, 1997

4. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria MULTIPLE MYELOMA Diagnostic criteria for MGUS Monoclonal Immunoglobulin (<3 g/dl) No anaemia, hypercalcaemia or renal insufficiency No osteolytic lesions Bone marrow infiltration with <10% plasma cells (no plasmablasts)

5. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria MULTIPLE MYELOMA Long-term Follow-up of Patients with MGUS MGUS 52% 12% 10% 26% Death unrelated to MGUS Alive with MGUS Paraprotein > 3g/dl Progression to MM(17%) NHL(5%) or Amyloidosis(3%) after 24-38 Years Probability Conclusion: The risk of progression of MGUS to MM (or a related disorder) is about 1% per year. Kyle RA et al., NEJM 2002

6. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria MULTIPLE MYELOMA Indications for therapy M-protein in serum and/or urine Hemoglobin Calcium or creatinine Lytic bone lesions Extramedullary plasmacytoma

7. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria MULTIPLE MYELOMA Primary Treatment < age 65 > age 65 (melphalan/prednisone or combination chemotherapy) (high-dose melphalan, followed by autotransplantation) Standard-dose chemotherapy High-dose therapy

8. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria MULTIPLE MYELOMA STANDARD-DOSE CHEMOTHERAPY IN MULTIPLE MYELOMA Single (MP) vs. combination chemotherapy (CCT) Therapy Response (%) MP 53 P<.00001 CCT60 No difference in survival No subsets with benefit n=6,633 (27 trials) Myeloma Trialists, JCO 1998

9. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria MULTIPLE MYELOMA TREATMENT Interferon-alpha TherapyRelapse-free survivalOverall survival at 5 years (%) at 5 years (%) IFN 2331 No IFN 1628 P=.00001 P=.008 Myeloma Trialists, Br J Haematol 1998 Meta-analysis of 20 trials (n = 4000)

10. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria STANDARD-DOSE THERAPY IN MM Second-line treatment Duration of remission / plateau-phase > 6 months Retreatment with initial therapy < 6 months VAD ID, VRID VMCP / VBAP DCEP Thalidomide Thal / Dexa

11. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria MULTIPLE MYELOMA

12. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria STANDARD versus HIGH-DOSE THERAPY IN MM Study Therapy %CR OS(months) P Attal (1996)VMCP/VBAP 544 MEL140+TBI2257<.001 Barlogie (1997) 1 ConventionalNA48 MEL200x24062+.01 Palumbo (1999) 1,2 MP 548 MEL100x2/34756+<.01 Lenhoff (2000) 1 Standard doseNA44 MEL 2003460+.001 Child (2001)ABCM1442 MEL2005352<.05 1 Pair-mate analysis 2 Patients at >60 years of age

13. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria PROGNOSTIC FACTORS FOR SURVIVAL AFTER HIGH-DOSE THERAPY No -13/13q-0.4<.0001 B2M < 2.5 mg/l0.6<.0001 < 12 months prior SDT0.7.0001 CRP < 4.0 mg/l0.7<.0002 Sensitive disease (SDT)0.7.0002 Days to 2 nd HDT 0.4.001 Any 2 nd HDT0.02<.0001 Non-IgA isotype0.7.002 Desikan et al., Blood 2000 RR P "Arkansas 1000 "

14. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria IFM 94 (Attal et al.) MEL140(+TBI) MEL140x2(+TBI) CR34%35% NS Median EFS31 months37 months.03 EFS at 6 years19%28% Median OS50 months58 months.02 OS at 6 years26%46% Interim analysis, January 2002 MULTIPLE MYELOMA SINGLE versus DOUBLE AUTOTRANSPLANTATION

15. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria CHROMOSOME 13q14 (FISH) AND SURVIVAL IN MM Study Therapy 1 n OS(months) P Perez-Simon (1998)SDT normal 3260 deleted 1614.001 Zojer (2000)SDT normal 5160+ deleted 4624 <.005 Fonseca (2002)SDT normal 14951 deleted 17635.02 Worel (2001)HDT normal 1772+ deleted 1124.012 Facon (2001)HDT normal 6865 deleted 4226.0001 13q14 1 SDT, standard-dose chemotherapy; HDT, high-dose therapy (MEL + autologous PBSCS)

16. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria PROGNOSTIC MODEL IN MM FEATURES MEDIAN SURVIVAL Königsberg (JCO 2000) 102 months 46 months 11 months No del13q and B2M < 4 mg/l Del13q or B2M > 4 mg/l Del13q and B2M > 4 mg/l Chromosome 13q14 (FISH) and  2M Facon (Blood 2001) > 111 months 47 months 25 months No del13q and B2M < 2.5 mg/l Del13q or B2M > 2.5 mg/l Del13q and B2M > 2.5 mg/l Standard-dose chemotherapy: High-dose chemotherapy:

17. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria THALIDOMIDE IN ADVANCED AND REFRACTORY MM 169 patients (76% with prior high-dose therapy). Thalidomide at a dose of 200-800 mg daily. Objective responses (25% tumor regression) in 37% of patients, with near-complete or complete remissions in 14%. Two-year event-free and overall survival rates were 20% and 48%, respectively. Barlogie et al., Blood 98: 492, 2001

18. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria TREATMENT OF MULTIPLE MYELOMA SUMMARY High-dose chemotherapy is superior to standard-dose chemotherapy in MM (improved CR rate, prolonged event-free and overall survival). The current standard of high-dose therapy is melphalan 200 mg/m 2 followed by autologous peripheral blood stem cell support, with some evidence suggesting a beneficial role of tandem transplantation. Cytogenetics has emerged as an important prognostic factor in MM, and deletion of chromosome 13q14 is a major independent parameter predicting for short survival of patients with MM. Since patients with del13q14 do poorly with current treatment approaches, they should be considered for enrollment in clinical trials evaluating novel agents and treatment strategies.