1. 1 ANCO ASH Highlights 2007: Multiple Myeloma Joseph M. Tuscano, MD University of California, Davis

2. 2 Abstracts ►[73] Bortezomib (Velcade )-Thalidomide-Dexamethasone (VTD) vs Thalidomide-Dexamethasone (TD) in Preparation for Autologous Stem-Cell (SC) Transplantation (ASCT) in Newly Diagnosed Multiple Myeloma ►[76] MMY-3002: A Phase 3 Study Comparing Bortezomib Melphalan Prednisone (VMP) with Melphalan Prednisone (MP) in Newly Diagnosed MM ►[74] A Randomized Trial of Lenalidomide Plus High-Dose Dexamethasone (RD) Versus Lenalidomide Plus Low-Dose Dexamethasone (Rd) in Newly Diagnosed Multiple Myeloma (E4A03): A Trial Coordinated by the Eastern Cooperative Oncology Group. ►[2716] The Efficacy and Toxicity of the RAD Regimen (Revlimid, Adriamycin, Dexamethasone) in Relapsed and Refractory Multiple Myeloma ►[310] A Prospective, Randomized, Phase III Study of Enoxaparin Versus Aspirin Versus Low-Fixed-Dose of Warfarin in Newly Diagnosed Myeloma Patients Treated with Thalidomide-Containing Regimens ►[2714] Lenalidomide, Bortezomib, and Dexamethasone (Rev/Vel/Dex) in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma (MM): Preliminary Results of a Phase II Study

3. 3 [73] Bortezomib (Velcade )-Thalidomide-Dexamethasone (VTD) vs Thalidomide-Dexamethasone (TD) in Preparation for Autologous Stem-Cell (SC) Transplantation (ASCT) in Newly Diagnosed Multiple Myeloma (MM). Session Type: Oral Session Michele Cavo, Francesca Patriarca, Paola Tacchetti, Monica Galli, Giulia Perrone, Maria Teresa Petrucci, Annamaria Brioli, Sara Bringhen, Lucia Pantani, Patrizia Tosi, Claudia Crippa, Elena Zamagni, Francesco Di Raimondo, Franco Narni, Claudia Cellini, Michela Ceccolini, Norbert Pescosta, Maria Cecilia Goldaniga, Vittorio Montefusco, Vincenzo Callea, Valerio De Stefano, Tommaso Caravita, Mario Boccadoro, Michele Baccarani Seragnoli Institute of Hematology, University of Bologna, Bologna, Italy; Italian Myeloma Network, GIMEMA, Italy

4. 4 VTD vs TD for SCT Induction ►Endpoints: Primary include CR+nCR post-induction: Secondary include:CR+nCR post-consolidation, TTP, EFS, OS, Stem cell yield, and Safety ► Patients: 450 planned patients: 256 enrolled (Arm A n=129, Arm B n=127) ► Dose: Three 21-day cycles Newly Diagnosed Cavo M, et al. ASH 2007, abstract #73 Phase III study: Planned interim analysis Arm A –VTD: Bortezomib 1.3mg/m 2 days 1, 4, 8, 11; Dex 40mg day of and day after bortezomib; Thal 200mg daily Maintenance Dex Arm B –TD: Thal 200mg daily; Dex 40mg/d days 1-4, 9-12 SC collection +  MEL 200 Consolidation VTD Consolidation TD RANDOMIZERANDOMIZE –DVT Prophylaxis: Pts randomized to LMWH (enoxaparin 40mg/d), Aspirin (100mg/d), or wafarin 1.25mg/d INDEX

5. 5 VTD vs TD for SCT Induction Newly Diagnosed Cavo M, et al. ASH 2007, abstract #73 ►Base-Line Patient Characteristics VTD (n=129) TD (n=127) Median age yrs (range)58 (34-66)57 (29-65) ISS (%) I II III 47 34 19 47 34 19 Median  2 -m mg/L (range) 2.9 (0.2-15)3.0 (1.3-12) Median albumin g/dL (range)3.9 (0.38-17.3)3.9 (1.3-59.9) Median creatinine mg/dL (range)1.0 (0.5-2.0)1.0 (0.46-2.3) Genetic abnormality Del13 pos (%) t(4;14) pos (%) Del17 pos (%) 49 23 10 44 19 8

6. 6 VTD vs TD for SCT Induction Newly Diagnosed Cavo M, et al. ASH 2007, abstract #73 ►Response* InductionPost-SCT VTD (n=129) TD (n=127) P value VTD (n=74) TD (n=79) CR+nCR36%9%<0.00157%28%  VGPR 60%27%<0.00177%54% < PR7%20%0.003-- *Modified EBMT criteria ►PBSC Harvest VTD (n=112) TD (n=108) P-value Median CD34+ cells (x10 6 /kg) (range)  4.0 x10 6 /kg (% pts) 9.2 (0-29) 94% 10.6 (0-37) 93% NS Median # of apheresis1 (0-5)2 (0-4)NS –Cytogenetic abnormalities [Del 13q and t(4;14)] had no adverse impact on CR+nCR post-induction; a significantly improved CR+nCR rate with VTD was seen in these patients (Del 13q [P<0.001] and t(4;14) [P=0.002]) vs with TD

7. 7 VTD vs TD for SCT Induction Newly Diagnosed Cavo M, et al. ASH 2007, abstract #73 ►Safety: Grade 3-4 AE (%) VTD (n=129) TD (n=127) P-value PN720.03 Skin rash6.510.01 Constipation42NS Infection(s) [excluding HZ]33 DVT36.50.01 Liver toxicity2.53NS Vomiting/diarrhea20NS Herpes Zoster infection10NS Cardiac02NS Other910.5NS –Discontinuation due to toxicity: 3% VTD vs 2% TD –Deaths due to toxicity: 0% VTD vs 1% TD –91% of pts received >90% of planned bortezomib administrations

8. 8 VTD vs TD for SCT Induction Newly Diagnosed Cavo M, et al. ASH 2007, abstract #73 ► Conclusions –VTD as primary therapy for MM significantly increased the rate of CR + nCR and  VGPR compared to TD and was not adversely influenced by t(4;14) or chromosome 13 deletion –Significant response benefit by VTD induction translated into a significantly higher probability of CR+nCR or  VGPR post-SCT –Grade 3-4 AE, including SAE, was similar in the two treatment arms; Exception: higher rate of PN and rash with VTD, and higher rate DVT with TD –Relatively low toxicity profile of VTD was reflected by: low discontinuation rate, high probability of receiving >90% planned dose, and absence of early deaths –Primary therapy with VTD did not adversely impair the efficiency of PBSC harvest

9. 9 [76] MMY-3002: A Phase 3 Study Comparing Bortezomib Melphalan Prednisone (VMP) with Melphalan Prednisone (MP) in Newly Diagnosed Multiple Myeloma. Session Type: Oral Session J.F. San Miguel, R. Schlag, N. Khuageva, O. Shpilberg, M. Dimopoulos, M. Kropff, I. Spicka, M. Petrucci, O. Samoilova, A. Dmoszynska, K. Abdulkadyrov, R. Schots, B. Jiang, A. Palumbo, M. Mateos, K. Liu, A. Cakana, H. Van de Velde, P. Richardson Hospital Universitario de Salamanca, Spain; Praxisklinik Dr. Schlag, W rzburg, Germany; SP Botkin Moscow City Clinical Hospital, Russian Federation; Rabin Medical Center, Petah-Tiqva, Israel; University of Athens School of Medicine, Greece; University of M nster, Germany; University Hospital Prague, Czech Republic; University La Sapienza, Rome, Italy; Nizhnii Novgorod Region Clinical Hospital, Russian Federation; Medical University of Lublin, Poland; St Petersburg Clinical Research Institute of Hematology Transfusiology, Russian Federation; Myelome Study Group Belgian Hematological Society, Belgium; People s Hospital, Peking University, China; Universita di Torino, Italy; Johnson Johnson PRD, Raritan, USA; Johnson Johnson PRD, Beerse, Belgium; Dana-Farber Cancer Institute, Boston, USA

10. 10 VMP vs MP VISTA: Phase III ►Endpoints: Primary: TTP; Secondary: CR rate, ORR, TTR, DOR, PFS, TNT, OS, QoL Newly Diagnosed San Miguel J, et al. ASH 2007, abstract #76 ARM A (VMP) VMP: Four 6-week cycles: Cycles 1-4 Bortezomib 1.3mg/m 2 days 1, 4, 8, 11, 22, 25, 29, 32; Melphalan 9mg/m 2 and prednisone 60mg/m 2 days 1-4 Followed by five 6-week cycles: Cycles 5-9 Bortezomib 1.3mg/m 2 days 1, 8, 22, 29; Melphalan 9mg/m 2 and prednisone 60mg/m 2 once daily on days 1–4 ARM B (MP) MP: Nine 6-week cycles: Cycles 1-9 Melphalan 9mg/m 2 and prednisone 60mg/m 2 days 1-4 Max of 9 cycles (total 54 weeks) in both Arms RANDOMIZERANDOMIZE –Independent data monitoring committee (IDMC) monitored safety data monthly –Safety assessed using NCI Common Toxicity Criteria –Response and progression assessed q3 weeks per EBMT 1 using central laboratory for M-protein quantification; results reported in real time to the investigator for evaluation Randomized, international phase 3 study: Planned interim analysis of VMP vs MP in previously untreated MM patients, not candidates for SCT Assessment of Efficacy and Safety 1. Bladé et al. Br J Haematol 1998;102:1115-23. ►Study Schema: INDEX

11. 11 VMP vs MP ► Intent to treat analysis (all subjects randomized) ► Designed to show a 33% improvement in TTP and 42% in OS – Statistical tests: two-sided  = 0.05 ► Stratification: β 2 microglobulin, albumin, region ► Time-to-event measurements –Time to progression (TTP): randomization to first evidence of PD/relapse – Progression free survival (PFS): randomization to first evidence of PD/relapse or death – Time to next therapy (TNT): randomization to first dose of subsequent anti- myeloma therapy, including treatment free interval (TFI)  TFI: last dose of study drug to first dose of subsequent anti-myeloma therapy Newly Diagnosed Statistical Methods San Miguel J, et al. ASH 2007, abstract #76 IDMC recommended study stop in September 2007 based on protocol-specified interim analysis (data cut-off 15 June 2007) VMP was significantly superior across all efficacy endpoints INDEX

12. 12 ►Characteristics VMP n=344 MP, n=338 Median age, years71 Aged ≥75 years, %3130 KPS ≤70%, %3533 ISS Stage I / II / III, %19 / 47 / 3519 / 47 / 34 IgG / IgA / Light chain, %64 / 24 / 862 / 26 / 8 ß 2 M 5.5 mg/L, %12 / 55 / 33 Median ß 2 M, mg/L4.24.3 CrCl ≤30/>30 - 60/>60 (ml/min), %6 / 48 / 465 / 50 / 46 Median serum Cr, mg/dL1.1 Albumin <3.5 g/dL, % Median albumin, g/dL 58 (3.3)59 (3.3) Lytic bone lesions, %6566 Median % plasma cells in bone marrow biopsy4041 VMP vs MP Newly Diagnosed Patient Demographics and Disease Characteristics San Miguel J, et al. ASH 2007, abstract #76 INDEX

13. 13 VMP vs MP Newly Diagnosed San Miguel J, et al. ASH 2007, abstract #76 ►Response VMP (n=336) MP (n=331) P-value M-Protein*EBMT 1 M-Protein*EBMT 1 CR IF- 35%30%5%4%<0.000001 PR46%40%45%31%  VGPR10%N/A5%N/A ORR (CR+PR)82%71%50%35% <0.000001 Time to Response 1 All Responders1.4 mos4.2 mos <10 -10 Time to CR4.2 mos5.3 mos <10 -10 Duration of Response 1 All Responders20 mos13 mos CR24 mos13 mos *Measured in serum or urine by central laboratory 1. Bladé et al. Br J Haematol 1998;102:1115-23. –Response rates, PFS and OS were not influenced by age ( <75 vs  75 yrs), CrCl (<60 vs  60 ml/min), or cytogenetics (FISH) (any t4-14, t14-16, 17p Del vs none)) INDEX

14. 14 VMP vs MP Newly Diagnosed San Miguel J, et al. ASH 2007, abstract #76 ►Overall survival ~ 40% reduced risk of death on VMP VMPMP OS @ 2-years83%70%  <75 year84%74%  ≥75 years79%60% Treatment related deaths 1%2% Median follow-up 16.3 mos VMP: not reached (45 deaths) MP: not reached (76 deaths) HR = 0.607, p = 0.0078 – VMP – MP MP: 338 320 301 280 220 157 116 69 29 7 VMP:344 315 300 290 235 168 115 72 36 4 Number of patients at risk ►Time to progression ~52% reduced risk of progression on VMP –VMP shows benefit in TTP across sub- groups analyzed  Time to Next Therapy (TTNT): not reached for VMP vs 21 mos for MP (p=0.000009); pts on VMP were 48% less likely to start second-line therapy  Treatment Free Interval (TFI): not reached for VMP vs 9 mos for MP (p=0.0001) VMP: 24.0 months (83 events) MP: 16.6 months (146 events) HR = 0.483, p < 0.000001 MP: 338 296 241 206 152 86 53 22 5 VMP:344 295 272 245 185 111 65 31 17 Number of patients at risk VMP MP INDEX

15. 15 VMP vs MP Newly Diagnosed San Miguel J, et al. ASH 2007, abstract #76 ► Grade 3/4 AE (%) VMP (n=340)MP (n=337) Gr 3Gr 4Gr 3Gr 4 Neutropenia30102315 Thrombocytopenia20171614 Anemia163208 GI1915<1 Peripheral Sensory Neuropathy13<100 Fatigue7120 Asthenia6<130 Pneumonia5241 Herpes Zoster3020 –Serious AE: 46% for VMP vs 36% for MP –Transfusion (26% vs 35%) and EPO support (34% vs 42%) were somewhat lower on VMP arm vs MP respectively –PN resolved or improved in 75% of cases in a median of 64 days –DVT was low (1%) and similar on both arms INDEX

16. 16 VMP vs MP Newly Diagnosed San Miguel J, et al. ASH 2007, abstract #76 ► Conclusions: –VMP significantly prolongs survival and is superior across all pre- specified efficacy endpoints in the largest MP-based phase III study –Rapid and durable responses with unprecedented CR rate (35%) –Prolonged TTP, time to next therapy (TTNT) / treatment-free interval (TFI), and OS –Data are robust and consistently superior across all prognostic subgroups –VMP was well tolerated, with patients on therapy for 46 weeks –Discontinuations due to AE were low and identical for both arms INDEX

17. 17 [74] A Randomized Trial of Lenalidomide Plus High-Dose Dexamethasone (RD) Versus Lenalidomide Plus Low-Dose Dexamethasone (Rd) in Newly Diagnosed Multiple Myeloma (E4A03): A Trial Coordinated by the Eastern Cooperative Oncology Group. Session Type: Oral Session S. Vincent Rajkumar, Susanna Jacobus, Natalie Callander, Rafael Fonseca, David Vesole, Michael Williams, Rafat Abonour, David Siegel, Philip Greipp Mayo Clinic, Rochester, MN, USA; Dana Farber Cancer Institute, Boston, MA, USA; University of Wisconsin, Madison, WI, USA; Mayo Clinic, Scottsdale, AZ, USA; St. Vincent s Comprehensive Cancer Center, New York, NY, USA; University of Virginia, Charlottesville, VA, USA; Indiana University Medical Center, Indianapolis, IN, USA; Hackensack University Medical Center, Hackensack, NJ, USA

18. 18 Lenalidomide Plus Standard- or Low-Dose Dexamethasone in Newly Diagnosed MM ECOG-E4A03: Phase III, Randomized Study Newly diagnosed, untreated MM (N=445) 25 mg/day po, days 1–21 Arm I. Lenalidomide 25 mg/day po, days 1–21 40 mg/daypo, days 1–4, 9–12, 17–20 Standard-dose dexamethasone 40 mg/day po, days 1–4, 9–12, 17–20(n=223) po, days 1–21 Arm II. Lenalidomide 25 mg/day po, days 1–21 po, days 1, 8, 15, 22 Lower-dose dexamethasone 40 mg/day po, days 1, 8, 15, 22(n=222) Arm III. Salvage therapy 200 mg/day po, days 1–28 Thalidomide 200 mg/day po, days 1–28 po, days 1–4, 9–12, 17–20 Standard-dose dexamethasone 40 mg/day po, days 1–4, 9–12, 17–20 Arm IV. Salvage therapy po, days 1–28 Thalidomide 200 mg/day po, days 1–28 po, days 1, 8, 15, 22 Lower-dose dexamethasone 40 mg/day po, days 1, 8, 15, 22 If PD within 4 mo Courses repeat q 28 days ≤1 yr in absence of PD or unacceptable toxicity 1 o Endpoint: RR at 4 mo; 2 o Endpoints: Safety in arms I, II; RR in arms III, IV Rajkumar SV et al. Presented at: 49 th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA Induction trial: Not intended to test efficacy of long-term lenalidomide/dex

19. 19 E4A03: Selected Patient Characteristics CharacteristicLD (n=223)Ld (n=222) ISS, % Stage I Stage I Stage II Stage II Stage III Stage III33.041.325.733.341.425.3 Male, % 58.354.1 Age, yr (range) 66 (36–87) 65 (35–85) ECOG PS ≤1, % 91.090.5 Serum M protein (g/dL) 3.23.1 Durie-Salmon stage III, % 79.375.2 MM bone disease, % 65.356.8 Patients eligible, n 195188 Rajkumar SV et al. Presented at: 49 th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA L=Lenalidomide; D=Standard-dose dexamethasone; d=Low-dose dexamethasone

20. 20 E4A03: Serious AEs (≥3%) Toxicity (≥Gr 3)LD, % (n=222)Ld, % (n=219)P Value* Hemoglobin8.16.80.718 Neutrophils5.45.51.000 Platelets11.718.70.047 DVT/PE25%9%<0.001 Infection/Pneumonia14%7%0.030 Fatigue13%10%0.294 Hyperglycemia 11% 6%0.126 Nonneuropathic weakness10%4%0.008 Cardiac ischemia3%0.5%0.068 Atrial fib/flutter3%0.5%0.122 Any non hem toxicity (≤4 mo)50%30%<0.001 Any non hem toxicity65%45%<0.001 Any toxicity (≥Gr 4)19%8%0.001 Early Deaths (≤4 mo)5%0.5%0.01 Rajkumar SV et al. Presented at: 49 th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA L=Lenalidomide; D=Standard-dose dexamethasone; d=Low-dose dexamethasone; *Fishers exact

21. 21 E4A03: E4A03: Causes of Death LD (N=46), nLd (N=25), n Progressive Disease 2617 Thromboembolic 51 Infection 43 Cardiac 62 Stroke 11 Respiratory Failure 10 Second Cancer 10 Unknown 21 Median Follow up 21 mos Rajkumar SV et al. Presented at: 49 th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA L=Lenalidomide; D=Standard-dose dexamethasone; d=Low-dose dexamethasone

22. 22 Response ≤4 cyclesBest Overall Response 21 Response, % 24 82 70 71 E4A03: E4A03: Response Data Rajkumar SV et al. Presented at: 49 th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA L=Lenalidomide; D=Standard-dose dexamethasone; d=Low-dose dexamethasone; *Fishers exact P=0.007 82 P=0.01 42 25 48 40 38 44 30 29 0 20 40 60 80 100 LD (n=190)Ld (n=196)LD (n=190)Ld (n=196) PR VGPR CR

23. 23 E4A03 Interim Analysis: E4A03 Interim Analysis: PFS, TTP and OS LDLdP value* Median PFS, mo19.321.90.0637 Median, TTP, mo 21.822.60.2117 Rajkumar SV et al. Presented at: 49 th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA No. of Subjects EventCensored Median (95% CL) LD Ld 223 222 22% (46) 11% (25) 79% (177) 89% (197) NA ( NA NA ) NA ( 30.55 NA ) Time in Months 1 0.8 0.6 0.4 0.2 0 0510152025 Probability P=0.0060* LD Ld L=Lenalidomide; D=Standard-dose dexamethasone; d=Low-dose dexamethasone; *Log rank

24. 24 E4A03 Interim Analysis: Conclusions ►Lenalidomide plus standard-dose deaxamethasone (LD) and lenalidomide plus low-dose dexamethasone (Ld) ►Lenalidomide plus standard-dose deaxamethasone (LD) and lenalidomide plus low-dose dexamethasone (Ld) are highly active in newly diagnosed MM ►Ld had lower response rates than LD, but within the 15% limit that was defined in study design as clinically equivalent ►Ld is associated with superior OS compared to LD ►Response duration, TTP or PFS with Ld not inferior to LD ►The excess mortality with LD was due to both disease progression as well as increased toxicity ►This study has major implications for the use of high-dose dexamethasone in the treatment of newly diagnosed MM Rajkumar SV et al. Presented at: 49 th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA

25. 25 [2716] The Efficacy and Toxicity of the RAD Regimen (Revlimid, Adriamycin, Dexamethasone) in Relapsed and Refractory Multiple Myeloma A Phase I/II Trial of Deutsche Studiengruppe Multiples Myelom. Session Type: Poster Session, Board #906-II Stefan Knop, Christian Gerecke, Peter Liebisch, Max S. Topp, Georg Hess, Uwe Platzbecker, Sandra Frohnert, Hermann Einsele, Ralf Bargou W rzburg University Hospital, W rzburg, Germany; Charit Campus Buch, Berlin, Germany; University Hospital, Ulm, Germany; University Hospital, Mainz, Germany; University Hospital, Dresden, Germany

26. 26 Tag 12345678910111223456789101112 Lenalidomide, Doxorubicin, and Dexamethasone in Relapsed MM: Results of Phase I/II Trial Dexamethasone 40 mg po Lenalidomide po Doxorubicin 24-h cont IV q d29 131415161718192021 max × 6 Dose LevelPt (n)LenalidomideDoxorubicinDexamethasonePegfilgrastim 1310 mg d1–214 mg/m 2 d1–440 mg d1–4, d17–20 2310 mg d1–216 mg/m 2 d1–440 mg d1–4, d17–20 3310 mg d1–219 mg/m 2 d1–440 mg d1–4, d17–20 4615 mg d1–219 mg/m 2 d1–440 mg d1–4, d17–20 4-G315 mg d1–219 mg/m 2 d1–440 mg d1–4, d17–206 mg; d6 5-G625 mg d1–219 mg/m 2 d1–440 mg d1–4, d17–206 mg; d6 Knop S. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA

27. 27 CharacteristicN = 69 Median age, yr (range)63 (46–77) Median no. of previous therapies (range)2 (1–3) Autologous transplantation, % 72 Allogeneic transplantation, % 12 Conventional therapy, % 16 Bortezomib, % 57 Thalidomide, % 20 Cytogenetic analysis: del(13); t(4;14); del(17p), % 46; 16; 19 RAD Trial in Relapsed MM: Patient Characteristics Knop S. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA

28. 28 AE*, n n=63 Gr 1Gr 2Gr 3Gr 4 Neutropenia3121614 Thrombocytopenia1210139 Constipation2200 Fatigue22900 PN 24200 Infection/fever22860 VTE1300 RAD Trial for Relapsed MM Response Rate (n = 38; EBMT criteria) ORR = 89% Patients (%) *Grades according to NCI CTC Knop S. Presented at: 49 th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA

29. 29 [310] A Prospective, Randomized, Phase III Study of Enoxaparin Versus Aspirin Versus Low-Fixed-Dose of Warfarin in Newly Diagnosed Myeloma Patients Treated with Thalidomide-Containing Regimens. Session Type: Oral Session Antonio Palumbo, Michele Cavo, Sara Bringhen, Giulia Perrone, Valeria Magarotto, Francesca Patriarca, Maria Teresa Petrucci, Monica Galli, Francesco Di Raimondo, Davide Rossi, Roberto Marasca, Massimo Offidani, Maria Goldaniga, Paolo Corradini, Claudia Crippa, Lucio Catalano, Vincenzo Callea, Antonella Gozzini, Patrizia Tosi, Mario Boccadoro Divisione di Ematologia dell Universit di Torino, Az. Osp. San Giovanni Battista, Torino, Italy; Istituto di Ematologia e Oncologia Medica Ser gnoli, Universit di Bologna, Bologna, Italy; Italian Multiple Myeloma Network, GIMEMA, Italy; First Authorship Equally Shared

30. 30 LMWH vs Warfarin vs ASA in Newly Diagnosed MM Treated with Thalidomide-Containing Regimens* *A prospective randomized GIMENA phase III trial Palumbo A et al. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA Thalidomide regimens VTD – TD – VMPT Randomize ASA WAR LMWH Aspirin Warfarin Enoxaparin 100 mg/day 1.25 mg/day 40 mg/day VMP No prophylaxis VTD-TD (<65 yr): 9 wk before ASCT VTD-TD (<65 yr): 9 wk before ASCT VMPT (>65 yr): 6 mo VMPT (>65 yr): 6 mo

31. 31 LMWH vs Warfarin vs ASA Prophylaxis For Thalidomide- Containing Regimens: Patient Characteristics Characteristic ASA (n=112) WAR (n=120) LMWH (n=115) Age (median)6059 ≥65 years17%20%16% MBI ≥30 kg/m 2 13%18%13% Central venous catheter31%37%22% Immobilization15%16%21% Cardiac disease/diabetes20%34%26% Surgery10%11%7% Inherited conditionsN/A ≥2 above risk factors24%34%22% Palumbo A et al. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA

32. 32 LMWH vs Warfarin vs ASA Prophylaxis For Thalidomide- Containing Regimens: VTE According to Risk Factors Patients (%) Palumbo A et al. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA 0123456 ASA WAR LMWH >2 risk factors1 risk factor0 risk factor

33. 33 [2714] Lenalidomide, Bortezomib, and Dexamethasone (Rev/Vel/Dex) in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma (MM): Preliminary Results of a Phase II Study. Session Type: Poster Session, Board #904-II Paul Richardson, Sundar Jagannath, Noopur Raje, Andrzej Jakubowiak, Sagar Lonial, Irene Ghobrial, Robert Schlossman, Amitabha Mazumder, Nikhil Munshi, Kathleen Colson, Mary McKenney, Melissa Farrell, Laura Lunde, Lawrence Giove, Sarah Kaster, Constantine Mitsiades, Teru Hideshima, Robert Knight, Dixie-Lee Esseltine, Kenneth Anderson Dana-Farber Cancer Institute, Boston, MA, USA; St. Vincent s Comprehensive Cancer Center, New York, NY, USA; Massachusetts General Hospital Cancer Center, Boston, MA, USA; University of Michigan, Ann Arbor, MI, USA; Winship Cancer Institute, Emory University, Atlanta, GA, USA; Celgene Corporation, Summit, NJ, USA; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA

34. 34 Phase I/II Study of Bortezomib, Lenalidomide and Dexamethasone in Newly Diagnosed MM Patients achieving ≥PR may proceed to ASCT after  4 cycles Maintenance therapy permitted in patients achieving ≥SD using weekly (d1 and d8) schedule of Bz, and Dex on d1, 2, 8, and 9 Antithrombotic therapy with daily aspirin (81 or 325 mg) Antiviral therapy as prophylaxis against Herpes Zoster * Dex, 40 mg/day d1, 2, 4, 5, 8, 9, 11 and 12; 20 mg/day, cycles 5–8; Amended to 20mg/10mg cycles 1-4/5-8 based on safety data Up to 8 21-D cycles* 1 2 4 5 8 9 11 12 14 21 Lenalidomide Bz Dex Richardson PG et al. Presented at: 49 th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA

35. 35 Dose level*Lenalidomide (mg/day)Bortzomib (mg/m 2 )Dex (mg)** 1151.040 2151.340 3201.340 4251.340 4M251.320 *An additional dose level, 4M, was introduced based on safety data; **20 mg, cycles 5–8 ►Phase I (Successive cohorts of 3–6 pts per dose level) –Dose escalation proceeded depending on occurrence of DLTs:  Gr ≥3 non-hematologic toxicity; Gr 4 thrombocytopenia with platelets 1 occasion despite transfusion support; Gr 4 neutropenia for >5 d and/or resulting in neutropenic fever  Inability to receive cycle 2/d1 dose due to drug-related toxicity –MTD: dose level prior to that resulting in ≥2 DLTs –10 additional pts to be enrolled at the MTD ►Phase II (35 pts to be enrolled at MTD or maximum planned dose) Bortezomib, Lenalidomide and Dexamethasone in Newly Diagnosed MM: Dose Escalation Richardson PG et al. Presented at: 49 th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA

36. 36 Phase l enrollment (N=33*)n Dose level 13 Dose level 23 Dose level 34†4† Dose level 46 Dose level 4M ¶ 17 † Phase ll enrollment (N=20* ¥ ) *as of 12/1/07 † 1 patient in each never received treatment; not included in MTD determination ¶ Starting Dex dose changed to 20 mg/day as safety data beyond cycle 1 indicated Dex at 40mg/day was not well tolerated ¥ 11 pts continue on treatment but have yet to complete ≥2 cycles as of 12/1/07 Richardson PG et al. Presented at: 49 th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA Bortezomib, Lenalidomide and Dexamethasone in Newly Diagnosed MM: Patient Disposition ►Two DLTs seen at dose level 4: Gr 3 hyperglycemia due to high-dose Dex (40 mg) ►Maximum planned dose level has been reached (4M): Len 25 mg; Bz 1.3 mg/m 2 ; Dex 20 mg ►Ph I enrollment complete; Ph II enrollment ongoing (at dose level 4M)

37. 37 Bortezomib, Lenalidomide and Dexamethasone in Newly Diagnosed MM: Patient Characteristics Characteristic (N=53)Value Median age, years (range)58 (22-86) Male, n (%)27 (51) Myeloma type, n (%) IgG36 (68) IgA14 (26)  light-chain 2 (4) light-chain 1 (2) ISS stage II/III at diagnosis, n (%)26 (49) Durie-Salmon stage III at diagnosis, n (%)16 (30) Richardson PG et al. Presented at: 49 th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA

38. 38 Bortezomib, Lenalidomide and Dexamethasone in Newly Diagnosed MM: Most Common Grade 3/4 AEs Toxicities have been manageable –No unexpected toxicities have been seen; no Gr  3 PN –No treatment-related mortality Patient, n Richardson PG et al. Presented at: 49 th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA

39. 39 Bortezomib, Lenalidomide and Dexamethasone in Newly Diagnosed MM: Response Data EBMT/UC Response (N=42 evaluable as of 12/1/2007)n(%) CR 9(21) nCR3(7) VGPR10(24) PR29(69) ≥PR41(98) Richardson PG et al. Presented at: 49 th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA ►Responses assessed by EBMT 1 criteria and Uniform Criteria (UC) 2 (modified to include nCR) 3 –After cycle 2, then after every cycle ►Responses for evaluable patients were confirmed by 2 assessments, 6 wks apart