Donna E. Reece, M.D.Princess Margaret Hospital

T t ONToronto, ON

16 October 200816 October 2008

Multiple Myeloma in Canadap y

Incidence 4/100,0002,000/yr in Canada

Prevalence6500/yr in Canada6500/yr in Canada

1000 deaths per yearMedian age 65 yrsg yIncidence in younger adults appears to be i iincreasing

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

Multiple MyelomaMultiple Myeloma

Marrow plasma cells > 10% Symptomatic myeloma =“CRAB”

Anemia (Hgb < 100)Bone lesionsCreatinine (> 176 umol/L)Creatinine (> 176 umol/L)Calcium > 2.8 mmol/L

Interaction between Myeloma Cell and Bone M Mi i tMarrow Microenvironment

Advances in Prognosis

International Staging System (ISS)Stage Criteria MedianStage 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%

Factors Affecting Myeloma Management in Canada

D il bilitDrug availabilityApproval from Health CanadaFunding from provinces

Myeloma drugs approved in Canadaye o a d ugs app o ed Ca adaMelphalanCyclophosphamideBisphosphonates (pamidronate, zolendronic acid, clodronate)Bortezomib (2nd line +)Bortezomib (2 d line +)Bortezomib + melphalan + prednisone (1st line therapy without ASCT)Lenalidomide for relapsed myeloma

Access programsSAP for thalidomide (but no funding)EAP for lenalidomide is closingTrial of bortezomib + melphalan + prednisone (limited number of centers)

Results of “Traditional” Initial TherapypyOverview

Dex-based induction+

Melphalan + Prednisoneuntil 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 mosed a S 0 36 os

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

Efforts to Improve Initial TherapyEfforts to Improve Initial Therapy

ASCT Melphalan + Prednisone

O ti i ASCT ( iTandem ASCTMaintenance therapy using novel agents

Optimize ASCT (eg. using melphalan 100 mg/m2)Add novel agents to M+Pnovel agents

New induction regimens containing novel agents

Add novel agents to M PUse IMiD + dexamethasone

Novel Agents in Multiple MyelomaNovel Agents in Multiple Myeloma

Thalidomide Bortezomib LenalidomideThalidomide Bortezomib Lenalidomide

EffiEfficacy:- As single agents, with steroids, in combinations

- As initial therapy or for relapsed/refractory MMAs initial therapy or for relapsed/refractory MM

Novel Agents in MyelomaAgent Class Effects ToxicityAgent Class Effects ToxicityThalidomide IMiD Decreased adhesion,

cytokines production,angiogenesis

Teratogenicity, PN, sedation, rash, constipation, DVTangiogenesis

Increased anti-myeloma immunitymyeloma immunity

Bortezomib Proteasomeinhibitor

Decreased adhesion, cytokine production,

Fatigue, PN, GI toxicity inhibitor y p ,

angiogenesis, NFkB, DNA repair

Decrease in neutrophils, platelets and lymphocytes

Lenalidomide

(CC-5013)

IMiD Decreased adhesionIncreased T cell proliferation, NK cell

t t i it IFN d

Myelosuppression, DVT

( )cytotoxicity, IFN-γ and IL-2

Activity of Novel Agents in Relapsed/Refractory Myeloma PatientsMyeloma 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%

Lenalidomide76% 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.

The Changing Landscape of Therapyg g p pyInitial Myeloma Therapy in Canada

Elderly patients ineligible for ASCTInduction therapy before ASCTInduction therapy before ASCTInitial therapy in “transplant uncertain” patients

Non-melphalan containing therapyNon melphalan containing therapyMay be of 2 broad types

Continuous “suppressive” therapy with IMiDs + steroidsCombination therapy with novel agents

High overall and CR/nCR rates

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

N=500

3 232

2

MP ArmStandard MP

at 6-wk intervals x 12

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

MEL100 x 2 ArmVADx2; cyclophosphamide 3 g/m2; Melphalan, 100 mg/m2

stopped at end of MP

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

IFM 99 06 MP MP Th l d MP M lIFM 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 (%)

352

7618

6518

Median PFS (mos) 17 8 27 5 19 4Median PFS (mos) 17.8 27.5 19.4

Overall survival (mos) 33.2 51.6 38.3≥ Grade 3 toxicity (%)

Any non-hemeNeutropeniaVTEPeripheral neuropathy

162640

4248126

58100

80Peripheral neuropathy 0 6 0

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

Randomized Trials in Elderly Myeloma PatientsMyeloma Patients

Study Regimen Overall Response

CR/nCR rate (%)

PFS/EFS(mos)

OverallSurvivalResponse

rate (%)(%) (mos) Survival

(mos)Facon1 MPT

MP7625

182

27.5*17 8

51.6*33 2MP 25 2 17.8 33.2

Palumbo2 MPTMP

7648

287

21.8*14 5

4547.6MP 48 7 14.5 47.6

Hulin3 MPTMP

6131

71

24.1*19.1

45.3*27.7

San Miguel4

VMPMP

7130

354

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

Randomized Trials in Elderly Myeloma Patients: Toxicity ComparisonsToxicity Comparisons

Study Rx Duration of Rx

Thaldose

≥ Gr 3 non-heme toxicity

≥ Gr 3 Neutropenia

VTE(%)

≥ Gr 3 PNof Rx dose

(%) heme toxicity

(%)Neutropenia

(%)(%) PN

(%)

Facon1 MPT 72 400 mg 42 48 12 6Facon MPTMP

7272

400 mg 4216

4826

124

60

Palumbo2 MPT 52 100 mg 49 16 12 10MP 52+ 25 17 2 1

Hulin3 MPTMP

7272

100 mg 5315

15 74

22MP 72 15 4 2

San Miguel4

VMPMP

5454

‐‐ 4636

4038

11

140

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 .

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 riskVMP high risk

VMP standard riskVMP 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

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 greaterToxicity is greaterThalidomide regimens require thromboprophylaxisPeripheral neuropathy is a concern

Data needed for risk groupsIn Canada, options include:

T t bt i f di f th lid idTry to obtain funding for thalidomideClinical trial

Management of Elderly Myeloma Patients in Canada: Clinical Trials

NCIC MY11 trial (closed)Melphalan 5 mg/m2 days 1-4Melphalan 5 mg/m days 1-4Lenalidomide 10 mg/days 1-21

O th Bi t h t i l f VOrtho Biotech trial of VMP

Celgene MM020 international trialCelgene MM020 international trialLenalidomide + weekly dex until progressionLenalidomide + weekly dex for 18 monthsMPT

New Approaches before ASCTNew Approaches before ASCT

Background: Patients in CR/nCR/VGPR afterASCT have better PFS and OS

Hypothesis: Achievement of CR/nCR/VGPR before ASCT will translate into improved outcome after ASCT

New Approaches before ASCTpp

Multiple induction regimens containing novel agentsMultiple induction regimens containing novel agents produce high CR/nCR rates (VAD-thal, CTD, VTD)Randomized trials in progressRandomized 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

DBd TrialDBd Trial

Newly Diagnosed Myelomay g y↓

Bortezomib 1.3mg/m2 i.v. days 1, 4, 8, 11Pegylated liposomal doxorubicin 30 mg/m2 IV day 4gy 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

DBd ResponsesDBd Responses

Responses Response by FISH

Response After After Response t(4;14) Del p53Response 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/ CRCR/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

CYBOR D TrialCYBOR-D TrialNewly Diagnosed MyelomaNewly Diagnosed Myeloma

↓Cyclophosphamide 300 mg/m2 p.o. weekly, days 1, 8, 15, 22

Bortezomib 1.3mg/m2 i.v. days 1, 4, 8, 11D th 40 d 1 4 9 12 17 2 0Dexamethasone 40mg p.o. days 1 – 4, 9 – 12, 17 – 2 0

(Q28 day cycles)↓

4 cycles (16 weeks)↓

Response AssessmentResponse Assessment↓

*Stem cell Collection↓

Off Study To Transplant OR Continue Meds for further 8 cycles

CYBOR-D Trial

N= 33 patients to date23 evaluable for toxicity/response after ≥ 1 cycle

Response after Cycle 4CR/nCR 9/14 ( 64%)VGPR 3/14 (21%)y p y

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

At least nCR in 64% of patientsAt 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

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

ECOG: Thalidomide + DexDexamethasone given days 1-4, 9-12 and 17-20 of a 28-day cycle in odd cycles, and days 1-4 in even cyclesyOverall 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;

E4A03: Schema for RD vs RdN= 445 pts

RAN @ 4 monthsDOM

Rev + Dexx4 cycles

CR/PR@ 4 monthsPts eligible for SCT proceed to SCT*

IZAT

Less

proceed to SCT

Thal + Rev + Low dose Dex CR/PR/St blT

ION

than PR

Dexx 4 cycles

dose Dexx 4 cycles

CR/PR/Stable

N

E4A03 Trial Results

Response rate with RevD was 82% versus 71% withResponse rate with RevD was 82% versus 71% with RevdBut, 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 yearsThe results in the small subset of patients who underwent ASCT after 4 cycles were similar to theunderwent ASCT after 4 cycles were similar to the Revd group

However the group that continued Revd was biasedHowever, the group that continued Revd was biasedtowards responding (good-risk patients)

Overall Survival: Primary Therapy beyond 4 Cycles of RD vs RdCycles 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

IMiD Induction Therapy without ASCT

Thal/Dex1 Dex1 RevD2,3 Revd2,3

Overall response

63% 46% 82% 71% → 89%

rateCR rate

8% 3% 4% 2% → 22%

Med TTP 22 4 6 5 25Med 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

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

Continuous suppression with IMiD + DexOverall response rates of 65-85%O ti l d f d th t i b t tiOptimal dose of dexamethasone uncertain, but continuous “full dose” likely detrimentalDurability of responses appear to be just under 2 years

Aggressive combinations, without ASCT, not well-studied in Canadain Canada

Options for Progressive Myelomain Canadain Canada

Second ASCT (if remission after the first was at least 2Second ASCT (if remission after the first was at least 2 years)Thalidomide +/- steroidsCyclophosphamide + prednisoneCyclophosphamide + prednisoneBortezomib

Single agentWith steroidsWith steroidsB + Lipo. Doxorubicin (Lipo. Doxorubicin) not fundedCY + P +B = “CYBOR”Oth bi tiOther combinations

Lenalidomide + dex (EAP)Clinical trials

Second ASCT for Relapsed MyelomaPrincess Margaret Hospital (N=61)cess a ga e osp a ( 6 )

Median age 56 (35-71) yearsMedian 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 yearsResults better if PFS after 1st transplant ≥2 years:Post 2nd ASCT Progression Free Survival

Grouped by =< or > 2 yrs PFS post 1st ASCT1.0

Post 2nd ASCT Overall Survival

Grouped by =< or > 2 yrs PFS post 1st ASCT1.0

Surv

ival

.8

.6

.4

.2

=< or > 2 yrs PFS

> 2yrs PFS

Surv

ival

.8

.6

.4

.2

=< or > 2 yrs PFS

> 2yrs PFS

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

PFS post ASCT2 (years)

6543210

Cum

S

0.0

=< 2yrs PFS

OS post ASCT2 (years)

86420

Cum

S

0.0

=< 2yrs PFS

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

304050

01020

PR MR SD PD

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

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

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

“CYBOR-P”W kl B t ib 1 5 / 2 + CY + PWeekly Bortezomib 1.5 mg/m2 + CY + P

N=13Overall RR 85% (CR/nCR rate 54%)

pf s:

0. 75

1. 00

)Only 2 progression events1-year PFS 83% and OS 100%

76 cycles evaluable for toxicity

0. 50

76 cycles evaluable for toxicityGr 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

0 100 200 300 400 500

Legend: Product -Li mi t Est i mat e Curve Censored Observat i ons

g p

Reece D, et al. JCO,2008 Epub ahead of pressProgression-free survival

Lenalidomide + Dex vs Dex + Placebo in Relapsed MMe apsed

75

100

%)

100MM-00975%) MM-010

25

50

75

Pl b /D

Len/Dex

Patie

nts

(%

25

50

75

Pl b /D

Len/Dex

Patie

nts

(%

Time to progression (months)0 10 20 30

0Placebo/Dex

5 15 25 0 5 10 15 20 250

Placebo/Dex

Time to progression (months)

P

Median time to progression (months)Median time to progression (months)

Len/Len/DexDex Placebo/DexPlacebo/Dex PP--value*value*// //

MMMM--009009 11.111.1 4.74.7 <0.001<0.001

MMMM--010010 11.311.3 4.74.7 <0.001<0.001

*`P-value from log-rank testWeber D, et al. NEJM 2007;357:2133Dimopoulos M, et al. NEJM 2007;357:2123

Myelosuppression with Lenalidamide +/-y ppCorticosteroids: MM 016 Expanded Access Trial at

Princess Margaret Hospital (N=70)

Parameter (%)Response rate 62 4%Response rate

CR/nCRPR

62.4%5.4%57%

G d 3 4 T i itGrade 3-4 ToxicitesNeutropeniaFebrile neutropeniaInfection

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

Lenalidomide Combinations in Relapsed/Refractory MM

AnthracyclinesDVd-R – PLD, vincristine, DEX, lenalidomideRAD – lenalidomide, adriamycin, DEX*, y ,

AlkylatorsRCD – lenalidomide, cyclophosphamide, DEX*CPR cyclophosphamide lenalidomide prednisoneCPR – cyclophosphamide, lenalidomide, prednisone

Novel agentsLenalidomide, bortezomib (+/- DEX)* L lid id if i DEX*Lenalidomide, perifosine, DEX* Lenalidomide, bevacizumab, DEX*

*ASH abstracts 2007

“CPR”: Phase I-II Trial Dose Levels28 d C l28-day Cycle

Dose Level

Cyclophosphamide Lenalidomide PrednisoneLevel

N Median#

Dose (mg/m2)Days 1, 8, 15

DoseDays 1-21

Dose (mg)Q 2 days

cyclesy , , y y

1 3 9 150 15 100

2 3 6 300 25 1002 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

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

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

t(4;14) Multiple Myeloma

15% of myeloma patientsOften associated with 13q deletionTendency for younger individualsOften IgA lambda subtypeLytic bone lesions less prominentAggressive biology

Beta 2-microglobulin level provides additional prognostic information after tandem ASCT

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

Results of ASCT in t(4;14) MMResults 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 8Gertz/2005 26 1 8.2 18.8

Moreau/ 2007 100 2 21 41Moreau/ 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

Treatment of Progressive t(4;14) MMTreatment of Progressive t(4;14) MMRegimen 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.

t(4;14) Canadian Trial( ; )Newly Diagnosed Myeloma with t(4;14)

↓↓

Bortezomib 1.3mg/m2 i.v. days 1, 4, 8, 11Pegylated 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 AssessmentResponse Assessment↓

*Stem cell Collection↓31 patients screened ↓

CYBOR-P X 8 cycles↓

Dex maintenance days 1-4

p- 3 on study

p53 Deletion Multiple Myeloma

Loss of a tumor suppressor geneCommonly found in cancerNoted in about 10% of myeloma patientsPrognosis with tandem ASCT also affected by beta 2 i l b li l l2-microglobulin levelBest treatment uncertain—novel agents recommendedrecommended

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.

Determinants of Treatment of Relapsed/Refractory Multiple Myeloma

Di l d fDisease - related factorsDuration of benefit of prior therapyDisease biology (e.g. cytogenetics) gy ( g y g )

Patient - related factorsPrior therapyR l i i t/f ilRenal impairment/failureConcomitant medical problems (e.g. peripheral neuropathy, decreased blood counts, diabetes)

Treatment – related factorsTime to responseToxicity profileToxicity profile

Approach to Myeloma at PMH

Eligible for ASCT Not eligible for gStudy candidate

gASCT

Study candidateyes no

Dex +/- thalMP +/- thal

Study candidateyes o

MVP Trial

noyes

CYBOR-DVDDR

t(4;14) study

MP +/ thalMVP Trialor

MM020

ASCT x 1 or 2

+/ - Maintenance(MY 10)

PMH Approach to Progressive Myelomapp g y

N i ASCTAfter ASCT No prior ASCT

≥ 1 year benefit

Trial CandidateSecond Repeat M+P

≥ 2 year benefity

Trial CandidateSecondASCT

Thalidomide +/- steroidsBortezomib + tipifarnib (MMRC)Bortezomib + Geminex (Mayo)

no yesp

Bortezomib +/- steroids +/- CYCY + P

Lenalidamide + Dex (EAP)CY + P + Lenalidomide (“CPR”)

Carfilzomib (MMRC)(Semaphore PI3K inhibitor [MMRC])

(Pomalidomide [MMRC])(Bortezomib + Vorinistat [MMRC])

(Lenalidamide + HuLuc 60)

Management of Myeloma in 2008 in CanadaSummary/Conclusions

New agents and combinations are available for allNew agents and combinations are available for all age groups and disease settings

Funding limitations are a problemFunding limitations are a problemAccess programs/clinical trials necessary to increase drug availability before funding available

The optimal approach for induction and disease progression has not yet been defined and may be different in biologic subtypesdifferent in biologic subtypesEfforts to match the best therapy with the disease biology desirablebiology desirable