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Disclosures for Palumbo Antonio, MD. Research Support/P.I. No relevant conflicts of interest to declare. Employee. No relevant conflicts of interest to declare. Consultant. Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millenium, Onyx. Major Stockholder.

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disclosures for palumbo antonio md
Disclosures for Palumbo Antonio, MD

Research Support/P.I.

No relevant conflicts of interest to declare

Employee

No relevant conflicts of interest to declare

Consultant

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

Major Stockholder

No relevant conflicts of interest to declare

No relevant conflicts of interest to declare

Speakers Bureau

Honoraria

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

No relevant conflicts of interest to declare

Scientific Advisory Board

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

slide2

Improving Outcomes in Myeloma

Should alkylators be used upfront in transplant-ineligible patients?

Yes/May be

Antonio Palumbo

University of Torino, Italy, EU

25min

slide4

PFS

1.00

1.00

0.75

0.75

0.50

0.50

3

3

-

-

years PFS

years PFS

Median

Median

PFS

PFS

0.25

Not

Not

reached

reached

MEL200

MEL200

60%

60%

0.25

HR 0.55

HR 0.868

MPR

MPR

36%

36%

25.88

25.88

months

months

P<

.0001

P = 0.542

0.00

0.00

0

10

20

30

40

50

60

0

10

20

30

40

50

60

Early vs late ASCT

MPR vs MEL 200

402 NDMM patients < 65 years

MPR

six 28-day courses

M: 0.18 mg/Kg/d, days 1-4

P: 2 mg/Kg/d, days 1-4

R: 10 mg/d, days 1-21

NO MAINTENANCE

Rd

four 28-day courses

R: 25 mg/d, days 1-21

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

1° R

2° R

MEL200

two courses

M: 200 mg/m2 day -2

Stem cell support day 0

R MAINTENANCE

28-day courses until relapse

R: 10 mg/day, days 1-21

Median follow-up 38 months

OS

Months

Months

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

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

slide5

100

100

MEL200-R

75

MPR-R

75

MEL200

50

MPR

50

MEL200-R

MEL200

25

25

MPR-R

MPR

0

0

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Months

MPR vs MEL200 vs MPR-R vs MEL200-R

Progression-free survival

Overall survival

Months

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

slide6

1.00

1.00

PAD MEL100

0.75

MEL200

0.75

0.50

0.50

VMP+VMPT

MPR

0.25

0.25

HR 0.55; P=.032

HR 0.39; P=.026

0.00

0.00

12

24

36

48

60

12

24

36

48

60

Early vs late ASCT

Role of CR after induction

MPR vs MEL200

Random

PAD MEL100 vs VMP+VMPT

No random

1-year landmark PFS CR patients only

1-year landmark PFS CR patients only

Months

Months

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

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

slide7

Progression-free survival

according to quality of response

+12 m

maint

Pre

maint

+3 m

maint

+6 m

maint

+18 m

maint

Dia

+12 m

maint

Pre

maint

+3 m

maint

+6 m

maint

+18 m

maint

Dia

MRD - CR +

Progression-free survival

100

MRD - CR +

80

60

Percent survival

40

MRD+ CR +

MRD + CR +

20

0

0

10

20

30

40

50

Months

MRD, minimal residual disease; CR complete response

Palumbo A, et al. Unpublished data.

slide8

Progression-free survival

according to quality of response

+12 m

maint

Pre

maint

+3 m

maint

+6 m

maint

+18 m

maint

Dia

+12 m

maint

Pre

maint

+3 m

maint

+6 m

maint

+18 m

maint

Dia

MRD - CR +

Progression-free survival

100

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

MRD - CR +

80

60

Percent survival

40

MRD+ CR +

MRD + CR +

20

0

0

10

20

30

40

50

Months

MRD, minimal residual disease; CR complete response

Palumbo A, et al. Unpublished data.

slide10

MPT meta-analysis:

which is the right T dosage?

Progression-free survival

Overall survival

Study

HR (95% CI)

HR (95% CI)

Study

HR (95% CI)

HR (95% CI)

MPT better

MP better

MPT better

MP better

FR < 75

0.50 (0.39– 0.65)

FR < 75

0.61 (0.45– 0.81)

Fr≥ 75

0.68 (0.48– 0.96)

Turkey

0.59 (0.35–0.99)

HOVON

0.75 (0.57–1.00)

Fr ≥ 75

0.61 (0.46–0.82)

Italy

0.62 (0.48–0.80)

Turkey

0.87 (0.46–1.67)

HOVON

0.79 (0.62–1.00)

Italy

1.04 (0.75–1.44)

NMSG

1.12 (0.85–1.47)

NMSG

0.89 (0.70–1.13)

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

0.82 (0.66–1.02)

Overall (I-squared = 61.7%,

p = 0.023)

0.67 (0.55– 0.80)

0.5

0.75

1

1.5

0.5

0.75

1

1.5

NOTE: weights are from random effects analysis

NOTE: weights are from random effects analysis

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

vmpt vt versus vmp in newly diagnosed elderly patients
VMPT-VT versus VMP in newlydiagnosedelderlypatients
  • Median follow-up: 54 mos

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

vmpt vt versus vmp in newly diagnosed elderly patients1
VMPT-VT versus VMP in newlydiagnosedelderlypatients
  • Dearopponent:
  • Randomizedstudy
    • Follow-up 54 mos
    • Age 71 yrs
    • PFS 35.3 mos
    • TTNT 46.6 mos
  • Median follow-up: 54 mos

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

slide14

Hematologic SPMs

Lenalidomide only

Lenalidomide + cyclophosphamide

Lenalidomide + melphalan

Melphalan only

0

0,5

1

1,5

2

Solid SPMs

Lenalidomide only

Lenalidomide + cyclophosphamide

Lenalidomide + melphalan

Melphalan only

0

0,5

1

1,5

2

Incidence Rate per 100 per year

Incidence rate per 100 per year

Different lenalidomide combinations

slide15

SPM and SAE

Cumulative incidence per 100 at 60 months

No Lenalidomide studies

Lenalidomide studies

slide16

SPM and SAE

Cumulative incidence per 100 at 60 months

No Lenalidomide studies

Dearopponent:

You start tohave:

…some… right

Lenalidomide studies

vcd vs vrd vs vcrd progression free survival
VCD vs VRD vs VCRDProgression free survival

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

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Proportion of patients

Censored VDCR

Censored VDC

Censored VDR

Censored VDC-mod

VDCR (N = 48)

VDC (N = 33)

VDR (N = 42)

VDC-mod (N = 17)

Time (days)

*censored observation

slide19

Bortezomib-Cyclophosphamide-Dexamethasone

  • 17 newly diagnosed transplant eligible and ineligible MM patients

VCDmod

For 8 three-week cycles

V: 1.3 mg/m2 d 1,4,8,11

C: 500 mg/m2 d 1,8,15

D: 40 mg d 1,8,15

MAINTENANCE

V

For 4 six-week cycles

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

For ASCT eligible:

Stem cell collection after cycle 4

Progression-free survival

Best response

100%

100

100

80

80

60

60

47%

Patients (%)

Patients (%)

40

40

29%

20

20

1-year rate 100%

6%

0%

0

0

420

480

540

0

120

180

240

300

360

60

PD

VGPR

sCR

CR

≥PR

Time (days)

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.

slide20

Carfilzomib, Cyclophosphamide, Dexamethasone

(CCyd)

MAINTENANCE

CCyd

Cycles 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

C

Until progression/intolerance

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

sCR

sCR/nCR/CR

≥VGPR

≥PR

96

94

100

89

100

76

80

72

64

63

75

60

46

41

50

40

24

15

13

20

25

1-year rate 86%

0

0

Cycle 2

Cycle 6

Cycle 9

0.0

2.5

5.0

7.5

10.0

12.5

15.0

17.5

20.0

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

Progression-free survival

Best response

Patients (%)

Patients (%)

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.

slide22

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
Subgroup analysesOS: Age >80 or <80 years OS: age >75 or <75 years

100

100

75

75

50

50

25

25

0

0

0

5

10

15

20

25

0

5

10

15

20

25

100

75

50

25

p=0.58

0

0

5

10

15

20

25

PFS: fit vs. frail

Patients (%)

fit

frail

Age < 75 years

Age > 75 years

p=0.27

p=0.02

OS: fit vs. frail

100

75

Patients (%)

50

Age < 80 years

Age > 80 years

fit

frail

25

p=0.001

0

0

5

10

15

20

25

Time (months)

Time (months)

*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
Dose adjustment recommendations for the treatment of frail elderly patients

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

slide25

Progression-free survival

Rd

vs.

CPR

vs.

MPR

CVP

vs.

VMP

vs.

VP

VD

vs.

VTD

vs.

VMP

1.0

1.00

1.00

0.8

0.6

0.75

0.75

0.4

0.50

0.50

0.2

0.25

0.25

0

0

4

8

12

16

20

24

28

32

36

40

44

0.00

0.00

0

5

10

15

20

25

30

35

40

0

5

10

15

20

25

Rd, len-dex

CPR, cyclophosphamide

MPR, melphalan

VP, bort-prednisone

CVP, cyclophosphamide

VMP, melphalan;

VD, bort-dex

VTD, thalidomide

VMP, melphalan

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.

Larocca A, et al. Gr. Emat. Milano 2012

Larocca A, et al. IMW 2013

Niesvizky R, et al. EHA 2010

rp mpr rp phase 2 study
RP-MPR-RP Phase 2 Study

Consolidation

Maintenance

Induction

Two drugs

Three drugs

Maintenance

RP:

Pred:50 mg/day, 3x/week

Len: 25 mg/day, d1–21

Four 28-day cycles

MPR:

Mel:2 mg, 3x/week

Pred:50 mg/day, 3x/weekLen:10–15 mg/day, d1–21

Six 28-day cycles

RP:

Len:10 mg/day, d1–21

Pred: 25 mg/day, 3x/week

28-day cycles until PD

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

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

conclusions

Conclusions

  • FIT PATIENTS
  • Tripletsshouldbeconsidered standard
  • Melphalantootoxic
  • Cyclophosphamidebettertolerated
  • UNFIT PATIENTS
  • Doubletpreferred