disclosures for palumbo antonio, md

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

Improving Outcomes in Myeloma

Should alkylators be used upfront in transplant-ineligible patients?

Yes/May be

Antonio PalumboUniversity of Torino, Italy, EU

25min

Early vs late ASCT

MPR vs MEL 200

Early vs late ASCT

NDMM, newly diagnosed multiple myeloma; Rd, lenalidomide plus low-dose dexamethasone; MPR, melphalan-prednisone-lenalidomide; R, lenalidomide maintenance; MEL200, melphalan 200 mg/m2

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

Median follow-up 38 months OS

402 NDMM patients < 65 years

Cavallo F, et al. EHA 2012;97:1142

Months

3-years OS

MPR

MEL200

79%

80%

HR 0.868

P = 0.5420.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60Months

PFS

HR 0.55

P< .00010.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60

3-years PFS

MPR

MEL200

36%

60%

Median PFS

Not reached

25.88 months

3-years PFS

MPR

MEL200

36%

60%

Median PFS

Not reached

25.88 months

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 MEL200 vs MPR-R vs MEL200-R

Months

MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m2; MEL100, melphalan 100 mg/m2; VMP, bortezomib-melphalan-prednisone; VMPT, VMP plus thalidomide; PAD, bortezomib-pegylated doxorubicin-dexamethasone; CR, complete response; PFS, progression-free survival

PAD MEL100 vs VMP+VMPTNo random

MPR vs MEL200Random

Months

Palumbo A, et al. Gr. Emat. Milano 19 November 2012

Early vs late ASCTRole of CR after induction

1-year landmark PFS CR patients only

1-year landmark PFS CR patients only

0.00

0.25

0.50

0.75

1.00

12

HR 0.39; P=.026

MEL200

MPR

24 36 48 60

HR 0.55; P=.032

0.00

0.25

0.50

0.75

1.00

PAD MEL100

VMP+VMPT

12 24 36 48 60

-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 +

Palumbo A, et al. Unpublished data.

-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 +


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 +

Palumbo A, et al. Unpublished data.

PLEASE•Do not compare CR rates•Do compare PFS rates

Standard of Care for

Elderly Patients

Fayers PM, et al. Blood. 2011;118:1239-47

MPT meta-analysis: which is the right T dosage?

MP betterMPT better


MPT better MP better

Overall survival

NOTE: weights are from random effects analysis

Overall (I-squared = 61.7%, p = 0.023)

FR < 75

NMSG

HOVON

Italy

Fr ≥ 75

Turkey

Study

0.67 (0.55– 0.80)

0.50 (0.39– 0.65)

0.89 (0.70–1.13)

0.79 (0.62–1.00)

0.62 (0.48–0.80)

0.61 (0.46–0.82)

0.59 (0.35–0.99)

HR (95% CI)HR (95% CI)

10.5 0.75 1.5

NOTE: weights are from random effects analysis

Overall (I-squared = 60.6%, p = 0.026)

NMSG

Study

Italy

FR < 75

HOVONFr ≥ 75

Turkey

0.82 (0.66–1.02)

1.12 (0.85–1.47)

HR (95% CI)

1.04 (0.75–1.44)

0.61 (0.45– 0.81)

0.75 (0.57–1.00)

0.68 (0.48– 0.96)

0.87 (0.46–1.67)

HR (95% CI)

10.5 0.75 1.5

MPT MP

mOS 39.3 m 32.7 mmPFS 20.3 m 14.9 m

VMPT-VT versus VMP in newly diagnosed elderly patients

• Median follow-up: 54 mos

Palumbo et al. ASH 2012 (Abstract 200), oral presentation

VMPT-VT VMP P

PFS 35.3 mos 24.8 mos < 0.0001

TTNT 46.6 mos 27.8 mos < 0.0001

Landmark analysis 4-year PFS Median PFS

33%31.5 mos

16%17.8 mos

5-year OS 61% 51%0.01

Median OS Not reached 60.6 mos

Landmark analysis 4-year OS Median OS

67%Not reached

55%54.2 mos

0.006

OS from relapse 3-year OS Median OS

47%27.8 mos

46%27.3 mos

VMPT-VT versus VMP in newly diagnosed elderly patients

• Median follow-up: 54 mos

Palumbo et al. ASH 2012 (Abstract 200), oral presentation

VMPT-VT VMP P

PFS 35.3 mos 24.8 mos < 0.0001

TTNT 46.6 mos 27.8 mos < 0.0001

Landmark analysis 4-year PFS Median PFS

33%31.5 mos

16%17.8 mos

5-year OS 61% 51%0.01

Median OS Not reached 60.6 mos

Landmark analysis 4-year OS Median OS

67%Not reached

55%54.2 mos

0.006

OS from relapse 3-year OS Median OS

47%27.8 mos

46%27.3 mos

Dear opponent:•Randomized study •Follow-up 54 mos•Age 71 yrs•PFS 35.3 mos•TTNT 46.6 mos

Melphalan limitations?

Incidence rate per 100 per yearDifferent lenalidomide combinations

Hematologic SPMs

0 0,5 1 1,5 2

Melphalan only

Lenalidomide + melphalan

Lenalidomide + cyclophosphamide

Lenalidomide only

Lenalidomide + melphalan

Lenalidomide + cyclophosphamide

Lenalidomide only

Solid SPMs

0 0,5 1 1,5 2

Melphalan only

Incidence Rate per 100 per year

0 5 10 15 20 25 30 35 40

Second Primary Malignancies

Adverse Events

Multiple Myeloma

0 5 10 15 20 25 30 35 40


Adverse Events

Multiple Myeloma

Cumulative incidence per 100

SPM and SAECumulative incidence per 100 at 60 months

No Lenalidomide studies

Lenalidomide studies

0 5 10 15 20 25 30 35 40


Adverse Events

Multiple Myeloma

0 5 10 15 20 25 30 35 40


Adverse Events

Multiple Myeloma

Cumulative incidence per 100

SPM and SAECumulative incidence per 100 at 60 months

No Lenalidomide studies

Lenalidomide studies

Dear opponent:

You start to have:

…some… right

Alternatives?

VCD vs VRD vs VCRDProgression free survival

VDCR (n = 48) VDR (n = 42) VDC (n = 33) VDC-mod (n = 17)

Median PFS, days (range) 710 (1*–802*) NE (1*–800*) NE (41–825*) NE (178*–515*)

PFS at 1 year, % 85 83 93 100

Subjects at risk:48 45 42 40 37 35 33 28 26 25 21 20 19 17 16 10 9 7 4 3 242 41 38 36 35 31 29 27 25 20 18 16 15 14 11 9 8 7 5 3 2 133 31 30 29 27 25 23 20 19 18 16 15 14 13 12 10 9 7 6 4 217 16 15 14 13 12 10 8 7 3 2 1

VDCR (N = 48)VDC (N = 33)VDR (N = 42)VDC-mod (N = 17)

Censored VDCRCensored VDCCensored VDRCensored VDC-mod

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Pro

porti

on o

f pat

ient

s

0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 480 510 540 570 600 630 660 690 720 750 780 810 840

Time (days)

*censored observation

Bortezomib-Cyclophosphamide-Dexamethasone

VFor 4 six-week cycles

V: 1.3 mg/m2 d 1,8,15,22

MAINTENANCE

VCDmodFor 8 three-week cyclesV: 1.3 mg/m2 d 1,4,8,11C: 500 mg/m2 d 1,8,15

D: 40 mg d 1,8,15

Best response

Patie

nts

(%)


Time (days)

Patie

nts

(%)

0

40

60

80

100

0 60 120 180 240 300

1-year rate 100%20

360 420 480 540

• 17 newly diagnosed transplant eligible and ineligible MM patients

For ASCT eligible:Stem cell collection after cycle 4

0

20

40

60

80

100

PD VGPR sCR CR ≥PR

VCDmod, bortezomib-cyclophosphamide-dexamethasone modified schedule; PR, partial response; VGPR, very good partial response; CR, complete response; sCR, stringent complete response; PD, progressive disease; V, bortezomib.

Kumar S, et al. Blood 2012.

0% 6%

29%

47%

100%

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%


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

(%)

Frail condition

PATIENT STATUS ASSESSMENT

- Age

- ADL - IADL

- Charlson co-morbidity score

FIT UNFIT FRAILAge <80 yr

ADL 6 IADL 8 Charlson 0

Fit >80 yr ADL 5

IADL 6-7 Charlson 1

Unfit >80 yrADL ≤4IADL ≤5

Charlson ≥2

Full-dose regimensDose level 0

Reduced-dose regimensDose level -1

Reduced-dose Palliative approach

Dose level -2

New treatment algorithm for elderly MM

Go-go moderate-go slow-go

ADL, Activity of Daily Living; IADL, Instrumental Activity of Daily Living; ASCT, autologous stem cell transplantation

Palumbo A. IMW 2013, oral presentation

Subgroup analyses

OS: Age >80 or <80 years

Time (months)

p=0.580

25

50

75

100

0 5 10 15 20 25

OS: age >75 or <75 years

Patie

nts

(%)

0

25

50

75

100

0 5 10 15 20 25

p=0.27Age < 75 yearsAge > 75 years

Patie

nts

(%)

OS: fit vs. frail

PFS: fit vs. frail

0

25

50

75

100

0 5 10 15 20 25

0

25

50

75

100

0 5 10 15 20 25Time (months)

p=0.02

p=0.001Age < 80 yearsAge > 80 years

fitfrail

fitfrail

*Frail defined as: ADL <4 or IADL <5 or Charlson >2 or unfit patient >80 yr (Unfit defined as: ADL 5 or IADL 6-7 or Charlson 1 or fit patient >80 y)

Dose adjustment recommendations for the treatment of frail elderly patients

Agent Dose level 0 Dose level – 1 Dose level – 2

Bortezomib 1.3 mg/m2 twice / weekd 1,4,8,11 / 3 wks

1.3 mg/m2 once / weekd 1,8,15,22 / 5 weeks

1.0 mg/m2 once / weekd 1,8,15,22 / 5 weeks

Thalidomide 100 mg/d 50 mg/d 50 mg qod

Lenalidomide 25 mg/dd 1-21 / 4 weeks

15 mg/dd 1-21 / 4 weeks

10 mg/dd 1-21 / 4 weeks

Dexamethasone 40 mg/dd 1,8,15,22 / 4 week

20 mg/dd 1,8,15,22 / 4 week

10 mg/dd 1,8,15,22 / 4 week

Melphalan 0.25 mg/kg d 1-4 / 4-6 weeks

0.18 mg/kg d 1-4 / 4-6 weeks

0.13 mg/kgd 1-4 / 4-6 weeks

Prednisone 50 mg qod 25 mg qod 12.5 mg qod

Cyclophosphamide

100 mg/dd 1-21 / 4 weeks

50 mg/dd 1-21 / 4 weeks

50 mg qodd 1-21 / 4 weeks

Palumbo et al. BLOOD, 27 OCTOBER 2011 118 (17):4519-4529


Rd, lenalidomide-dexamethasone; CPR, cyclophosphamide-prednisone-lenalidomide; MPR, melphalan-prednisone-lenalidomide; CVP, cyclophosphamide-bortezomib-prednisone; VMP, bortezomib-melphalan-prednisone; VP, bortezomib-prednisone; VD, bortezomib-dexamethasone; VTD, bortezomib-thalidomide-dexamethasone.

VD VTD VMPvs. vs.CVP VMP VPvs. vs.Rd CPR MPRvs. vs.

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 30 35 40

Larocca A, et al. IMW 2013 Niesvizky R, et al. EHA 2010Larocca A, et al. Gr. Emat. Milano 2012

1.0

0.8

0.6

0.4

0.2

0

0 4 8 12 16 20 24 28 32 36 40 44

VP, bort-prednisoneCVP, cyclophosphamideVMP, melphalan;

VD, bort-dexVTD, thalidomideVMP, melphalan

Rd, len-dex CPR, cyclophosphamide MPR, melphalan

RP-MPR-RP Phase 2 Study

Falco P, et al. Leukemia. 2013;27:695-701

MPR, melphalan, prednisone, Lenalidomide; RP, Lenalidomide, prednisone;RP-MPR-RP, Lenalidomide-prednisone induction followed by melphalan-prednisone-Lenalidomide consolidation and Lenalidomide-prednisone maintenance.

MPR:Mel: 2 mg, 3x/weekPred: 50 mg/day, 3x/weekLen:10–15 mg/day, d1–21

Six 28-day cycles

RP:Pred: 50 mg/day, 3x/weekLen: 25 mg/day, d1–21

Four 28-day cycles

RP:Len:10 mg/day, d1–21Pred: 25 mg/day, 3x/week

28-day cycles until PD

Consolidation MaintenanceInduction

Three drugs Two drugs Maintenance

ConclusionsFIT PATIENTS

• Triplets should be considered standard• Melphalan too toxic• Cyclophosphamide better tolerated

UNFIT PATIENTS

• Doublet preferred

Thank you

disclosures for palumbo antonio, md

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