[PPT] - Donna E. Reece, M.D. Princess Margaret Hospital T Toronto, ON t PowerPoint Presentation

SLIDE 1

Donna E. Reece, M.D. Princess Margaret Hospital T t ON Toronto, ON 16 October 2008 16 October 2008

SLIDE 2

Multiple Myeloma in Canada p y

Incidence 4/100,000

2,000/yr in Canada

Prevalence

6500/yr in Canada 6500/yr in Canada

1000 deaths per year Median age 65 yrs

g y

Incidence in younger

adults appears to be i i increasing

Kyle RA, Rajkumar SV. N Engl J Med 2004;351:1860–73 Canadian Cancer Statistics; 2007. Available at www.cancer.ca

SLIDE 3

Multiple Myeloma Multiple Myeloma

Marrow plasma cells > 10% Symptomatic myeloma

=“CRAB”

Anemia (Hgb < 100) Bone lesions Creatinine (> 176 umol/L)

Creatinine (> 176 umol/L)

Calcium > 2.8 mmol/L

SLIDE 4

Interaction between Myeloma Cell and Bone M Mi i t Marrow Microenvironment

SLIDE 5

Advances in Prognosis

International Staging System (ISS)

Stage Criteria Median Stage Criteria Median I Serum β2-microglobulin <3.5 mg/L 62 mo. Serum albumin ≥ 3.5 g/dL II Not stage I or III 44 mo. III Serum β2-microglobulin ≥ 5.5 mg/L 29 mo.

Cytogenetic abnormalities

t(4;14)=15% p53 deletion=10%

SLIDE 6

Factors Affecting Myeloma Management in Canada

D il bilit

Drug availability

Approval from Health Canada Funding from provinces

Myeloma drugs approved in Canada

ye o a d ugs app o ed Ca ada

Melphalan Cyclophosphamide Bisphosphonates (pamidronate, zolendronic acid, clodronate) Bortezomib (2nd line +) Bortezomib (2 d line +) Bortezomib + melphalan + prednisone (1st line therapy without ASCT) Lenalidomide for relapsed myeloma

Access programs
SAP for thalidomide (but no funding)
EAP for lenalidomide is closing
Trial of bortezomib + melphalan + prednisone (limited number of centers)

SLIDE 7

Results of “Traditional” Initial Therapy py

Overview

Dex-based induction +

Melphalan + Prednisone until plateau

ASCT

Overall response rate 80% Overall response rate 40 50% Overall response rate 80% CR/nCR 20%-30% Median PFS 20-36 mos Overall response rate 40-50% CR/nCR 5% Median PFS 12-15 mos

ed a S 0 36

s

Median OS 48-60 mos Median PFS 12 15 mos Median OS 30-36 mos

SLIDE 8

Efforts to Improve Initial Therapy Efforts to Improve Initial Therapy

ASCT

Melphalan + Prednisone O ti i ASCT ( i

Tandem ASCT Maintenance therapy using

novel agents

Optimize ASCT (eg. using

melphalan 100 mg/m2)

Add novel agents to M+P

novel agents

New induction regimens

containing novel agents Add novel agents to M P

Use IMiD + dexamethasone

SLIDE 9

Novel Agents in Multiple Myeloma Novel Agents in Multiple Myeloma

Thalidomide Bortezomib Lenalidomide Thalidomide Bortezomib Lenalidomide

Effi Efficacy:

As single agents, with steroids, in combinations
As initial therapy or for relapsed/refractory MM

As initial therapy or for relapsed/refractory MM

SLIDE 10

Novel Agents in Myeloma

Agent Class Effects Toxicity Agent Class Effects Toxicity

Thalidomide IMiD

Decreased adhesion, cytokines production, angiogenesis Teratogenicity, PN, sedation, rash, constipation, DVT angiogenesis Increased anti- myeloma immunity myeloma immunity

Bortezomib Proteasome inhibitor

Decreased adhesion, cytokine production, Fatigue, PN, GI toxicity

inhibitor

y p , angiogenesis, NFkB, DNA repair Decrease in neutrophils, platelets and lymphocytes

Lenalidomid e (CC-5013) IMiD

Decreased adhesion Increased T cell proliferation, NK cell t t i it IFN d Myelosuppression, DVT

( )

cytotoxicity, IFN-γ and IL-2

SLIDE 11

Activity of Novel Agents in Relapsed/Refractory Myeloma Patients Myeloma Patients

Agent CR/nCR PR Overall

Thalidomide1 Thalidomide +Dex2 < 5% < 5% 28% 40-50% 30% 50% Thalidomide +Dex < 5% 40 50% 50% Bortezomib3,4 B t ib + D

5 6

5% / 5% 5% / 5 10% 20-25% 35 55% 30-40% 40 50% Bortezomib + Dex5,6 5% / 5-10% 35-55% 40-50% Lenalidomide7 6% 18% 25 40% Lenalidomide Lenalidomide + Dex8,9 6% 19% 18% 51% 25-40% 70%

1Glasmacher A, et al,Br J Haematol 132: 584-593,2005;2 Palumbo A, et al. Hematol J 2004; 5:31 8-320; 3Richardson PG, et al. N

Engl J Med 352:2487-98, 2005; 4Richardson P, et al. Blood 110:3557-60, 2007; 5Jagannath S et al. Haematologica 91:929-32, 2006;

6Kropff MH, et al. Leuk Res 29:587-90, 2005; 7Richarson PG, et al. Blood 108; 3458-64, 2006; Weber DM, et al. N Engl J Med

357:2133-42, 2007; Dimopoulos M, et al. N Engl J Med 357:2123-32, 2007.

SLIDE 12

The Changing Landscape of Therapy g g p py Initial Myeloma Therapy in Canada

Elderly patients ineligible for ASCT Induction therapy before ASCT Induction therapy before ASCT Initial therapy in “transplant uncertain” patients

Non-melphalan containing therapy Non melphalan containing therapy May be of 2 broad types

Continuous “suppressive” therapy with IMiDs + steroids Combination therapy with novel agents

High overall and CR/nCR rates

SLIDE 13

IMF 99-06: Treatment of Newly Diagnosed Myeloma Patients 65–75 Years

N=500

3 2 3 2 2 MP Arm

Standard MP at 6-wk intervals x 12

MP-Thal Arm

MP as Arm 1 + Thal at MTD but ≤400 mg/day,

MEL100 x 2 Arm

VADx2; cyclophosphamide 3 g/m2; Melphalan, 100 mg/m2 stopped at end of MP

Facon T et al. Lancet 2007;360:1209-1218.

SLIDE 14

IFM 99 06 MP MP Th l d MP M l IFM 99-06:MP vs MP-Thal and MP vs Mel 100 Newly Diagnosed MM Aged 65–75 Years

MP MP + thal Mel 100 x 2 Overall response rate (%) CR rate (%) 35 2 76 18 65 18 Median PFS (mos) 17 8 27 5 19 4 Median PFS (mos) 17.8 27.5 19.4 Overall survival (mos) 33.2 51.6 38.3 ≥ Grade 3 toxicity (%) Any non-heme Neutropenia VTE Peripheral neuropathy 16 26 4 42 48 12 6 58 100 8 Peripheral neuropathy 6

Facon T et al. Lancet 2007;360:1209-1218

SLIDE 15

Randomized Trials in Elderly Myeloma Patients Myeloma Patients

Study Regimen Overall Response CR/nCR rate (%) PFS/EFS (mos) Overall Survival Response rate (%) (%) (mos) Survival (mos) Facon1 MPT MP 76 25 18 2 27.5* 17 8 51.6* 33 2 MP 25 2 17.8 33.2 Palumbo2 MPT MP 76 48 28 7 21.8* 14 5 45 47.6 MP 48 7 14.5 47.6 Hulin3 MPT MP 61 31 7 1 24.1* 19.1 45.3* 27.7 San Miguel4 VMP MP 71 30 35 4 24.0* 16.6 83%* 70%

(2 ) (2 yrs)

1Facon et al. Lancet 2006;370:1209-18; 2Palumbo et al. Blood May 26 2008 [Epub]; 3Hulin et al.

Blood 2007;110:abstract #75; 4San Miguel et al. Blood 2007;110:abstract # 76 .

*statistically significant

SLIDE 16

Randomized Trials in Elderly Myeloma Patients: Toxicity Comparisons Toxicity Comparisons

Study Rx Duration

f Rx

Thal dose ≥ Gr 3 non- heme toxicity ≥ Gr 3 Neutropenia VTE (%) ≥ Gr 3 PN

f Rx

dose (%) heme toxicity (%) Neutropenia (%) (%) PN (%) Facon1 MPT 72 400 mg 42 48 12 6 Facon MPT MP 72 72 400 mg 42 16 48 26 12 4 6 Palumbo2 MPT 52 100 mg 49 16 12 10 MP 52+ 25 17 2 1 Hulin3 MPT MP 72 72 100 mg 53 15 15 7 4 2 2 MP 72 15 4 2 San Miguel4 VMP MP 54 54

‐‐

46 36 40 38 1 1 14

1Facon et al. Lancet 2006;370:1209-18; 2Palumbo et al. Lancet 2006; 367:825-31; 3Hulin et al. Blood

2007;110:abstract #75; 4San Miguel et al. Blood 2007;110:abstract # 76 .

SLIDE 17

VMP: Effect of FISH Cytogenetics

FISH: any (t4-14, t14-16, 17p Del) vs. None

Best M-protein Response n Total ( 16 ) High Risk ( 26) Std Risk ( 139) Response, n (%) (N=165) (N=26) (N=139) CR (IF-) 32% 35% 32% ≥PR 82% 81% 82%

TTP OS

≥PR 82% 81% 82%

VMP standard risk VMP high risk VMP standard risk VMP high risk

VMP standard risk (N=142): 23.1 months (34 events) VMP high risk (N=26): 19.8 months (7 events) HR = 1.297 (95% CI: 0.55, 3.06) VMP standard risk (N=142): not reached (16 events) VMP high risk (N=26): not reached (3 events) HR = 1.009 (95% CI: 0.278, 3.663)

San Miguel et al. Blood 2007;110: abstract #76

SLIDE 18

New Approaches in Elderly Myeloma Patients: Summary

Addition of novel agent to melphalan and prednisone

improves outcome

Whether MP followed by novel agent at relapse produces

similar or inferior results is uncertain

Toxicity is greater

Thalidomide regimens require thromboprophylaxis Peripheral neuropathy is a concern

Data needed for risk groups In Canada, options include:

T t bt i f di f th lid id

Try to obtain funding for thalidomide Clinical trial

SLIDE 19

Management of Elderly Myeloma Patients in Canada: Clinical Trials

NCIC MY11 trial (closed)

Melphalan 5 mg/m2 days 1-4 Melphalan 5 mg/m days 1-4 Lenalidomide 10 mg/days 1-21

O th Bi t h t i l f V

Ortho Biotech trial of VMP Celgene MM020 international trial Celgene MM020 international trial

Lenalidomide + weekly dex until progression Lenalidomide + weekly dex for 18 months MPT

SLIDE 20

New Approaches before ASCT New Approaches before ASCT

Background: Patients in CR/nCR/VGPR after

ASCT have better PFS and OS

Hypothesis: Achievement of CR/nCR/VGPR

before ASCT will translate into improved outcome after ASCT

SLIDE 21

New Approaches before ASCT pp

Multiple induction regimens containing novel agents Multiple induction regimens containing novel agents

produce high CR/nCR rates (VAD-thal, CTD, VTD)

Randomized trials in progress Randomized trials in progress

Thal + Dex vs VAD (MAG) VAD vs Bortezomib + Dex (IFM)

( )

VTD vs Thal + Dex (Bologna)

Canadian trials

“DBd” = Lipo. doxorubicin + bortezomib + dex “CYBOR-D” = cyclophosphamide + bortezomib + dex

SLIDE 22

DBd Trial DBd Trial

Newly Diagnosed Myeloma y g y ↓ Bortezomib 1.3mg/m2 i.v. days 1, 4, 8, 11 Pegylated liposomal doxorubicin 30 mg/m2 IV day 4 gy p g y Dexamethasone 40mg p.o. days 1 – 4, 9 – 12, 17 – 2 0 (cycle 1) then days 1-4 (cycles 2-4) (Q21 day cycles) ↓ 4 cycles (12 weeks) ↓ Response Assessment ↓ Stem cell Collection ↓ ASCT

SLIDE 23

DBd Responses DBd Responses

Responses Response by FISH

Response After After Response t(4;14) Del p53 Response After DBd (N=50) After ASCT (N=41) Response t(4;14) (N=4) Del p53 (N=4) Overall 39(78%) (92.7%) CR/nCR 11(22%) 12(29 3%) Overall 4(100%) 3(75%) CR/ CR CR/nCR 11(22%) 12(29.3%) PR 28(56%) 26(63.4%) CR/nCR

PR

4(100%) 3(75%) Belch A, et al. IMW, 2007

SLIDE 24

CYBOR D Trial CYBOR-D Trial

Newly Diagnosed Myeloma Newly Diagnosed Myeloma ↓ Cyclophosphamide 300 mg/m2 p.o. weekly, days 1, 8, 15, 22 Bortezomib 1.3mg/m2 i.v. days 1, 4, 8, 11 D th 40 d 1 4 9 12 17 2 0 Dexamethasone 40mg p.o. days 1 – 4, 9 – 12, 17 – 2 0 (Q28 day cycles) ↓ 4 cycles (16 weeks) ↓ Response Assessment Response Assessment ↓ *Stem cell Collection ↓ Off Study To Transplant OR Continue Meds for further 8 cycles

SLIDE 25

CYBOR-D Trial

N= 33 patients to date

23 evaluable for

toxicity/response after ≥ 1 cycle

Response after Cycle 4

CR/nCR 9/14 ( 64%) VGPR 3/14 (21%)

y p y

14 have completed 4 cycles VGPR 3/14 (21%) PR 2/14 (14%) MR 0/14 ( 0%) SD/NR 0/14 ( 0%)

At least nCR in 64% of patients At least PR in 100%

Toxicity (≥ Gr 3 )
Heme 24%, Neutropenia 20%

Hyperglycemia17%

Hyperglycemia17%
Sensory neuropathy 5%
Infection 5%

Trial modified to: Weekly bortezomib 1.5 mg/m2 Weekly dex after cycle 2

Overall incidence of neuropathy 69%

Reeder CB, et al. Blood 2007;110: abstract #3601.

y y

SLIDE 26

Induction Therapy in “Transplant Uncertain” Induction Therapy in Transplant Uncertain Patients: ECOG IMiD Trials

ECOG: Thalidomide + Dex

Dexamethasone given days 1-4, 9-12 and 17-20 of a

28-day cycle in odd cycles, and days 1-4 in even cycles y

Overall response rate 63% (8% CR), with median TTP

22 months

ECOG E4A03: Rev + Dex versus Rev+ weekly dex

Rajkumar et al. Blood 2006;110 abstract#; Rajkumar et al. Blood 2007;110: abstract#74;

SLIDE 27

E4A03: Schema for RD vs Rd N= 445 pts

R A N @ 4 months D O M Rev + Dex x4 cycles CR/PR @ 4 months Pts eligible for SCT proceed to SCT* I Z A T Less proceed to SCT Thal + Rev + Low dose Dex CR/PR/St bl T I O N than PR Dex x 4 cycles dose Dex x 4 cycles CR/PR/Stable N

SLIDE 28

E4A03 Trial Results

Response rate with RevD was 82% versus 71% with Response rate with RevD was 82% versus 71% with

Revd

But, more early deaths in RevD group

, y g p

Although Dex was reduced for toxicity, it was was not

routinely decreased after 4 cycles

Median TTP was around 2 years The results in the small subset of patients who

underwent ASCT after 4 cycles were similar to the underwent ASCT after 4 cycles were similar to the Revd group

However the group that continued Revd was biased

However, the group that continued Revd was biased towards responding (good-risk patients)

SLIDE 29

Overall Survival: Primary Therapy beyond 4 Cycles of RD vs Rd Cycles of RD vs. Rd

93% Rd 82% RD 93% Rd

0 073 (Wil 0 073 (Wil ) 0 569 (l k) p=0.073 (Wilcop=0.073 (Wilcoxon); p=0.569 (log-rank) xon); p=0.569 (log-rank)

Rajkumar V, et al. ASCO 2008, abstract #8504

SLIDE 30

IMiD Induction Therapy without ASCT

Thal/Dex1 Dex1 RevD2,3 Revd2,3 Overall response 63% 46% 82% 71% → 89% rate CR rate 8% 3% 4% 2% → 22% Med TTP 22 4 6 5 25 Med TTP (mos) 22.4 6.5

25

(Med remission duration)

Med OS 32

93%

Med OS (mos)

32

93%

(2 yr)

1Rajkumar V, et al. Blood 2006;108 abstract #795; 2Rajkumar V, et al. Blood 2007;110: abstract #74; 3Rajkumar V, et al. ASCO 2008: abstract #8504

SLIDE 31

Initial Therapy in “Transplant Uncertain” Initial Therapy in Transplant Uncertain Myeloma Patients

Continuous suppression with IMiD + Dex

Overall response rates of 65-85%

O ti l d f d th t i b t ti

Optimal dose of dexamethasone uncertain, but continuous

“full dose” likely detrimental

Durability of responses appear to be just under 2 years

Aggressive combinations, without ASCT, not well-studied

in Canada in Canada

SLIDE 32

Options for Progressive Myeloma in Canada in Canada

Second ASCT (if remission after the first was at least 2

Second ASCT (if remission after the first was at least 2 years)

Thalidomide +/- steroids Cyclophosphamide + prednisone Cyclophosphamide + prednisone Bortezomib

Single agent

With steroids

With steroids B + Lipo. Doxorubicin (Lipo. Doxorubicin) not funded CY + P +B = “CYBOR”

Oth bi ti

Other combinations

Lenalidomide + dex (EAP) Clinical trials

SLIDE 33

Second ASCT for Relapsed Myeloma Princess Margaret Hospital (N=61) cess a ga e

sp a (

6 )

Median age 56 (35-71) years Median time to relapse after first ASCT 33 mos (10-86) Overall response rate 88% (8% CR) TRM 3% TRM 3% Median PFS from ASCT 15.8 mos, OS 4.2 years Results better if PFS after 1st transplant ≥2 years:

Post 2nd ASCT Progression Free Survival Grouped by =< or > 2 yrs PFS post 1st ASCT

1.0

Post 2nd ASCT Overall Survival Grouped by =< or > 2 yrs PFS post 1st ASCT

1.0

Survival

.8 .6 .4 .2

=< or > 2 yrs PFS

> 2yrs PFS

Survival

.8 .6 .4 .2

=< or > 2 yrs PFS

> 2yrs PFS

Mikhael et al. Blood 2007;110:abstract #110

PFS post ASCT2 (years)

6 5 4 3 2 1

Cum S

0.0 =< 2yrs PFS

OS post ASCT2 (years)

8 6 4 2

Cum S

0.0 =< 2yrs PFS

SLIDE 34

Oral Cyclophosphamide and Prednisone Oral Cyclophosphamide and Prednisone After ASCT at PMH (n = 59)

30 40 50 10 20 PR MR SD PD

Median PFS 19 mos; median OS 29 mos PR rate 40%; MR rate 20%

Trieu et al. Mayo ClinProc 2005:80:578-82.

Median PFS 19 mos; median OS 29 mos PR rate 40%; MR rate 20%

SLIDE 35

“CYBOR-P” W kl B t ib 1 5 /

2 + CY + P

Weekly Bortezomib 1.5 mg/m2 + CY + P

N=13

Overall RR 85% (CR/nCR rate

54%)

pf s: 0.75 1.00

)

Only 2 progression events 1-year PFS 83% and OS 100%

76 cycles evaluable for toxicity

0.50

76 cycles evaluable for toxicity

Gr 4 ↓ ANC 1.3% Gr 4 ↓ pl 2.6%

0.00 0.25

Gr 3 ↓ pl 1.3% Gr 1 PN in 7 patients (55%) Shingles in 4 patients

pf sday 100 200 300 400 500 Legend: P roduct -Li m i t E st i m ate C urve C ensored O bservat i ons

g p

Reece D, et al. JCO,2008 Epub ahead of press

Progression-free survival

SLIDE 36

Lenalidomide + Dex vs Dex + Placebo in Relapsed MM e apsed

75 100

%)

100 MM-009 75

%)

MM-010 25 50 75 Pl b /D Len/Dex

Patients (%

25 50 75 Pl b /D Len/Dex

Patients (% Time to progression (months)

10 20 30 Placebo/Dex 5 15 25 5 10 15 20 25 Placebo/Dex

Time to progression (months) P

Median time to progression (months) Median time to progression (months) Len/ Len/Dex Dex Placebo/Dex Placebo/Dex P P-

value*

value* / / MM MM-

009

009 11.1 11.1 4.7 4.7 < 0.001 < 0.001 MM MM-

010

010 11.3 11.3 4.7 4.7 < 0.001 < 0.001

*`P-value from log-rank test

Weber D, et al. NEJM 2007;357:2133 Dimopoulos M, et al. NEJM 2007;357:2123

SLIDE 37

Myelosuppression with Lenalidamide +/- y pp Corticosteroids: MM 016 Expanded Access Trial at Princess Margaret Hospital (N=70)

Parameter (%) Response rate 62 4% Response rate CR/nCR PR 62.4% 5.4% 57% G d 3 4 T i it Grade 3-4 Toxicites Neutropenia Febrile neutropenia Infection 49% 16% 26% Thrombocytopenia 39% Supportive care needs Platelet transfusion 41% G-CSF to maintain full dose of lenalidomide 63%

Reece D, et al. Blood 2006;108: abstract #3548, #3550

SLIDE 38

Lenalidomide Combinations in Relapsed/Refractory MM

Anthracyclines

DVd-R – PLD, vincristine, DEX, lenalidomide RAD – lenalidomide, adriamycin, DEX*

, y ,

Alkylators

RCD – lenalidomide, cyclophosphamide, DEX* CPR

cyclophosphamide lenalidomide prednisone

CPR – cyclophosphamide, lenalidomide, prednisone

Novel agents

Lenalidomide, bortezomib (+/- DEX)*

L lid id if i DEX*

Lenalidomide, perifosine, DEX* Lenalidomide, bevacizumab, DEX*

*ASH abstracts 2007

SLIDE 39

“CPR”: Phase I-II Trial Dose Levels 28 d C l 28-day Cycle

Dose Level Cyclophosphamide Lenalidomide Prednisone Level N Median # Dose (mg/m2) Days 1, 8, 15 Dose Days 1-21 Dose (mg) Q 2 days cycles y , , y y 1 3 9 150 15 100 2 3 6 300 25 100 2 3 6 300 25 100 3 6 4 300 25 100 3

(Expanded)

3 1 300 25 100

Reece, et al. ASH 2008, submitted

DLT not identified; all patients remain on study

SLIDE 40

FISH Ab liti i M l C ll FISH Abnormalities in Myeloma Cells

t(4;14) p53 deletion t(4;14) p53 deletion

SLIDE 41

t(4;14) Multiple Myeloma

15% of myeloma patients Often associated with 13q deletion Tendency for younger individuals Often IgA lambda subtype Lytic bone lesions less prominent Aggressive biology

Beta 2-microglobulin level provides additional

prognostic information after tandem ASCT

May respond to therapy but relapses quickly May respond to therapy, but relapses quickly

SLIDE 42

Results of ASCT in t(4;14) MM Results of ASCT in t(4;14) MM

Author/Year N #ASCT Median PFS (mos) Median OS (mos)

Chang/2004 16 1 9.9 18.3 Gertz/2005 26 1 8 2 18 8 Gertz/2005 26 1 8.2 18.8 Moreau/ 2007 100 2 21 41 Moreau/ 2007 100 2 21 41

Chang et al. Bone Marrow Transplant 2005;36:793; Gertz et al. Blood 2005;106:2837; Moreau et al. Leukemia 2007 2007;21:2024

SLIDE 43

Treatment of Progressive t(4;14) MM Treatment of Progressive t(4;14) MM

Regimen N Response Median Median g p rate TTP (mos) OS (mos)

Cyclophosphamide + prednisone/MP1 11 0 (63% SD)

prednisone/MP1

Thalidomide or dex1 17 41% 4.7

Bortezomib +/-

steroids2 6 67% 10.5 15.5

1Jaksic W, et al. J Clin Oncol 2003; 23:7069; 2 Chang H, et al. Leuk Res 2007; 31:779-782.

SLIDE 44

t(4;14) Canadian Trial ( ; )

Newly Diagnosed Myeloma with t(4;14) ↓ ↓ Bortezomib 1.3mg/m2 i.v. days 1, 4, 8, 11 Pegylated liposomal doxorubicin 30 mg/m2 i.v. day 4 Dexamethasone 40mg p.o. days 1 – 4, 9 – 12, 17 – 2 0 (cycle 1) Dexamethasone 40mg p.o. days 1 4, 9 12, 17 2 0 (cycle 1) then days 1-4 and 15-18 (cycles 2-4) (Q21 day cycles) ↓

↓

4 cycles (12 weeks) ↓ Response Assessment Response Assessment ↓ *Stem cell Collection ↓

31 patients screened

↓ CYBOR-P X 8 cycles ↓ Dex maintenance days 1-4

p

3 on study

SLIDE 45

p53 Deletion Multiple Myeloma

Loss of a tumor suppressor gene Commonly found in cancer Noted in about 10% of myeloma patients Prognosis with tandem ASCT also affected by beta

2 i l b li l l 2-microglobulin level

Best treatment uncertain—novel agents

recommended recommended

SLIDE 46

Overall Survival with Len/Dex C di A l i f MM016 (N 120) Canadian Analysis of MM016 (N=120)

t(4;14) p53 deletion

Bahlis et al. ASH 2007, personal communication.

SLIDE 47

Determinants of Treatment of Relapsed/Refractory Multiple Myeloma

Di l d f

Disease - related factors

Duration of benefit of prior therapy Disease biology (e.g. cytogenetics)

gy ( g y g ) Patient - related factors

Prior therapy

R l i i t/f il

Renal impairment/failure Concomitant medical problems (e.g. peripheral neuropathy,

decreased blood counts, diabetes) Treatment – related factors

Time to response Toxicity profile Toxicity profile

SLIDE 48

Approach to Myeloma at PMH

Eligible for ASCT Not eligible for g

Study candidate

g ASCT

Study candidate

yes no

Dex +/- thal MP +/- thal Study candidate

yes

MVP Trial

no yes

CYBOR-D VDDR t(4;14) study MP +/ thal MVP Trial

r

MM020 ASCT x 1 or 2 +/ - Maintenance (MY 10)

SLIDE 49

PMH Approach to Progressive Myeloma pp g y

N i ASCT After ASCT No prior ASCT

≥ 1 year benefit

Trial Candidate

Second Repeat M+P

≥ 2 year benefit y

Trial Candidate

Second ASCT Thalidomide +/- steroids

Bortezomib + tipifarnib (MMRC) Bortezomib + Geminex (Mayo) no yes

p Bortezomib +/- steroids +/- CY CY + P

Lenalidamide + Dex (EAP) CY + P + Lenalidomide (“CPR”) Carfilzomib (MMRC) (Semaphore PI3K inhibitor [MMRC]) (Pomalidomide [MMRC]) (Bortezomib + Vorinistat [MMRC]) (Lenalidamide + HuLuc 60)

SLIDE 50

Management of Myeloma in 2008 in Canada

Summary/Conclusions

New agents and combinations are available for all New agents and combinations are available for all

age groups and disease settings

Funding limitations are a problem

Access programs/clinical trials necessary to increase