Disclosures for Palumbo Antonio, MD

Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millenium, OnyxHonoraria

Scientific Advisory Board

Speakers Bureau

No relevant conflicts of interest to declareMajor Stockholder

Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millenium, OnyxConsultant

No relevant conflicts of interest to declareEmployee

No relevant conflicts of interest to declareResearch Support/P.I.

No relevant conflicts of interest to declare

No relevant conflicts of interest to declare

Presentation includes discussion of the off-label use of a drug or drugs

Case presentation

History

• 48 year-old man• Newly diagnosed myeloma

• Haemoglobin 123 g/l• IgG-λ M-protein peak 38 g/l• 14% bone marrow plasma cells• No chromosomal abnormalities • Several bone lytic lesions

• Induction: 4 courses of VTD MEL200 and ASCT • After ASCT: Immunofixation negative CR

VTD = bortezomib, thalidomide, dexamethasone.

Question 1 Which is the best therapeutic option?

• 1. No treatment • 2. Maintenance with thalidomide • 3. Maintenance with lenalidomide• 4. Maintenance with bortezomib

Question 2

Which is the optimal duration?

• 1. Maintenance for 1 year • 2. Maintenance for 2 years• 3. Maintenance until progression or intolerance• 4. No maintenance

Improving Outcomes in Myeloma

Case 4: Patient who has responded well to induction therapy – should

maintenance therapy be recommended, and if so, what strategy?

Antonio PalumboUniversity of Torino, Italy, EU

25min

Maintenance

Thalidomide Maintenance35% reduced risk of progression

16% reduced risk of death

Ludwig H, et al. Blood. 2012

Lenalidomide Maintenance51% reduced risk of progression

23% reduced risk of deathProgression Free SurvivalStudy Maintenance Control

N N

CALGB 100104 231 229 0.48 (0.36, 0.63)MM 015 152 154 0.34 (0.18, 0.64)IFM 2005-02 307 307 0.50 (0.39, 0.64)RV-MM-PI-209 198 204 0.52 (0.40, 0.67)

Total (95% CI) 888 894 0.49 (0.41, 0.58)

Favors treatment Favors controlOverall SurvivalStudy Maintenance Control

N N

CALGB 100104 231 229 0.61 (0.42, 0.88)MM 015 152 154 0.79 (0.53, 1.18)IFM 2005-02 307 307 1.06 (0.77, 1.46)RV-MM-PI-209 198 204 0.62 (0.42, 0.92)

Total (95% CI) 888 894 0.77 (0.62, 0.95)

Favors treatment Favors control

95% CI 95% CI

Hazard ratio (fixed)95% CI

Hazard ratio (fixed)95% CI

Hazard ratio (fixed) Hazard ratio (fixed)

0.5 1 0.2 2 5

0.5 1 0.2 2 5

McCarthy PL, et al. N Engl J Med 2012; Palumbo A, et al. N Emgl J Med 2012; Attal M, et al. N Emgl J Med 2012; Palumbo A, et al. ASCO 2013.

Bortezomib Maintenance 31% reduced risk of progression

27% reduced risk of death

Sonneveld P, et al. J Clin Oncol 2012; Palumbo A, et al. J Clin Oncol. 2010.

VMP, bortezomib-melphalan-prednisone; VMPT-VT, VMP plus thalidomide followed by bortezomib-thalidomide; VAD-T, vincristine-adriamycin-dexamethasone followed by thalidomide; PAD-V, bortezomib-adriamycin-dexamethasone followed by bortezomib.

Progression Free SurvivalStudy Maintenance Control

N N

VMPT-VT vs VMP 250 253 0.67 (0.50, 0.90)PAD-V vs VAD-T 413 414 0.75 (0.62, 0.90)

Total (95% CI) 663 667 0.71 (0.54, 0.87)

Favors treatment Favors controlOverall SurvivalStudy Maintenance Control

N N

VMPT-VT vs VMP 250 253 0.74 (0.55, 0.99)PAD-V vs VAD-T 413 414 0.73 (0.56, 0.96)

Total (95% CI) 663 667 0.73 (0.56, 0.99)

Favors treatment Favors control

95% CI 95% CI

Hazard ratio (fixed) Hazard ratio (fixed)

Hazard ratio (fixed) Hazard ratio (fixed)

95% CI 95% CI

0.5 1 0.2 2 5

0.5 1 0.2 2 5

Early vs. Late ASCT

0

25

50

75

100

0 10 20 30 40 50 60 70

MEL200-R

MEL200

MPR-R

MPR

Months

100

0 10 20 30 40 50 60 70

0

25

50

75

MEL200-R

MEL200

MPR-R

MPR

Months

Progression-free survival Overall survival

MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m2; R, lenalidomide maintenance

MPR vs. MEL 200

Rdfour 28-day coursesR: 25 mg/d, days 1-21d: 40 mg/d, days 1,8,15,22

MPRsix 28-day coursesM: 0.18 mg/Kg/d, days 1-4 P: 2 mg/Kg/d, days 1-4R: 10 mg/d, days 1-21

MEL200two coursesM: 200 mg/m2 day -2Stem cell support day 0

NO MAINTENANCE

R MAINTENANCE28-day courses until relapseR: 10 mg/day, days 1-21

1° R 2° R

Early vs. Late ASCT vs. Maintenance vs. Placebo

Rationale

- Continuous treatment

-100

0

100

200

300

400

500

5000100001500020000

PC/u

L

Dia Pre maint

+3 m maint

+6 m maint

+12 m maint

+18 m maint

-100

0

100

200

300

400

500

5000100001500020000

PC/u

L

Dia Pre maint

+3 m maint

+6 m maint

+12 m maint

+18 m maint

Progression-free Survival According to Quality of Response

MRD - CR-

MRD+ CR-

Progression-free survival

MRD, minimal residual disease; CR complete response

0 10 20 30 40 500

20

40

60

80

100

Months

Perc

ent s

urvi

val

MRD - CR -

MRD + CR -

Tumor Load During Maintenance Absolute PC in maint in CRD (no relapsed pz)

(assessed by flow cytometry)

0.1

1

10

100

1000

10000

PC/u

L

Resistant Relapse

Korde N, et al. Blood. 2011;117: 5573-81.

NormalPregerminal B cells

Precursordisease

Multiple myeloma

Extramedullarymyeloma

Clinical Phase

Primary IgH translocations

Hyperdiploidy

Cyclin D gene dysregulation

Deletion of chromosome 13

NRAS mutation

KRAS and FGFR3 mutations

MYC up-regulation

MYC rearrangement

p18, p53 and Rb gene inactivation

Karyotypic and epigenetic adnormalities

NFkB-activating mutations

Secondary IgH translocations

BONE MARROW MICROENVIRONMENT CHANGES• Osteoclast activation• Osteoblast inhibition

• Increased angiogenesis• Altered expression of cytokines, growth factors,

and adhesion molecules

Biological Events

Clonal Evolution

Patie

nts

(%)

Time

0.00

0.25

0.50

0.75

1.00

0 5 10 15 20 25

0.00

0.25

0.50

0.75

1.00

0 5 10 15 20 25

Spontaneous clonal evolution

Drug-related clonal evolution

R Maintenance vs. No Maintenance

HR 0.52, 95% CI 0.40-0.67, P <.0001

Months

0

25

50

75

100

0

10 20 30 40 50 60 70

R, lenalidomide

PFS from diagnosis

HR 0.82, 95% CI 0.55-1.22, P =.32 0

25

50

75

100

0 10 20 30 40 50 60

R maint.

No maint.

Months

OS from relapse

Delayed clonal evolution

Faster clonal evolution

Chemoresistant relapse

Chemosensitive relapse

R maint.

No maint.

VT Maintenance vs. No Maintenance

VMP, bortezomib-melphalan-prednisone; VMPT, bortezomib-melphalan-prednisone-thalidomide; VT, bortezomib-thalidomide maintenance

PFS from diagnosis OS from relapse

HR 0.58, 95% CI, 0.47-0.71, P < 0.00010

25

50

75

100

0 10 20 30 40 50 60 70 80

Delayed clonal evolution

Faster clonal evolution

VMPT-VT

VMP

HR 0.92, 95% CI, 0.66-1.28, p =.630

25

50

75

100

0 10 20 30 40 50 60

Chemoresistant relapse

Chemoresistant relapse

VMPT-VT

VMP

Months Months

Until progression?

PFS: Landmark AnalysesMaintenance vs. Placebo

Median PFS HR (p value)

MPR-R 26 months 0.34 (< 0.001)

MPR 7 months N/A

Lenalidomide MaintenanceMPR

Palumbo A, et al. N Engl J Med. 2012

Time (months)

Patie

nts

(%)

0

25

50

75

100

0 10 205 15 25

M, melphalan; P, prednisone; R, lenalidomide; V, bortezomib; T, thalidomide; PFS, progression-free survival; NA, not available

Progression-free SurvivalLandmark Analysis

Time (months)

VT MaintenanceVMPT Off therapy

4-years PFS Median PFS

VMPT-VT 33% 31.5 months

VMP 16% 17.8 months

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60 70

Patie

nts

(%)

HR 0.56, 95% CI, 0.44-0.71, p<0.0001

Overall Survival (OS) 30% Reduced Risk of Death

Patie

nts

(%)

Time (months)

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60 70 80 90

5-years OS Median OS

VMP

VMPT-VT

51% 60.6 months

61% Not reached

HR 0.70, 95% CI, 0.52-0.92, P = 0.01

Off therapyVT MaintenanceVMPT

What is new?

Carfilzomib, Cyclophosphamide, Dexamethasone (CCyd)

• 58 newly diagnosed elderly MM patients enrolled at 10 Italian centers

CUntil progression/intolerance

C: 36 mg/m2 d 1,2,15,16

MAINTENANCE

CCydCycles 1-9

C: 20 mg/m2 d 1,2 followed by 36 mg/m2 d 8,9,15,16,22 (cycle 1); 36 mg/m2 d

1,2,8,9,15,16,22 (cycle 2-9); Cy: 300 mg/m2 d 1,8,15

d: 40 mg d 1,8,15,22

Best response

Patie

nts

(%)

0

25

50

75

100

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0

1-year rate 86%

Progression-free survival

13 1524

41 46

646372 76

89 94 96

0

20

40

60

80

100

Cycle 2 Cycle 6 Cycle 9

sCR sCR/nCR/CR ≥VGPR ≥PR

Time (months)CCyd, cyclophosphamide-cyclophosphamide-dexamethasone; C, carfilzomib; PR, partial response; VGPR, very good partial response; CR, complete response; sCR, stringent complete response; nCR, near complete response.

Patie

nts

(%)

Carfilzomib, Lenalidomide, Dexamethasone (CRd)

Jakubowiak AJ, et al. Blood 2012.

• 53 newly diagnosed transplant eligible and ineligible MM patients enrolled at 4 US centers

CRdCycles 9-24

C: 20/27/36 mg/m2, d 1,2, 15,16R: 25 mg/m2, d 1-21d: 20 mg, d 1,8,15,22

MAINTENANCE

RECOMMENDED

R (off protocol)Cycles 25+

L: 25 mg/day on days 1-21

CRdCycles 1-8

C: 20/27/36 mg/m2, d 1,2,8,9,15,16R: 25 mg/m2, d 1-21

d: 40 mg (cycles 1-4) 20 mg (cycles 5-8), d 1,8,15,22

For ASCT eligible:Stem cell collection after cycle 4

1-year rate 97%2-year rate 92%

Progression-free survivalMedian follow-up 13 months (range 1-20)

9881

62

42

0

20

40

60

80

100≥PR ≥VGPR ≥nCR sCR

Patie

nts

(%)

Best responseMedian 12 cycles (range 1-25)

CRd, cyclophosphamide-lenalidomide-dexamethasone; R, lenalidomide; ASCT, autologous stem cell transplantation; PR, partial response; VGPR, very good partial response; CR, complete response; sCR, stringent complete response.

Savona MR, et al. ASH 2012: Abstract 203; Kumar, et al. ASH 2012: Abstract 332

Dose-Escalation Study of Oprozomib (ONX0912)

Cohort 1st Daily Dose, mg 2nd Daily Dose, mg Total Daily Dose, mg/d1-4 60-120 60-90 120-210

• Administered on days 1-5 of a 14-day cycle

1 8 15 22 28

MLN9708 maintenanceDays 1, 8, 1528-day cycles

Induction: up to 12 x 28-day treatment cycles Maintenance

MLN9708 MLN9708 MLN9708

Dex 40 mg Dex 40 mg Dex 40 mg Dex 40 mg

Lenalidomide 25 mg, days 1–21

Ixazomib-lenalidomide-dexamethasone in previously untreated MM

1 8 15 22 28

MLN9708 maintenanceDays 1, 8, 1528-day cycles

Induction: up to 12 x 28-day treatment cycles Maintenance

MLN9708 MLN9708 MLN9708

Dex 40 mg Dex 40 mg Dex 40 mg Dex 40 mg

Lenalidomide 25 mg, days 1–21

Ixazomib-Lenalidomide-Dexamethasone in Previously Untreated MM

Kumar, et al. ASH 2012: Abstract 332

Phase 1 Phase 2 Total

ORR 100% 90% 92%

≥ VGPR 53% 58% 55%

CR + nCR 33% 29% 28%

Response rates

MM, multiple myeloma; ORR, overall response rate; VGPR, very good partial response; CR, complete response; nCR, near complete response; Dex, dexamethasone.

Conclusions

• Until progression

• IF all toxicities within grade 1

• Thalidomide Cost

• Lenalidomide Oral, PN

• Bortezomib Injection, SPM

Thank You