1. Multiple Myeloma: ASH 2005 Steven Coutre, M.D. Associate Professor of Medicine Division of Hematology Stanford University School of Medicine

2. Quality of Remission Impacts Survival Alexanian R et al. BMT. 2001;27:1037

3. Complete Remission Matters Alexanian R et al. BMT. 2001;27:1037

4. Bladé J et al. Br J Haematol. 1998;102:1115 IBMTR (EBMT) Criteria for Complete and Partial Response  Complete response requires all of following –No serum/urine M protein by IFE for ≥6 wk –<5% plasma cells in bone marrow aspirate –No increase in size or number of lytic bone lesions –Disappearance of soft tissue plasmacytomas  Partial response requires all of following –  50% reduction in serum M protein  6 wk –  90% reduction in 24-hr urinary light chain excretion –  50% reduction in soft tissue plasmacytomas –No increase in size or number of lytic bone lesions

5. Melphalan 4 mg/m 2 Days 1-7 for 6 cycles + Prednisone 40 mg/m 2 Days 1-7 for 6 cycles + Thalidomide 100 mg/day* continuously (n = 129) Previously untreated patients with multiple myeloma Median age: 72 years (N = 255) Melphalan 4 mg/m 2 Days 1-7 PO for 6 cycles + Prednisone 40 mg/m 2 Days 1-7 for 6 cycles (n = 126) Randomization Six 4-week cycles *Thalidomide administration continued until relapse or progressive disease. Palumbo A, et al. ASH 2005. Abstract 779. Thalidomide Plus Melphalan/ Prednisone as First-line MM Therapy  Italian Myeloma Network study: randomized, multicenter, phase III trial Part way through the study, enoxaparin was added to MPT group for 4 months as prophylaxis against clots.

6. Thalidomide Plus Melphalan/ Prednisone as First-line MM Therapy Median event-free survival longer for MPT vs MP 29.2 months vs 13.6 months (P <.001) 36-month OS: 80% vs 64% for MPT vs MP; P =.20 Reduced DVT rates in MPT group for patients receiving vs not receiving prophylactic enoxaparin 3% vs 18.4% (P =.005) More deaths due to adverse events in MPT arm Palumbo A, et al. ASH 2005. Abstract 779. CR/nCR MPT 20 40 60 Percentage of patients MP PR 45% 60% 0 28% 7% P <.001 Response Rates Grade 3-4 Adverse Event MPT, % (n =129) MP, % (n =126) P Value Thromboembolism122.001 Infections102.01 Peripheral neuropathy 101.001 Hematologic2225NS

7. Standard Melphalan + Prednisone + Thalidomide (up to 400 mg/day*) (n = 124) 12 courses every 6 weeks Patients with multiple myeloma 65-75 years of age (N = 436) Standard Melphalan + Prednisone (n = 191) 12 courses every 6 weeks *Thalidomide administered at maximum tolerated dose. VAD: Vincristine + Doxorubicin + Dexamethasone (n = 121) 2 courses Cyclophosphamide (3 g/m 2 ) + G-CSF Melphalan (100 mg/m 2 ) + Autologous SCT + G-CSF 2 courses Thalidomide Plus Melphalan/ Prednisone in Older MM Patients Facon T, et al. ASH 2005. Abstract 780. Randomized, multicenter trial IFM 99-06: 3rd interim analysis MPT MP MEL100

8. Thalidomide Plus Melphalan/ Prednisone in Older MM Patients Longest OS with MPT MPT vs MP; P =.0008 Median not reached at Month 56 vs 30.3 months MPT vs MEL100; P =.014 Median not reached at month 56 vs 38.6 months Longest PFS with MPT MPT vs MP; P <.0001 Median 29.5 vs 17.2 months MPT vs MEL100; P =.0001 Median 29.5 vs 19.0 months Facon T, et al. ASH 2005. Abstract 780. 2 7 40 15 49 81 17 41 72 0 20 40 60 80 100 Complete Response ≥ 90% Response ≥ 50% Response MP MPT MEL100 Percentage of Patients 17 41 12 11 32 5 39 100 6.5 0 20 40 60 80 100 Severe Infection NeutropeniaDVT Patients, % MP MPT MEL100

9. Lenalidomide Plus Dexamethasone for Treatment-Naive Multiple Myeloma Nonrandomized phase II study (N = 34) Oral lenalidomide 25 mg/day, Days 1-21 Dexamethasone 40 mg/day, Days 1-4, 9-12, 17-20; Days 1-4 only after 4 cycles Daily prophylaxis with aspirin for deep venous thrombosis Able to harvest adequate stem cells (> 3 x 10 6 CD34 cells/kg) in all patients proceeding to ASCT Rajkumar SV, et al. ASH 2005. Abstract 781. Response Rates With Lenalidomide Plus Dexamethasone (n=34) OutcomeLenalidomide/Dex, n (%) Objective response31 (91) Complete response2 (6) nCR/VGPR11 (32) Partial response18 (53)

10. Lenalidomide Plus Dexamethasone for Treatment-Naive Multiple Myeloma Rajkumar SV, et al. ASH 2005. Abstract 781. Grade 3/4 Toxicity in Treatment-Naive Patients Treated With Lenalidomide and Dexamethasone Grade 3/4 ToxicityLenalidomide + Dexamethasone, % (n=34) HEMATOLOGIC Neutropenia Anemia Thrombocytopenia 15 6 0 NONHEMATOLOGIC Fatigue Muscle weakness Anxiety Agitation Constipation 18 6 3

11. Bortezomib in Patients with Previously Untreated Multiple Myeloma Richardson, P. et al. ASH 2005 abstract # 2548 Best Response: (n=60) Adverse Event N=29 # of Pts (%) PN36 (55) Fatigue6 (21) Rash5 (17) Nausea3 (10) Constipation3 (10) VZV † 3 (10) URI2 (7) All AE were grade 1-2, except two grade 4 (fluid overload and meningitis), one grade 3 PN

12. Richardson, P. et al. ASH 2005 abstract # 2548 Bortezomib in Patients with Previously Untreated Multiple Myeloma Treatment-Emergent PN (n = 65) Reported in 36 pts (55%) Grade 1: 23 (2 additional pts had grade 1 PN at study entry but remained stable throughout the study) Grade 2: 12 Grade 3: 1 Dose reduction or discontinuation due to PN 4 pts, grade 1 PN (1.3 to 1.0 mg/m 2 ; 3 had further reduction to 0.7 mg/m 2 ) 9 pts, grade 2 PN (1.3 to 1.0 mg/m 2 ; 2 had further reduction to 0.7 mg/m 2 ) 1 pt, grade 3 PN discontinued treatment during cycle 3

13. Bortezomib + Melphalan and Prednisone in Elderly Untreated MM Patients Phase II: Expanded up to 60 pts: bortezomib 1.3 mg/m 2 Response Best ORR: 86% (N = 53) following a median of 5 cycles CR 30%, nCR 13%, PR 43% Mateos, M. et al. ASH 2005, abstract #786 *Hernandez, Br J H, 2004 42% 6 cycles of MP Best Response 5 cycles V-MP 86%

14. Bortezomib ± Dexamethasone as First-line Multiple Myeloma Treatment Nonrandomized, prospective phase II trial (N = 50) Overall response rate with bortezomib + dexamethasone: 90% Median PFS: 15 months Jagannath S, et al. ASH 2005. Abstract 783. 8% 2% 10% 8% 71% 40% 8% 25% 2% 25% 0 20 40 60 80 100 Bortezomib ± Dexamethasone Bortezomib Alone at Cycle 2 SD/PD MR PR nCR CR Best Response Percentage of Patients Adverse EventGrade 3/4, % Sensory neuropathy/ neuropathic pain 12 Fatigue4 Anorexia2 Abdominal pain/cramps2 Neutropenia10 Thrombocytopenia2 Diarrhea6 Myalgia2

15. clinicaloptions.com/onco Multiple Myeloma  RESPONSE –Response Rates: Bortexomib ± Dex (N=48 evaluable)  CR + nCR + PR = 90%; CR + nCR = 19% –Bortezomib alone: (at cycle 2)  CR + nCR + PR = 50%; CR + nCR = 10% –Survival:  Median PFS = 15 months  OS = Median OS not reached; estimated survival at 12 months 93% Newly Diagnosed Bortezomib +/- Dexamethasone for Previously Untreated Multiple Myeloma Jagannath S, et al. ASH 2005, abstract #783 SLIDE 15

16. clinicaloptions.com/onco Multiple Myeloma Newly Diagnosed Bortezomib +/- Dexamethasone for Previously Untreated Multiple Myeloma Jagannath S, et al. ASH 2005, abstract #783 SLIDE 16  Addition of Dexamethasone (n = 36) Additional responses observed in 23 of 36 patients (64%) Response improved by 2 levels in 22% (n = 8) SD to PR: 8 Response improved by 1 level in 42% (n =15) SD to MR: 4 MR to PR: 9 PR to nCR: 1 nCR to CR: 1

17. clinicaloptions.com/onco Multiple Myeloma ►CONCLUSIONS –Bortezomib alone and in combo with Dex is an effective therapy in newly diagnosed MM –Response rate with bortezomib ± dexamethasone was 90% with a CR + nCR rate of 19% –Estimated 1-year survival rate is 93% –Bortezomib is a feasible option for induction therapy –Stem cell harvest was successful and engraftment was prompt –Adverse events were predictable and manageable Bortezomib +/- Dexamethasone for Previously Untreated Multiple Myeloma Jagannath S, et al. ASH 2005, abstract #783 SLIDE 17 Newly Diagnosed

18. Reduced Dose PAD Combination Therapy  Patients: n=20 –Treatment: Induction: four 21 day cycles prior to transplant: Bortezomib 1.0 mg/m 2 days 1,4, 8, 11 Adriamycin 9 mg/m 2 – by infusion or IV push days 1-4 Dex 40 mg PO - Cycle 1: d 1-4, 8-11, 15-18; Cycle 2 – 4: d 1-4 PBSC harvested followed by MEL200 and PBSCT Popat R, et al. ASH 2005,Abstract #2554 1 Oakervee et al., Br J. Haematol 2005; 129 755-762 ResponseFollowing PAD (n=19)Following PBSCT (n=13) CR2 (11) 6 (46) nCR1 (5) 1 (8) CR + nCR3 (16%) 7 (54%) VGPR5 (26) 1 (8) PR9 (47) 5 (38) CR + PR89% 100% –Stem cell mobilization was not affected

19. Reduced Dose PAD Combination Therapy Popat R, et al. ASH 2005, Abstract #2554

20. First-line Bortezomib, Thalidomide + Dexamethasone in Multiple Myeloma Nonrandomized, single-center, open-label study (N = 38) Treatment-naive patients Response compared with previous thalidomide/ dexamethasone study Wang M et al. ASH 2005. Abstract 784. Response OutcomesBTD, % (n = 38) TD, % (n = 137) P Value Overall response* Complete response † 92 18 66 13 <.01.41 Response following BTD and subsequent intensive therapy ‡ Partial Complete 100 66 34 --- *> 50% reduction in serum myeloma protein and/or > 90% reduction in Bence Jones protein excretion. † > 75% reduction in serum myeloma protein and/or > 99% reduction in Bence Jones protein excretion. ‡ Intensive therapy supported by autologous blood stem cells for patients without serious complications following BTD.

21. –Bortezomib continues to demonstrate superior survival despite > 62% of HD dex pts crossing over to bortezomib –Median OS: 29.8 months (95% CI: 23.2, not estimable) vs 23.7 months (95% CI: 18.7, 29.1); hazard ratio = 0.77; P = 0.0272 1-year survival rate: 80% vs 67%; P = 0.0002 Updated Results of APEX Trial Richardson P, et al. ASH 2005, abstract 2547 SURVIVAL Overall and 1-Year Survival P=.0272

22. RESPONSE Overall response (CR + PR) improved from 38% to 43% 76/135 responders (56%) - improved response after week 6 (cycle 2) 20 pts MR or PR to CR 56 pts MR to PR Response, % 0 10 20 30 40 50 60 70 80 90 100 Update 9% CR 34% PR 43% (7% nCR) 38% 6% CR 32% PR (7% nCR) Initial analysis *CR + PR Median TTP, months 6.2 Median TTR*, months 1.4 CR0.8 PR1.4 nCR0.8 Median DOR*, months7.8 CR9.9 PR7.6 nCR11.5 Updated Results of APEX Trial Richardson P, et al. ASH 2005, Abstract 2547

23. Conclusions –Despite rapid initial response, many pts achieve best response after longer duration of therapy Responders received median of 10 cycles Best M-protein response occurs > cycle 8 for ~20% of pts responding to bortezomib –Pts receiving bortezomib earlier appear to have longer survival and higher RR –Pts achieving higher quality of response (100% M-protein reduction) have longer response duration Updated Results of APEX Trial Richardson P, et al. ASH 2005, Abstract 2547

24. Dexamethasone 40 mg on Days 1-4, 9-12, 17-20* Lenalidomide 25 mg, Days 1-21 and placebo, Days 22-28 (n = 176) Dexamethasone 40 mg on Days 1-4, 9-12, 17-20* Placebo on Days 1-28 (n = 175) *After 4 courses, dexamethasone intensity reduced to 40 mg daily on Days 1-4 only. Patients with relapsed/refractory multiple myeloma (N = 351) Lenalidomide/Dex vs Dex Alone for Relapsed/Refractory MM MM-010: multicenter, phase III trial Dimopoulos MA, et al. ASH 2005. Abstract 6.

25. 0.00 0.25 0.50 0.75 1.00 % Without Progression Time to Progression (Weeks) P <.001 901020304050607080 Lenalidomide/Dex vs Dex Alone for Relapsed/Refractory MM Median time to progression Len/Dex: 11.3 months Dex: 4.7 months Lenalidomide/dexamethasone Dexamethasone alone Dimopoulos MA, et al. ASH 2005. Abstract 6.

26. Lenalidomide/Dex vs Dex Alone for Relapsed/Refractory MM Superior response with addition of lenalidomide Improved OS with Len/Dex in North American study MM-010 (P <.013) Hematologic side effects more common for lenalidomide Grade 3/4 ToxicitiesLenalidomide/Dexamethasone, % (n = 176) Dexamethasone, % (n = 175) Neutropenia272 Anemia64 Thrombocytopenia106 Deep vein thrombosis55 Pulmonary embolism41 Dimopoulos MA, et al. ASH 2005. Abstract 6. 59 42 17 24 20 4 0 40 60 80 100 OverallPartialCR/nCR Len/Dex Dex P <.001 Patients, % Response

27. Bortezomib Plus Lenalidomide for Relapsed/Refractory Multiple Myeloma Phase I study of lenalidomide plus bortezomib (n = 24) 21-day cycles (maximum of 8) at 8 different dosing schedules Bortezomib 1.0 or 1.3 mg/m 2, Days 1, 4, 8, 11 Lenalidomide 5-30 mg/day, Days 1-14 2 reports of dose-limiting toxicity No thrombotic events Little peripheral neuropathy Total response rate: 67% Richardson PG, et al. ASH 2005. Abstract 365. CR nCR PR MR SD PD Response Rates (n = 21) 43% 14% 29% 5%

28. Conclusions Combination regimens for front-line therapy are achieving higher response rates including true CR No apparent adverse impact on stem cell harvesting Challenges What patients benefit from transplant? Is there a role for maintenance therapy after initial treatment or post-transplant? Molecular definitions of response