1. Relapsed and Refractory Myeloma Case 1 James R. Berenson, MD Medical & Scientific Director Institute for Myeloma & Bone Cancer Research Los Angeles, CA

2. Disclosures Speakers’ bureau, research support, and consulting: Amgen, Celgene, Millennium, and Onyx

3. Relapsed/Refractory Multiple Myeloma Case 1 76 year-old white female presented in Oct ‘11 w/ –Severe mid-back pain –Anemia w/ hemoglobin 10.0 –Workup: Labs –IgG 3760 –M-protein 2.62 –24-hour urine paraprotein 650 mg –B2M 3.7, albumin 3.3 (Stage 2 ISS) –Creatinine 1.5 Bone marrow 40% plasma cells Bone survey w/ lytic lesions throughout the axial skeleton and long bones and T10 VCF Patient received initial treatment –Kyphoplasty at T10 –Zoledronic acid 4 mg monthly –Cyclophosphamide, bortezomib and dexamethasone

4. Relapsed/Refractory Multiple Myeloma Case 1 (cont’d) Course –Back pain resolved following kyphoplasty –After 4 cycles of initial therapy IgG 1170 (from 3760) M-protein 0.59 (from 2.62) 24-hour urine M-protein 45 mg (from 650 mg) Other labs- creatinine 1.0, hemoglobin 11.7 –Patient continued treatment for 3 additional cycles w/ myeloma labs increasing IgG 1500 M-protein 0.79 24 hour urine paraprotein 81 mg Other labs- creatinine 1.1, hemoglobin 11.5

5. Relapsed/Refractory Multiple Myeloma: Case 1 At this point, you should 1.Start lenalidomide and oral steroids 2.Stop CYBORD 3.Repeat labs 4.Continue present regimen 5.Start another bortezomib-containing combination

6. Relapsed/Refractory Multiple Myeloma: Case 1 Labs were repeated 1 month later –IgG now 1800 –M-protein 1.01 –24 hour urine M-protein 237 mg –Creatinine 1.5; hemoglobin 10.6 What next?

7. Individualize Your Choice for the Myeloma Patient Based on: Co-morbid conditions Disease Work/ Lifestyle Renal, Bone, Marrow, Subjective, Rate of ProgressionG enetics? How active is the patient? Mobility? Is potential neuropathy an issue? (e.g.- surgeon, pianist) Diabetes mellitus (steroids) Cardiac (Doxorubicin, PLD) Neuropathy (Thalidomide) Prior treatments Responsea nd for how long? Side effects and tolerability

8. Principles of Treating Relapsed/Refractory Multiple Myeloma Be sure a patient has really progressed before changing therapy –REPEAT MYELOMA LABS! Try to use drugs patient has not seen before HOWEVER, –progression on one drug in combination does not mean that drug will not be effective w/ another agent e.g., pts progressing from bortezomib w/ melphalan often respond to bortezomib w/ PLD Even different drugs in the same class may be active so that –bortezomib+melphalan failures may respond to other alkylating agents- cyclophosphamide or bendamustine –LEN failures may respond to THAL or POM and vice versa –bortezomib failures respond to carfilzomib –pts progressing from a drug at one dose may respond to the same drug at a higher dose- e.g., LEN –the same combination may be effective again if the patient has not seen the combination in a long time

9. Bortezomib + PLD vs. Bortezomib in Previously Treated MM 1° Endpoint: TTP 2° Endpoints: OS*, ORR BORT 1.3 mg/m 2 PLD 30 mg/m 2 N=646 RANDOMIZERANDOMIZE 14811 Days (n=324) (n=322) q 3 weeks up to 8 cycles *Not enough events to determine statistical significance in overall survival. ORR=overall response rate; OS=overall survival; TTP=time to progression. Ddoxorubicin HCl liposome injection Prescribing Information, Distributed by Ortho Biotech Products, L.P., Raritan, NJ. Rev’d May 2007

10. Bortezomib + Pegylated Liposomal Doxorubicin (PLD) + Dexamethasone for Patients with Previously Untreated Myeloma: A Phase II Trial Days 1 2 3 4 5 6 7 8 9 10 11 29 Cycle repeats Bortezomib: 1.0 mg/m 2 IV PLD: 5 mg/m 2 IV infusion Dexamethasone 40 mg IV Berenson et al. Brit J Haematol, 2011  MR: 86%  Reduced incidence of PN & PPE

11. Efficacy and Safety of Bendamustine plus Bortezomib in R/RMM: A Phase 1/2 trial Patients were assigned to one of 3 cohorts receiving doses of intravenous bendamustine at 50 mg/m2 (cohort 1), 70 mg/m2 (cohort 2), or 90 (cohort 3) mg/m2 in combination with a fixed dose of intravenous bortezomib (1.0 mg/m2) according to the schedule in Figure 1. Berenson et al. Brit J Haematol 2012

12.  No DLT was observed at any dose level 50 mg/m2 (n = 5) 70 mg/m2 (n = 4) 90 mg/m2 (n = 5)  The maximum dose of bendamustine (90 mg/m2) was well tolerated in combination with bortezomib 1.0 mg/m2 and was designated as the MTD  Overall response rate Overall 48% (1 CR, 2 VGPR, 9 PR, & 7 MR) At MTD (90 mg/m2) 52% Bortezomib-exposed (n=31) 42% Alkylator-exposed (n=28) 46% Bendamustine & Bortezomib: Results

13. CR, complete response; nCR, near complete response; Len + Dex, lenalidomide, dexamethasone; PR, partial response; ORR, overall response rate; RRMM, relapsed/refractory multiple myeloma. Lenalidomide + Dexamethasone in R/R MM Phase 3 Trials–Response 1,2 1. Weber DM, et al. N Engl J Med. 2007;357:2133-2142. 2. Dimopoulos M, et al. N Engl J Med. 2007;357:2123-2132. CR rates were significantly higher in the Len + Dex arm of each trial compared with Placebo + Dex (P <.001) Both OS & TTP superior in Len + Dex arm

14. Phase II Study of Bortezomib plus Lenalidomide and Dex (VRD) in Rel/Ref MM: Updated Results After >2 Years’ Follow-up 1 Richardson PG et al. ASH 2010, abstract #3049 –Endpoints: Primary: PFS; Secondary: ORR (≥MR), DOR, TTP, OS, safety –Patients: 64 pts with relapsed/refractory MM; median age 65 years (range 32–83); ISS stage I/II/III/unknown (%): 27/25/23/25; median 2 (range 1–3) prior therapies –Study design: –Anticoagulation with aspirin ± warfarin or LMWH, and antiviral prophylaxis against herpes zoster were required

15. Richardson PG et al. ASH 2010, abstract #3049 –Safety: Median cycles received: 11 (range 1–48) Median treatment duration: 7.9 months (range 0.4–36); 66% of pts completed ≥8 cycles with all three drugs Best response,% CR/nCR11/14 PR/VGPR36/3 ORR (≥MR)78 Median duration of ≥MR: 8.3 months Median duration of ≥PR: 8.4 months Outcom es Median, mos 1-yr, % 2-yr, % TTP9.53716 PFS9.53615 OS268655 Results: 62 pts evaluable for response Gr ≥3 AE, %VRD (n=64) Neutropenia30 Thrombocytopenia22 Lymphopenia11 Leukopenia9 Hyperglycemia9 Hyponatremia8 Hypophosphatemia8 Fatigue5 Diarrhea3 Limb edema3 Pain in extremity2 Phase II Study of Bortezomib plus Lenalidomide and Dex (VRD) in Rel/Ref MM: Updated Results After >2 Years’ Follow-up

16. DVD-R (Bortezomib + Pegylated Liposomal Doxorubicin + Dexamethasone + Lenalidomide) for Patients with R/R MM: A Phase II Trial Days 1 2 3 4 5 6 7 8 9 10 11 12 13 14 29 Cycle repeats Bortezomib: 1.0 mg/m 2 IV PLD: 4 mg/m 2 IV infusion Dexamethasone 40 mg IV Berenson et al. Leukemia 2012 Len 10 mg po qd d1-14  MR: 85%  No PPE; PN only 25%

17. Bendamustine (B) w/ Lenalidomide (L) and Dexamethasone (D): Phase 1/2 Trial R/R MM patients N=29 Regimen (28-day cycles) –B 75-100 mg/m 2 d1 & 2 –L 5-10 mg qd d1-21 –Dex 40 mg PO weekly MTD: B 75/ L 10/ D 40 Results (only 25 considered evaluable for response) –ORR (> PR): 52% w/ 24% VGPR –MR 24% –PFS: 6.1 mo Lentzsch et al. Blood 2012

18. Retreatment w/ IMiD compounds for MM Patients Retrospective study in 140 pts treated firstline w/ –THAL/DEX- 58% –LEN/DEX- 42% Retreatment w/ a regimen containing –THAL- 24% –LEN- 76% # of treatments before retreatment - median of 2 (range 1-6) 89% received IMiD compound w/ DEX 113 considered evaluable for response –44% > PR –MR not reported Madan et al. Blood 2011 LEN (n=48) LEN THAL (n=11) THAL LEN (n=58) THAL THAL (n=23) > PR54%20%48%30%

19. Relapsed/Refractory Multiple Myeloma For patients failing CYBORD regimens upfront, treatment options include all of the following except 1.PLD w/ BOR +/- steroids 2.Bendamustine w/ BOR 3.Len w/ steroids 4.Len w/ steroids + BOR 5.Len w/ oral melphalan