1. Sundar Jagannath, MD Professor of Medicine New York Medical College Chief, Multiple Myeloma Program St. Vincent’s Comprehensive Cancer Center Frontline Treatment of Multiple Myeloma: Current Options for Initial Therapy This program is supported by an educational grant from

2. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma About These Slides  Our thanks to the presenters who gave permission to include their original data  Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma Overview  Transplantation-Ineligible Patients –Phase III Trials –Combinations With Novel Agents –IMIDs  Transplantation-Eligible Patients  Is CR the Objective of Therapy?  Role of Maintenance Therapy

4. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma Recent Updates on MM With Impact on Clinical Practice  What is the best therapy for newly diagnosed MM? –Transplantation-ineligible patients –Transplantation-eligible patients  Does choice of initial therapy matter? –PFS –OS  Should therapy be tailored according to –Age –High risk –Renal impairment  How long to treat?  Have novel therapies improved transplantation outcome?

5. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma What Is Multiple Myeloma?  B-cell malignancy of plasma cells  The classic triad of hallmarks –Monoclonal (M) protein in the blood and/or urine –Monoclonal plasmacytosis –Osteolytic lesions

6. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma Epidemiology  Approximately 20,580 new cases and 10,580 deaths from MM are expected in the United States in 2009  Slightly more common in men than in women  Incidence in blacks is approximately twice than that in whites  Mean age at diagnosis is 62 yrs for men and 61 yrs for women –75% of men are older than 70 yrs of age –79% of women are older than 70 yrs of age Cancer facts and figures 2009. American Cancer Society; 2009. Horner MJ, et al, eds. SEER cancer statistics review, 1975-2006. National Cancer Institute. NCCN practice guidelines.

7. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma Major Symptoms at Diagnosis  Bone pain: 58%  Fatigue: 32%  Weight loss: 24%  Paresthesias: 5%  11% are asymptomatic or have only mild symptoms at diagnosis Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33.

8. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma Diagnostic Criteria for Symptomatic Multiple Myeloma  Monoclonal plasma cells in bone marrow (≥ 10%) [1]  M protein in serum and/or urine [1]  ≥ 1 CRAB features of organ damage [2] C: Calcium elevation (> 11.5 mg/L or ULN) R: Renal dysfunction (serum creatinine > 2 mg/dL) A: Anemia (Hgb < 10 g/dL or 2 g < normal) B: Bone disease (lytic lesions or osteoporosis) 1. Kyle RA, et al. N Engl J Med. 2002;346:564-569. 2. Durie BG, et al. Hematol J. 2003;4:379-398.

9. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma International Staging System for Symptomatic Myeloma  Stage 1 –β 2 -M < 3.5 –ALB  3.5  Stage 2 –Neither stage 1 nor 3  Stage 3 –β 2 -M  5.5 Greipp PR, et al. J Clin Oncol. 2005;23:3412-3420. β 2 -M = serum β 2 -microglobulin in mg/dL; ALB = serum albumin in g/dL.

10. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma Major Adverse Prognostic Factors  Karyotypic deletion 13 or hypodiploidy  High plasma cell labeling index  Molecular genetics: t(4;14), t(14;16), or 17p-  High LDH, β 2 -M, or CRP  Increased circulating plasma cells  Plasmablastic morphology  Low albumin

11. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma Challenges in Management  Currently incurable in most patients  Standard chemotherapy response rates: 50% to 70% –Complete responses: rare (< 10%); median survival 3 yrs  Stem cell transplantation prolongs survival, but not curative –Complete response: 20% to 40%; median survival: 5 yrs  Treatment of relapse –Previous options inadequate  New treatment options have improved OS; although not curative –Complete responses and life expectancy improved for all patients –New options for relapsed patients  Additional studies needed NCCN Practice Guidelines. Rajkumar SV, et al. Mayo Clin Proc. 2002;77:813-822. Kumar SK, et al. Blood. 2008;111:2516-2520. Attal M, et al. N Engl J Med. 1996;335:91-97. Rajkumar SV, et al. Bone Marrow Transpl. 2000;26:979-983.

12. Frontline Treatment of Multiple Myeloma: Phase III Trials Transplantation Ineligible

13. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma MP vs MPT: Efficacy Palumbo A, et al. Blood. 2008;112:3107-3114. Outcome Melphalan/ Prednisone (n = 164) Melphalan/ Prednisone/ Thalidomide (n = 167) HR (95% CI)P Value Median PFS, mos 14.521.80.63 (0.48-0.81).0004  No. of events 125111-- Median OS, mos 47.645.01.04 (0.76-1.44).79  No. of events 7077--

14. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma MP vs MPT in Myeloma: Toxicity Toxicity, % GIMEMA [1] Grade 3/4 AEs IFM 99 [2] Grade 3/4 AEs IFM 01 [3] Grade 2-4 AEs MPTMPMPTMPMPTMP VTE11212464 Peripheral neuropathy10N/A60205 Neutropenia16174826239 Thrombocytopenia341410N/A Anemia3414 N/A Infection102139N/A DiscontinuationN/A 45N/A4211 1. Palumbo A, et al. Blood. 2008;112:3107-3114. 2. Facon T, et al. Lancet. 2007;370:1209-1218. 3. Hulin C, et al. ASH 2007. Abstract 75.

15. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma Thal/Dex vs MP in Newly Diagnosed Myeloma (N = 288; Median Age: 72 Yrs) Ludwig H, et al. Blood. 2009;113:3435-3442.  Median TTP: 21.2 mos with TD vs 29.1 mos with MP (HR, 1.26; 95% CI,.88-1.80; log-rank P =.2)  Median OS: 41.5 mos with TD vs 49.4 mos with MP (HR, 1.55; 95% CI, 1.06-2.27; log-rank P =.024)  Median OS in pts > 75 yrs 19.8 mos with TD vs 41.3 mos with MP (P =.071) Response, %Thal/Dex (n = 145) MP (n = 143) P Value Complete response221.0 VGPR2411.004 CR + VGPR2613.006 PR4237--

16. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma Phase III VISTA Study: VMP vs MP in Untreated MM Pts Ineligible for HDT-ASCT  Pts (N = 682): symptomatic MM/end-organ damage with measurable disease –≥ 65 yrs or < 65 yrs of age but not transplant eligible –≥ 75 yrs of age: 31% in VMP arm, 30% in MP arm –KPS ≥ 60%  Stratification: β2-microglobulin, albumin, region VMP (n = 344) Cycles 1-4 Bortezomib 1.3 mg/m 2 IV Days 1, 4, 8, 11, 22, 25, 29, 32 Melphalan 9 mg/m 2 IV and prednisone 60 mg/m 2 IV Days 1-4 Cycles 5-9 Bortezomib 1.3 mg/m 2 IV Days 1, 8, 22, 29 Melphalan 9 mg/m 2 IV and prednisone 60 mg/m 2 IV Days 1-4 MP (n = 338) Cycles 1-9 Melphalan 9 mg/m 2 IV and prednisone 60 mg/m 2 IV Days 1-4 9 x 6-wk cycles (54 weeks) in both arms  Primary endpoint: TTP  Secondary endpoints: CR rate, ORR, time to response, DOR, time to next therapy, OS, PFS, QoL (PRO) San Miguel JF, et al. N Engl J Med. 2008;359:906-917. RANDOMIZERANDOMIZE

17. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma VISTA Study of VMP vs MP in Untreated Myeloma: Efficacy Data EndpointVMP (n = 337) MP (n = 331) P Value ORR*71%35%<.001 CR*30%4%<.001 TTP24 mos16.6 mos<.001 Median OS at 16.3 mosNR -- San Miguel JF, et al. N Engl J Med. 2008;359:906-917. *EBMT criteria.

18. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma VISTA Study of VMP vs MP in Newly Diagnosed MM: Updated Efficacy Data  Median follow-up of 36.7 months  35% reduced risk of death with VMP vs MP (HR,.653; P =.0008)  Median OS with VMP not estimable vs 43.1 mos with MP  Median time to subsequent treatment 28.1 mos with VMP vs 19.2 mos with MP (HR,.527; P <.001)  3-yr OS 68.5% with VMP vs 54% with MP Mateos M-V, et al. ASH 2009. Abstract 3859

19. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma VMP: Efficacy in Pts With Poor Prognostic Characteristics  VMP produced consistent efficacy in TTP and OS endpoints, regardless of poor prognostic characteristics OutcomeTTPOS Median, mosHR (95% CI) Median, Mos HR (95% CI) Age, yrs ≥ 75NR0.956 (0.579-1.579) NR1.572 (0.975-2.535) < 7523.1NR CrCl, mL/min 2 ≥ 6021.70.666 (0.416-1.066)NR1.205 (0.725- 2.005) < 60NR Cytogenetics High risk*19.81.297 (0.55-3.06)NR1.104 (0.444- 2.743) Standard risk23.1NR San Miguel JF, et al. ASH 2008. Abstract 650. *High-risk defined as t(4;14), t(14;16), del(17p) by FISH.

20. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma VMPT vs VMP in Newly Diagnosed Myeloma Pts ≥ 65 yrs (physiologic age) or transplantation ineligible Primary endpoint: PFS RANDOMIZERANDOMIZE VMPT (n = 177)* Bortezomib* 1.3 mg/m 2 IV Days 1, 8, 15, 22 Melphalan 9 mg/m 2 Days 1-4 Prednisone 60 mg/m 2 Days 1-4 Thalidomide 50 mg Days 1-35 9 x 5-wk cycles VMP (n = 177)* Bortezomib* 1.3 mg/m 2 IV Days 1, 8, 15, 22 Melphalan 9 mg/m 2 Days 1-4 Prednisone 60 mg/m 2 Days 1-4 Bortezomib 1.3 mg/m 2 q 15 days Thalidomide 50 mg/day Maintenance No maintenance *Biwkly V: VMP, 61 pts; VMPT, 70 pts Until relapse Palumbo A, et al. ASH 2008. Abstract 652.

21. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma Phase III: VMPT vs VMP Median follow-up: 16.1 mos  Incidence of grade 3/4 hematologic AEs generally comparable between arms  Grade 3/4 nonhematologic AEs more frequent in VMPT vs VMP arm: infections, sensory neuropathy, fatigue, thrombosis, cardiac events  Treatment discontinuations similar with VMPT (3%) and VMP (4%) Outcome, %VMPT (n = 221)VMP (n = 229)P Value CR3521<.0001 VGPR1621-- CR + VGPR5142.06 PFS, 3 yrs7156.13 OS, 3 yrs9089.75 Palumbo A, et al. ASH 2009. Abstract 8515.

22. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma Reduction in Bortezomib Dose Reduces Neurotoxicity Reducing bortezomib from biwkly to wkly in VMP appears to reduce neurotoxicity without loss of efficacy Outcome, %VMP VISTA (N = 340) [1] APEX (N = 331) [2] SUMMIT (N = 202) [3] VMP Biwkly (N = 42) [4,5] VMP Wkly (N = 116) [4,5] VMP Wkly (N = 260) [6] Sensory PN (grade 3/4) 138121429 Neuralgia (grade 3/4) 927123--- CR30*6†6† 10 ‡ 272018 CR + PR71*38 † 27 ‡ 8258 1. San Miguel JF, et al. N Engl J Med. 2008;359:906-917. 2. Richardson PG, et al. N Engl J Med. 2005;352:2487-2498. 3. Richardson PG, et al. N Engl J Med. 2003;348:2609-2617. 4. Palumbo A, et al. ASH 2008. Abstract 652. 5. Palumbo AP, et al. ASCO 2009. Abstract 8515. 6. Mateos MV, et al. ASH 2008. Abstract 651. *N = 337. † N = 315. ‡ N = 193.

23. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma MP + Novel Agents in Older Pts MPT [1] (N = 125) MPT [2] (N = 167) MPV [3] (N = 337) VMPT [4,5] (N = 221) MPT [6] (N = 113) Age > 75 yrs, %0253223100 Efficacy  CR + PR, %7669716862  CR, %131630357  PFS, mos2822 7124  OS at 3 yrs, %~ 65~ 607290~ 55 MP + novel agent is better! 1. Facon T, et al. Lancet. 2007;370:1209-1218. 2. Palumbo A, et al. Blood. 2008;112:3107-3114. 3. San Miguel JF, et al. N Engl J Med. 2008; 359:906-917. 4. Palumbo A, et al. ASH 2008. Abstract 652. 5. Palumbo AP, et al. ASCO 2009. Abstract 8515. 6. Hulin C, et al. J Clin Oncol. 2009;27:3664-3670.

24. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma Summary: Melphalan/Prednisone + Novel Agents in Transplantation-Ineligible MM  MP + novel agent is the standard of care  MPV overcomes adverse prognostic features  Reduction in bortezomib dose intensity reduces neurotoxicity without affecting efficacy

25. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma Response Rates Based on Risk Stratification With Len/Dex Therapy (N = 100) High Risk  FISH –Del 17p –t(4;14) –t(14;16)  Cytogenetic del 13  Cytogenetic hypodiploidy  PCLI >3% Standard Risk  All others including: –Hyperdiploid –t(11;14) –t(6;14) Response, %AllHigh Risk (n = 16) Standard Risk (n = 84) P Value CR + VGPR4438450.36 ≥PR8881890.56 Kapoor P, et al. Blood. 2009;114:518-521.

26. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma Outcome Based on Risk Stratification (Nonrandomized) With Len/Dex Therapy Kapoor P, et al. Blood. 2009;114:518-521. Outcome, %High RiskStandard RiskP Value PFS, mos18.5 36.5 <.001 3-Yr OS, %7786NS N = 100

27. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma Risk Assessment for VTEs in MM Pts Receiving Thalidomide or Lenalidomide  Individual risk factors –Obesity (BMI ≥ 30) –Previous VTE –Central venous catheter or pacemaker –Associated disease –Cardiac disease –Chronic renal disease –Diabetes –Acute infection –Immobilization –Major surgery –Blood clotting disorders  VTE prophylaxis  Individual risk factors or myeloma- related risk factors (eg, hyperviscosity) –If ≤ 1 risk factor present, ASA 81- 325 mg/day –If ≥ 2 risk factors present, LMWH (equivalent to enoxaparin 40 mg/day) or full-dose warfarin (target INR: 2-3)  MM therapy–related risk factors (eg, high-dose dexamethasone, doxorubicin, multiagent chemotherapy) –LMWH (equivalent to enoxaparin 40 mg/day) or full-dose warfarin (target INR: 2-3) Palumbo A, et al. Leukemia. 2008;22:414-423.

28. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma Phase I/II: New Combinations (A) Efficacy CRD [1] (N = 53) VRD [2] * (N = 65) VCRD [3] (N = 25) VCD/VTD [4] (N = 43) Best response, n (%)  ORR  ≥ nCR  ≥ VGPR 45 (85) NR 17 (32) 65 (100) † 29 (44) 49 (74) † 25 (100) 9 (36) ‡ 17 (68) 41 (96) 15 (35) 24 (56) Median OSNR at 8 mos86%, 12 mo est *Dexamethasone 20 mg on Days 1,2, 4, 5, 8, 9, 11, 12 † Independent of ISS stage and high-risk cytogenetics. ‡ ≥ CR. 1. Kumar S, et al. ASH 2008. Abstract 91. 2. Richardson P, et al. ASH 2008. Abstract 92. 3. Kumar S, et al. ASH 2008. Abstract 93. 4. Bensinger W, et al. ASH 2008. Abstract 94.

29. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma Summary: Frontline Therapy With Lenalidomide  Lenalidomide/dexamethasone is an excellent choice for frontline therapy –For transplantation-eligible patients –For transplantation-ineligible patients  Mobilization of stem cells can be challenging with growth factors alone –Adequate stem cells may be collected after 4-6 cycles of treatment  DVT prophylaxis is mandatory –Aspirin may be adequate in most patients –Warfarin may be indicated for patients with thromboembolic risk factors

30. Frontline Treatment of Multiple Myeloma: Phase III Trials Transplantation Eligible

31. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma Autologous Stem Cell Transplantation  Mel 200/m 2 standard conditioning regimen  Sufficient performance score, and adequate liver, pulmonary, cardiac function needed  Higher PR and CR rates than conventional chemotherapy  Higher OS and EFS than conventional Rx  Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines.

32. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma Stem Cell Transplantation Key issues  Efficacy compared with conventional chemotherapy  Timing: early vs delayed  Single vs tandem  Role of allogeneic and miniallogeneic transplantations  Maintenance post-SCT

33. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma Phase III E4A03: Len + High-Dose Dex vs Len + Low-Dose Dex in Newly Diagnosed Pts  Primary endpoint: response at 4 mos  Equivalence: ORR in the Rd arm < 15% Rajkumar SV, et al. ASH 2008. Abstract 799. Pts with newly diagnosed myeloma CR or PR < PR Off study for SCT or continue at physician’s discretion CR/PR/SD RD: Lenalidomide 25 mg PO Days 1-21 and high-dose dexamethasone* Rd: Lenalidomide 25 mg PO Days 1-21 and low-dose dexamethasone † Thal/Dex (4 cycles) 4 cycles *Dexamethasone given on Days 1-4, 9-12, 17-20 for a total of 480 mg. † Dexamethasone given on Days 1, 8, 15, 22 for a total of 160 mg.

34. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma Len + High or Low-Dose Dex (E4A03): Response  3-yr OS rates converged (P =.467) with all pts crossed over to low dose  Successful stem cell harvesting in 97.6% (n = 167)  3-yr OS for high dose or low dose followed by SCT: 92% High DoseLow DoseP Value Overall response at 4 cycles, % 7968.008 ≥ VGPR within 4 cycles, % 4224<.0001 Best overall response, % 8170.009 ≥ VGPR, % 5040.040 CR (IF-), % 1310-- OS, % 1-yr OS 8796.0002 2-yr OS 7587-- Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.

35. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma E4A03: Serious Nonhematologic Adverse Events  Most common AEs (grade ≥ 3): –DVT/PE: 26% Len/Dex vs 12% Len/dex (P =.0003) –Infection/pneumonia: 16% Len/Dex vs 9% Len/dex (P =.04) –Fatigue: 15% Len/Dex vs 9% Len/dex (P =.08) Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.

36. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma IFM 2005/01: Bort/Dex vs VAD Induction  Phase III, randomized  Bortezomib/dexamethasone vs vincristine/doxorubicin/dexamethasone (VAD) in transplantation eligible patients  Higher ORR, longer PFS with bortezomib/dexamethasone vs VAD –Response higher both before transplantation and after each subsequent transplantation  OS comparable in both study 2 arms  Bortezomib/dexamethasone well tolerated –Higher incidence of PN

37. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma GIMEMA: VTD vs TD in Newly Diagnosed Patients  Induction: three 21-day cycles –Bortezomib 1.3 mg/m 2 on Days 1, 4, 8, and 11; thalidomide 100-200 mg/day on Days 1-63; dexamethasone 320 mg/cycle  Consolidation: two 35-day cycle –Bortezomib 1.3 mg/m 2 on Days 1, 8, 15, and 22; thalidomide 100 mg/day on Days 1-70; dexamethasone 320 mg/cycle Cavo M, et al. ASH 2008. Abstract 158. Pts aged ≤ 65 yrs with symptomatic MM (N = 460) Bortezomib/ thalidomide/ dexamethasone (n = 226) Thalidomide/ dexamethasone (n = 234) Induction CTX Melphalan 200 PBSC Collection Transplantation Consolidation Bortezomib/ thalidomide/ dexamethasone Thalidomide/ dexamethasone Dexamethasone Maintenance

38. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma VTD vs TD for SCT Induction  Higher response rate with VTD induction –VGPR or better: VTD 61% vs TD 28% (P <.001) –CR: VTD 19% vs TD 5% (P <.0001)  PFS at 30 months –VTD 76% vs TD 58% (P =.009)  OS, no significant difference to date –Longer follow-up needed Cavo M, et al. ASH 2009. Abstract 351.

39. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma Summary: Frontline Treatment With Bortezomib Before Transplant  Bortezomib induction therapy improves outcome posttransplantation  Bortezomib combination is superior to thalidomide and dexamethasone alone  High-risk group shows benefit with bortezomib induction

40. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma StudyAgePhaseNRegimen1-Yr OS, % 2-Yr OS, % 3-Yr OS, % Rajkumar, E1A00 1 Med: 65III207Thal Dex vs Dex8072< 70 Rajkumar, MM003 2 Med: 65III470Thal Dex vs Dex8371~ 60 Palumbo 3 Med: 72III331MPT vs MP ~ 87 ~ 83~ 60 Facon 4 65-75III447 MPT v MP v M100 88~ 78~ 65 San Miguel, VISTA 5 Med: 71III682MPV vs MP~ 908372 E4A03 Arm A 6 Med: 65III214LD887875 E4A03 Arm B 7 Med: 65III207Ld968874 Attal, IFM 8 < 65III200Auto vs Chemo~ 88~ 80~ 65 Child, MRC 9 < 65III401Auto vs Chemo~ 87~ 75~ 70 Barlogie, S9321* 10 ≤ 70 III516Auto vs Chemo~ 84~ 78 ~ 60 Attal, IFM 11 < 60III3991 vs 2 Auto Tx~ 90~ 75~ 65 Barlogie, TT II 12 < 75 † III668 TT2 ± Thal 92~ 84~ 75 Intent to Treat 1, 2, and 3-Yr Survival Rates in Phase III Newly Diagnosed MM Trials *ITT population. † 80% < 65 yrs of age.

41. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma Recent Updates on MM With Impact on Clinical Practice  What is the best therapy for newly diagnosed MM? –Transplantation-ineligible patients –MPV with wkly bortezomib –Ld –MPT –Transplantation-eligible patients –Triplets VTD or VRD –Ld or VD  Does choice of initial therapy matter? Yes  How long to treat? –Transplantation ineligible: 1 yr –Transplantation eligible: induction + transplantation  Have novel therapies improved overall transplantation outcome? Yes

42. Frontline Treatment of Multiple Myeloma: Is CR the Objective of Therapy?

43. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma  CR is a primary endpoint in many cancer trials, but does not per se translate into survival benefit [1]  CR is a posttreatment prognostic factor –Not important before when CR < 10% –Important now when CR is between 30% to 70% –Not important in the future when CR is > 90%  Durability of CR –CR to dexamethasone: short lived, median 12 mos –CR to transplantation: longer duration, 3+ yrs  When myeloma evolves from monoclonal gammopathy of undetermined significance (MGUS), lower CR rate has no adverse consequences [2]  In gene expression profiling studies, CR is important only in high-risk pt subgroup 3 1. Barlogie B, et al. Blood. 2006;108:2134. 2. Zhan F, et al. Blood. 2007;109:1692-1700. 3. Haessler J, et al. Clin Cancer Res. 2007;13:7073-7079. Is CR Always the Objective of Therapy?

44. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma CR is Critical in High Risk Myeloma  N = 326  Using gene expression profiling, a survival benefit with CR was observed only in a small high-risk subgroup –13% of patients (HR: 0.23; P =.001),  Most patients with low-risk disease had comparable survival outcomes, regardless of whether or not CR was achieved –HR: 0.68; P =.128  CR per se does not confer favorable outcome in majority (87%) of patients with MM Haessler J, et al. Clin Cancer Res. 2007;13:7073-7079.

45. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma Treatment of Newly Diagnosed MM  CR does not always predict outcome!  With current drugs, CR cannot be achieved in all pts  Choose a therapy with the highest likelihood for CR and stay with it  Do not pursue CR outside of a clinical trial

46. Role of Maintenance Therapy

47. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma Post-ASCT Maintenance NThal DoseCR RatePFSOS Barlogie668 400 mg until prog or AE 62% vs 43% 5 yr: 56% vs 44% 5 yr: NS Attal597 400 mg until prog or AE 67% vs 55% (CR + VPGR) 3 yr: 52% vs 36% 4 yr: 87% vs 77% Spencer243 200 mg 12 mos 1-yr maint 63% vs 40% 3 yr: 63% vs 36% 3 yr: 90% vs 81% Barlogie B, et al. N Engl J Med. 2006;354:1021-1030. Attal M, et al. Blood. 2006;108:3289-3294. Spencer A, et al. J Clin Oncol. 2009;27:1788-1793. Maintenance therapy with immunomodulators improves PFS and OS

48. clinicaloptions.com/oncology Spanning the Continuum of Care in Multiple Myeloma Conclusions  Maintenance posttransplantation with immunomodulatory agent should be considered for pts with < VGPR after transplantation  Maintenance therapy prolongs PFS and perhaps OS  Continued reports on bortezomib and lenalidomide maintenance are awaited

49. Go Online for More CCO Coverage of Multiple Myeloma Interactive Virtual Presentations review and consider challenging patient cases with guidance from expert faculty members Text-Based Modules plus downloadable PowerPoint slides clinicaloptions.com/oncology