Experience with bortezomib (Velcade) in multiple myeloma. Peter Černelč Clinical center Ljubljana Department of Haematology

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1 Experience with bortezomib (Velcade) in multiple myeloma Peter Černelč Clinical center Ljubljana Department of Haematology

2 Our experience with bortezomib (Velcade) in multiple myeloma 1. Our first experience with bortezomib in International Phase 3b Study: : 6 patients from Clinical center Ljubljana included 2. Bortezomib use in everyday clinical practice: Case report of 68 y old male with IgA lambda MM 3. Current treatment guideliness for multiple myeloma

3 Preliminary Safety and Efficacy Results from an International Phase 3b Study for Expanded Access to Bortezomib in 624 Patients with Relapsed and/or Refractory Multiple Myeloma Presented ASH 2006

4 Study characteristics - International, multicenter, open-label phase 3b study - Enrolment of 93 study centers from 21 countries - Study start: May Study end: April 2006

5 Mikhael JR, et al. ASH 2006, abstract # 3530 International Phase 3b Study for Expanded Access to Bortezomib with Rel/Ref MM Trial Design: International multicenter open-label phase 3b study Study Objectives: Primary objective was to provide expanded access to treatment with bortezomib in patients with relapsed or refractory MM treated with 2 prior lines of therapy Secondary objectives were to evaluate safety and response to treatment based on changes in serum and urine M-M protein levels and KPS

6 Mikhael JR, et al. ASH 2006, abstract # 3530 Patients: 624 patientsp with relapsed or refractory MM and 2 prior lines of therapy; patients with PD as the best response to prior bortezomib and patientsp with Gr 2 PN (periferal neuropathy) were excluded

7 Mikhael JR, et al. ASH 2006, abstract # 3530 Dose and Schedule: up to eight 21-day cycles Bortezomib 1.3 mg/m 2 days 1, 4, 8, and 11 Dex 20 mg PO on the day of and day after bortezomib Added after cycle 2 for PD or after cycle 4 for SD Treatment could be extended beyond 8 cycles in responding patients

8 Mikhael JR, et al. ASH 2006, abstract # 3530 Median of 5 treatment cycles were completed (range, 0 13) Dex was added (at any time point) in 33% of patients Number of patients completing cycle, % Treatment Exposure ( N= 624) Number of treatment cycles completed Treatment Cycle

9 SWOG (Southwest Oncology Group) criteria Response to Velcade treatment was evaluated using SWOG criteria:

10 Response: 590 evaluable patientsp atients: ORR (CR + PR) 54% with VGPR 35% Response by M-Protein* Responses by Treatment Cycle Best Overall Response (n=590)* 100% 80% 60% 40% 20% 0% 3.9% 16.1% 20.8% 19.7% Cycle 2 (n=534) 8.7% 23.3% 19.4% 16.0% Cycle 4 (n=412) 11.2% 24.6% 21.4% 16.7% Cycle 6 (n=285) CR VGPR PR MR SD PD 100% 80% 60% 40% 20% 0% 12.0% 23.2% 18.8% 16.6% 17.3% 12.0% Best Response VGPR 35% ORR (CR+PR) 54% CR VGPR PR MR SD PD Treatment cycle completed *Additional 11 patients had response assessment based on changes in KPS but did not have M-protein assessment * Response assessed by modified SWOG criteria Mikhael JR, et al. ASH 2006, abstract # 3530

11 Response Time to First Response* Cumulative probability of response to therapy Time (Weeks) *First response defined as having SD or better Mikhael JR, et al. ASH 2006, abstract # 3530

12 Adverse Events (N= 624) Common Treatment-Related AE* occurring in > 10% of patients Mikhael JR, et al. ASH 2006, abstract # 3530

13 Conclusions In this phase 3b study for expanded access to Bortezomib, response rates were high, even in heavily pretreated patients, with PR or better achieved in 54% and 35% in VGPR, Bortezomib was well tolerated with manageable adverse events in relapsed/refractory multiple myeloma in a broad clinical setting, Safety profile comparable to previous experience in phase II and phase III clinical studies. Mikhael JR, et al. ASH 2006, abstract # 3530

14 Bortezomib is effective also in newly diagnosed patients (clinical studies presented at ASH 2006) Study Regimen Pts (n) CR / ncr ORR Comment on PBSC collection or subsequent HDT/SCT Mateos et al. VELCADE + Melphalan/Prednisone (VMP) Jagannath et al. Harousseau et al. VELCADE +/- Dexamethasone (VD) 6 cycles HDT/SCT VELCADE +/- Dexamethasone (VD) 4 cycles HDT/SCT Popat et al. VELCADE +/- Doxorubicin/Dexamethasone Dexamethasone (PAD)- Cohort 1 4 cycles HDT/SCT Popat et al. VELCADE +/- Doxorubicin/Dexamethasone Dexamethasone (PAD)- Cohort 2 4 cycles HDT/SCT Orlowski et al. VELCADE + Doxil (liposomal doxorubicin) Wang et al VELCADE +Thalidomide/ Thalidomide/Dexamethasone (VTD) 2 cycles HDT/SCT Badros et al. VELCADE + DT-PACE 2 cycles HDT/SCT 60 43% 89% NA (patients not eligible for transplant) 48 19% 90% 12/12 pts had successful haematological recovery after HDT/SCT 48 21% 67% 45 pts; median CD34+ yield of 6.7 x 10 6 /kg 21 29% 95% 20 pts had successful PBSC harvest (median CD+ yield of 3.8 x 10 6 /kg) 19 16% 89% NR 15 13% 80% NR 38 18% 92% 22 pts underwent subsequent HDT/SCT without serious complications 12 17% 83% Median CD34+ field of 20.6 x 10 6 /kg Adequate numbers of stem cells were collected with prompt engraftment after SCT.

15 1) Patients eligible for transplant Vel/Dex vs. VAD Induction in Newly Diagnosed MM: Preliminary Analysis of IFM Trial Trial Design: Randomized multicenter phase III trial of VAD vs. Vel/Dex as induction therapy prior to SCT, preliminary analysis on first 165 patients in newly-diagnosed, symptomatic MM pts 65 yrs. Response: by investigator assessment; evaluated by modified EBMT criteria By Induction Therapy VAD (A1+A2) N=82 Vel/Dex (B1+B2) N=79 CR/nCR 9% 20% CR 4% 9% VGPR 17% 23% CR+VGPR 26% 43% PR (incl( VGPR) 59% 62% CR+PR 67% 82% By Consolidation Therapy No DCEP (A1+B1) N=78 DCEP (A2+B2) N=64 11% 28% 3% 14% 26% 13% 37% 68% 79% 41% 61% 89% MR+SD 20% 9% PD 2% 3% Not assessable 9% 3% D/c due to toxicity 2% 3% 19% 1% 11% 0 23% Harousseau et al. ASH 2006, abstract # 56

16 2) Patient not eligible for transplant Velcade/melphalan melphalan/prednison prednison vs MP 1 cycle VMPV vs 6 cycles MP: 1st cycle VMP (n=53) 70% 42% 6 cycles MP* (n=96) 70% 60% 62% 70% 60% *historical control 50% 40% 30% 20% 10% 0% 6% 2% CR IF- CR IF+ 24% 6% PR MR SD 50% 40% 30% 20% 10% 0% 39% 27% 31% 3% CR IF+ PR MR SD/PD Mateos et al. Blood June (Epub ahead of print) *Hernandez et al. Br J Haematol 2004;127:159 64

17 VMP Progression free survival P=0.002 V-MP: 91% MP: 66% Overall survival V-MP: 90% P= MP: 62% Median follow-up: 16 months (11 24) Mateos et al. Blood June (Epub ahead of print)

18 Velcade in Waldenström s macroglobulinemia Goy 1 Strauss 2 Chen 3 Phase II trials Trial Patients n/n* PR Heaviliy pretreated patients with relapsed or refractory B-cell B NHL Heavily pre-treated patients with relapsed or refractory NHL or HD (median 4 prior therapies) Previously untreated or relapsed non- refractory WM (Partial response) MR (Minimal response) SD (Stable disease) ORR (Overall response rate) ( PR) 2/ % 5/ % 19/ % Dimopoulos 4 Treon 5 Previously treated WM (8/10 patients received 3 prior therapies) Patients with WM with at least 1 prior therapy 10/ % 26/ % *n = evaluable pts with WM; N = total enrollment pts with NHL; PR in pts with WM. 1. Goy A, et al. J Clin Oncol 2005; 23: , 2. Strauss SJ, et al. Ann of Oncol 2005; 16(suppl. 5): abstract 097, 3. Chen CI, et al. Poster presented at: 46 th Annual Meeting of the American Society of Haematology; December 4 7, 2004; San Diego, California. Abstract 3278, 4. Dimopoulos MA, et al. Haematologica 2005; 90: , 5. Treon S, et al. Blood 2005; 106(11): 490.

19 Case report 68 year-old man O.F. with IgA lambda multiple myeloma first presented in january 2001 with anaemia and miga. Treatment: july 01- may 02: A+P, 8x sept april 04: thal+p, 7m. april 04 - july 04: VAD, 5x nov febr. 05: DAC, 4m febr maj 05: Velcade, 3 cycles, 15 months in CR

20 Concentration of serum M protein in pt. with IgA lambda multiple myeloma Concentration of serum globulins g/l ,5 9,5 15,2 12,9 17,6 13, July 2001 May 2002 September April 2004 July 2004 November 2004 Date February ,4 2, May 2005 January 2006 mig α2 β August 2006 December ,6 5,3 Marec 2007

21 Case report Cytogenetic analysis in 68 year-old man with IgA lambda multiple myeloma in march 2007 Cytogenetic analysis results del13 del17p t(4;14) t(14;16) neg neg neg neg

22 Current treatment guidelines for multiple myeloma

23 Classification of active multiple myeloma High-Risk (25%) Standard-Risk (75%) ** FISH Del 17p-:35-50 % t(4;14): % t(14;16): 2-10 % Cytogenetic Deletion 13 (30-55 %) Cytogenetic Hypodiploidy PCLI >3% FISH t(11;14): % t(6;14)*: 3-4 % Cytogenetic Hyperdiploidy *not yet in clinical practice **Low risk with β-2 microglobulin > 5.5 mg/l (in absence of renal failure) or LDH >upper limit of normal may be at higher risk.

24 Bortezomib in patients with del(13q), t(4;14), t(11;14), AMP CKS1B H. Chang, et al. Leukemia Research 2006; doi: /j.leukres No statistically significant difference in response to bortezomib, b, PFS and OS for patients with or without cytogenetic abnormalities

25 Bortezomib is effective in high- and low-risk disease Response to bortezomib by prognostic factor Age 65 years Age <65 years β 2 M >2.5 mg/l β 2 M 2.5 mg/l No. of patients n=116 n=199 n=230 n=77 Refractory to prior treatment n=199 Not refractory to prior treatment n= % CR + PR Richardson et al. JCO 2005;23(Abstract 6533); Presentation at ASCO 2005

26 Tolerability and efficacy of bortezomib in patients with renal impairment Subanalysis of SUMMIT and CREST Toxicity profile similar in patients with normal vs impaired renal function Mean serum creatinine appears unaffected by bortezomib Proteasome activity in blood assay unaffected by renal function Comparable response rates in patients with compromised renal function Creatinine clearance n ORR (%) (ml/min) > < Jagannath et al. Cancer 2005;103:

27 Guideliness for transplant eligible patients Transplant Eligible (age < 65 years) High Risk* Standard Risk Bortezomib/dex VAD Collect Stem Cells Transplant Second transplant if not in CR or VGPR after first *t(4;14) non transplant approach

28 Guideliness for transplant ineligible patients Transplant Ineligible (age > 65 years) High Risk Standard Risk Bortezomib/dex (also for patients with renal failure) MPT (melphalan/prednisone/ thalidomide) MP (melphalan/prednisone) VAD or dex in patients with renal failure CP (ciclophosphamide/prednisone)

29 Guideliness for relapsed/refractory multiple myeloma First relaps* second relaps/refractory Previous bortezomib No previous bortezomib Repeat bortezomib/dex in case that after first treatment PR or better was achieved, Bortezomib/dex, VAD, Thalidomid/dex IF NOT: VAD, Thalidomid/dex *For minimizing possible adverse events, especially periferal neuropathy that can be irreversible after thalidomid, bortezomib treatment should start before thalidomid

30 Guideliness for supportive therapy in multiple myeloma Supportive therapy Bone disease Anemia Kidney failure Infection Bisphosphonates: -clodronate -pamidronate -zolendronate -ibandronate Recombinant erythropoetins: -epoetin alfa -epoetin beta -darbepoetin alfa -Intensive hydration -Dyalisis -Non-nephrotoxic chemotherapy (e.g. bortezomib) -Wide spectrum Antibiotics -Immunoglobulins -G-CSF -Vaccination (S. pneumonie, H. influenze)

31 Conclusions Bortezomib is highly effective in both young and elderly patients with MM Bortezomib has broad utility in MM: effective in patients with high-risk and low-risk disease effective in patients with comorbidities Preliminary data suggest that bortezomib increases osteoblastic activity Adverse events with bortezomib are manageable PN is reversible in a majority of patients Bortezomib has demonstrated efficacy as part of induction regimens: high response rates with acceptable toxicity profiles does not adversely affect stem cell mobilization or engraftment

32 Conclusions Routine cytogenetic and FISH studies is important in determining not just prognosis, but possibly the optimal choice of therapies. Bortezomib or bortezomib-based regimen was found to have activity against myeloma cells in the high-risk patients and in relapsed/refractory multiple myeloma