New standards of care for NDMM patients not eligible for ...

Thierry FACON, MD

Professor of HematologyService des Maladies du Sang

University of LilleLille, France

New standards of care for NDMM

patients not eligible for transplant

Changing demographics•Increase in life expectancy

•Aging of the population

•Increase in number of elderly

Epidemiology of Elderly

0

10

20

30

40

50

60

Europe North

America

Oceania Asia Latin Am North

Africa

Sub

Saharian

2000

2015

2030

2050

National Accademy of Sciences 2007: US Bureau of Census

World population: % of people 65+

3

Multiple Myeloma affects primarily elderly

patients

SEER: New MM Cases by Age Group

Available from http://seer.cancer.gov/statfacts/html/mulmy.html. Accessed on 06/2014.

http://seer.cancer.gov/statfacts/html/mulmy.html

Refresher on MPT and VMP data

A journey back in time...

MPT: melphalan, prednisone, thalidomide VMP: bortezomib, melphalan, prednisone

MPT becomes a standard of care

Facon T, et al. Lancet. 2007;370:1209-18. Fayers PM, et al. Blood. 2011;118: 1239-47.

VMP becomes a standard of care

San Miguel JF, et al. N Engl J Med. 2008;359: 906-17.

VISTA Trial: MP + Bortezomib (VMP) vs. MP

San Miguel et al. JCO 2013; 31(4):448-55.

Bortezomib twice a week x 4 cycles + weekly x 5 cycles

RR (CR) (%): 71(30) vs. 35(4)

TTP

Time (months)

0 3 6 9 12 15 18 21 24 27

0

20

40

60

80

100

VMP

MP

Pati

en

ts w

ith

ou

t even

t (%

)

VMP: 24.0 months

MP: 16.6 months, P < 0.000001

OS

Time (months)

Median follow-up 60 months

Median OS:

VMP: 56m

MP: 43m, P = 0.0008

Pati

en

ts w

ith

ou

t even

t (%

)

0

20

40

60

80

100

0 6 12 18 24 36 42 54 66 7848 60 7230

Back to present day

The benefits of continuous therapy in elderly patients

8

Benboubker L, et al. N Engl J Med. 2014;371:906-17.

Continuous therapy with lenalidomide

A new treatment paradigm

9

RA

ND

OM

IZA

TIO

N 1

:1:1

Arm B

Rd18

Arm C

MPT

LEN + LoDEX: 18 Cycles (72 wks) LENALIDOMIDE 25 mg D1-21/28

LoDEX 40 mg D1,8,15, & 22/28

MEL + PRED + THAL 12 Cycles (72 wks)MELPHALAN 0.25 mg/kg D1-4/42

PREDNISONE 2 mg/kg D1-4/42

THALIDOMIDE 200 mg D1-42/42

PD

, O

S,

an

d

Su

bs

eq

ue

nt

an

ti-M

M T

x

PD

or

Un

accep

tab

le T

ox

icit

y

Active Treatment + PFS Follow-up PhaseScreening LT Follow-Up

Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL (100 mg D1-42/42); MEL 0.2 mg/kg D1–4

10

• Stratification: age (≤ 75 y vs. > 75 y), country, and ISS stage (I or II vs. III)

• Thromboprophylaxis was mandatory

FIRST Trial: Study Design

LEN + LoDEX: ContinuouslyLENALIDOMIDE 25 mg D1-21/28

LoDEX 40 mg D1,8,15, & 22/28

Arm A

Continuous Rd

Benboubker L, et al. NEJM. 2014;371:906-17.

• Primary endpoint: PFS (Rd vs. MPT)

• Key secondary endpoints: OS, QoL, TTF, Time to 2nd AMT, DOR, Safety

MPT, melphalan, prednisone, thalidomide;

Rd, lenalidomide plus low-dose dexamethasone; Rd18, Rd for 18 cycles.

Facon T, et al. J Clin Oncol. 2015;33 Suppl:abstract 8524.

Poster presentation.

IFM 2007-01 - FIRST Trial: PFS according to

investigator assessment

Hazard ratio

Rd vs MPT: 0.69; p < 0.001

Rd vs Rd18: 0.71; p < 0.001

Rd18 vs MPT: 0.99; p = 0.866

0 6 12 18 24 30 36 42 48 54 60 66 72

Rd 535 411 330 276 225 186 161 117 66 26 6 0

Rd18 541 414 337 276 174 125 89 53 27 13 3 0

MPT 547 391 312 249 180 129 87 59 25 12 1 0

1.0

0.8

0.6

0.4

0.2

0

Su

rviv

al

pro

bab

ilit

y

PFS (months)Number at risk:

40.8%

22.5 %

23.1 %

Median PFS 4-year PFS

Rd (n = 535) 26.0 months 33%

Rd18 (n = 541) 21.0 months 14%

MPT (n = 547) 21.9 months 13%

72 w

eeks

Median follow-up of 45.5 months as of 3 March 2014


Rd, lenalidomide plus low-dose dexamethasone;

Rd18, Rd for 18 cycles.

Facon T, et al. J Clin Oncol. 2015;33 Suppl:abstract 8524. Poster

presentation.

IFM 2007-01 - FIRST Trial: Overall survival

Median OS 4-year OS

Rd (n = 535) 58.9 months 60%

Rd18 (n = 541) 56.7 months 57%

MPT (n = 547) 48.5 months 51%

Hazard ratio

Rd vs MPT: 0.75; p = 0.002

Rd vs Rd18: 0.91; p = 0.30

0 6 12 18 24 30 36 42 48 54 60 66 72

1.0

0.8

0.6

0.4

0.2

0

Su

rviv

al

pro

bab

ilit

y

OS (months)

697 deaths (43% of ITT)


FIRST Trial: Safety – Selected Grade 3–4 TEAEs

Continuous Rd

(n=532)

Rd 18

(n=540)

MPT

(n=541)

Hematological (%)

Anemia 18.2 15.7 18.9

Neutropenia 27.8 26.5 44.9

Thrombocytopenia 8.3 8.0 11.1

Febrile neutropenia 1.1 3.0 2.6

Non-hematological (%)

Infections 28.9 21.9 17.2

Pneumonia 8.1 8.3 5.7

Diarrhea 3.9 3.3 1.5

Constipation 2.3 1.9 5.4

Peripheral sensory neuropathy 1.1 0.4 9.4

DVT and/or PE 7.9 5.6 5.4

Cataract 5.8 2.6 0.6

DVT, deep-vein thrombosis; PE, pulmonary embolism; TEAEs, treatment-emerging adverse events.

Facon T, et al. Blood. 2013;122:abstract 2.

13

Severity of AEs graded according to NCI CTCAE v3.0.

FIRST Trial: Safety – Selected Grade 3–4

TEAEs

14

Continuous Rd

(n=532)

Rd 18

(n=540)

MPT

(n=541)

Hematological (%)

Neutropenia 27.8 26.5 44.9

Non-hematological (%)

Infections 28.9 21.9 17.2

DVT and/or PE 7.9 5.6 5.4

Cataract 5.8 2.6 0.6

SPM, n (%)

Any, n (%) 45 (8.5) 50 (9.3) 54 (10.0)

Invasive, n (%)

Hematologic

Solid tumor

21 (3.9)

3 (0.6)

18 (3.4)

33 (6.1)

2 (0.4)

32 (5.9)

30 (5.5)

12 (2.2)

18 (3.3)

Noninvasive (NMSC), n (%) 27 (5.1) 20 (3.7) 26 (4.8)

Facon T, et al. Blood. 2013;122:Abstract 2.

Severity of AEs graded according to NCI CTCAE v3.0.

DVT, deep-vein thrombosis; MPT, melphalan, prednisone, thalidomide; NMSC, non-melanoma skin

cancer; pt, patient; PE, pulmonary embolism; Rd, lenalidomide plus low-dose dexamethasone; Rd18,

lenalidomide plus low-dose dexamethasone for 18 cycles; SPM, second primary malignancies; TEAEs,

treatment-emerging adverse events.


Rd, lenalidomide plus low-dose dexamethasone; Rd18, Rd for 18 cycles. Hulin C et al. Haematologica. 2015;100 Suppl:abstract S429. Oral presentation.

IFM 2007-01 - FIRST Trial: Age analysis –

PFS

Rd

Rd18

MPT

349

348

359

222

231

218

188

193

177

155

125

126

129

94

92

117

66

61

90

38

39

54

20

18

22

9

9

6

3

1

275

277

266

0

0

0

Rd

Rd18

MPT

186

193

188

108

106

94

88

83

72

70

49

54

57

31

37

44

23

26

27

15

20

12

7

7

4

4

3

0

0

0

136

137

125

Pa

tie

nts

(%

)

100

80

60

40

20

0

PFS (months)

0 6 12 18 24 30 36 42 48 54 60 66

Pa

tie

nts

, %

100

80

60

40

20

0

PFS (months)

0 6 12 18 24 30 36 42 48 54 60 66

Hazard ratio (95% CI)

Rd vs MPT: 0.64 (0.53–0.77)

Rd vs Rd18: 0.68 (0.56–0.82)

Rd18 vs MPT: 0.97 (0.81–1.15)

Median,

months

Rd continuous 28.1

Rd18 21.6

MPT 22.4

Age ≤ 75 Years Age > 75 Years

Median,

months

Rd continuous 20.3

Rd18 19.4

MPT 19.8


Rd vs MPT: 0.80 (0.62–1.03)

Rd vs Rd18: 0.78 (0.61–1.01)

Rd18 vs MPT: 1.03 (0.80–1.33)

37%

13%

15%

26%

10%

11%



Rd, lenalidomide plus low-dose dexamethasone; Rd18, Rd for 18 cycles. Hulin C et al. Haematologica. 2015;100 Suppl:abstract S429. Oral presentation.

IFM 2007-01 - FIRST Trial: Age analysis –

OS

Rd

Rd18

MPT

186

193

188

108

106

94

88

83

72

70

49

54

57

31

37

44

23

26

27

15

20

12

7

7

4

4

3

0

0

0

136

137

125

Rd

Rd18

MPT

349

348

359

311

309

306

295

287

291

272

265

262

249

246

244

231

229

223

171

164

161

110

99

88

55

49

41

12

13

8

329

328

330

0

0

0

Pa

tie

nts

(%

)

100

80

60

40

20

0

OS (months)

0 6 12 18 24 30 36 42 48 54 60 66

Pa

tie

nts

(%

)

100

80

60

40

20

0

OS (months)

0 6 12 18 24 30 36 42 48 54 60 66



Rd vs MPT: 0.76 (0.60–0.96)

Rd vs Rd18: 0.90 (0.71–1.15)

Rd18 vs MPT: 0.84 (0.66–1.06)


Rd vs MPT: 0.72 (0.54–0.96)

Rd vs Rd18: 0.91 (0.68–1.22)

Rd18 vs MPT: 0.79 (0.60–1.04

Median,

months

4-yr,

%

Rd continuous 60.9 64

Rd18 60.6 61

MPT 55.3 57

Median,

months

4-yr,

%

Rd continuous 52.3 52

Rd18 45.7 48

MPT 37.8 39


Grade 3/4 Nonhematologic TEAEs

DVT, deep vein thrombosis; MPT, melphalan, prednisone, thalidomide; PE, pulmonary embolism; Rd, lenalidomide plus low-dose dexamethasone; Rd18,

lenalidomide plus low-dose dexamethasone for 18 cycles; TEAE, treatment-emergent adverse event.

Grade 3/4

TEAEs, %


Rd

Continuous

(n = 347)

Rd18

(n = 348)

MPT

(n = 357)

Rd

Continuous

(n = 185)

Rd18

(n = 192)

MPT

(n = 184)

Nonhematologic (≥ 10% in either age group)

Infections 30 21 16 29 23 20

Cardiac disorders 12 6 6 12 9 13

Fatigue 7 8 5 9 10 8

Back pain 6 7 5 10 4 5

Peripheral

sensory

neuropathy

1 1 10 1 0 8

TEAEs of special interest

Cataract 8 3 < 1 3 2 1

DVT 7 3 3 3 5 2

PE 4 3 5 4 3 2

18

Side Effects of Tx

Fewer side

effects

More side

effects

• Rd resulted in a significant reduction in patient-reported Side Effects of Tx

vs. MPT at most time points

Visit

Ch

an

ge F

rom

Baseli

ne

** *

* **

* * *

20

15

10

5

0

−5

C2D1 Mo 3 Mo 6 Mo 12 Mo 18

Rd

MPT

•• •

•

* P ≤ 0.05 vs. baseline (1-sample t-test).

• P ≤ 0.05 Rd vs. MPT (2-sample t-test).

EORTC, European Organisation for Research and Treatment of Cancer; Mo, month; MPT, melphalan, prednisone, thalidomide; Rd, lenalidomide plus

low-dose dexamethasone; Tx, treatment.

Delforge M, et al. Haematologica. 2015 ;100:826-33.

FIRST Trial: EORTC QLQ-MY20 Results

MPT, melphalan, prednisone, thalidomide; Rd, lenalidomide plus low-

dose dexamethasone; Rd18, Rd for 18 cycles; RI, renal impairment.

Dimopoulos M, et al. Haematologica. 2015;100 Suppl:abstract P274.

Poster presentation.

IFM 2007-01/FIRST Trial: Impact of renal impairment : PFS

• PFS benefits were observed in pts with no RI to moderate RI with Rd continuous

No RI1.0

0.8

0.6

0.4

0.2

0.00 6 12 18 24 30 36 42 48 54 60 66 72

Surv

ival p

robability

PFS (months)

Mild RI1.0

0.8

0.6

0.4

0.2

0.00 6 12 18 24 30 36 42 48 54 60 66 72

Surv

ival p

robability

PFS (months)

Moderate RI1.0

0.8

0.6

0.4

0.2

0.00 6 12 18 24 30 36 42 48 54 60 66 72

Surv

ival p

robability

PFS (months)

Severe RI1.0

0.8

0.6

0.4

0.2

0.00 6 12 18 24 30 36 42 48 54 60 66 72

Surv

ival p

robability

PFS (months)

4-yr, %

Rd continuous 41.3

Rd18 19.0

MPT 18.4

Hazard Ratio (95% CI)

Rd vs MPT: 0.67 (0.48–0.93)

Rd vs Rd18: 0.69 (0.50–0.96)

4-yr, %

Rd continuous 34.3

Rd18 13.9

MPT 12.7


Rd vs MPT: 0.70 (0.55–0.88)

Rd vs Rd18: 0.71 (0.57–0.89)

4-yr, %

Rd continuous 26.9

Rd18 9.0

MPT 11.8


Rd vs MPT: 0.65 (0.48–0.88)

Rd vs Rd18: 0.63 (0.46–0.85)

4-yr, %

Rd continuous 22.2

Rd18 0

MPT 0


Rd vs MPT: 0.80 (0.48–1.33)

Rd vs Rd18: 0.95 (0.55–1.61)


• In patients achieving CR, ≥ VGPR, or ≥ PR, PFS was prolonged with

Rd continuous vs Rd18

CR, complete response; HR, hazard ratio; PFS, progression-free survival;

PR, partial response; Rd, lenalidomide and low-dose dexamethasone; Rd18,

Rd for 18 cycles; VGPR, very good partial response.

Bahlis N et al. Haematologica. 2015;100 Suppl:abstract P277. Poster

presentation.

IFM 2007-01 - FIRST Trial - Impact of Response: PFSMedian follow-up of 45.5 months as of 3 March 2014

Favors Rd Continuous Favors Rd18

0.1

25

0.2

50.5 1 2

P R

V G P R

C R

Subgroup HR & 95% CI

Median PFS (mos)HR (95% CI)

P ValueRd Continuous Rd18

60.0 41.00.39 (0.25-0.61)

< .001

50.9 30.00.46 (0.36-0.59)

< .001

33.2 23.10.62 (0.52-0.73)

< .001

4-year PFS in CR pts (%)

Rd Continuous Rd18

75 40

FIRST (MM-020): Impact of Cytogenetics

Baseline Cytogenetics

FISH, fluorescence in situ hybridization; MPT, melphalan, prednisone, and thalidomide; pt, patient; Rd, lenalidomide plus low-dose dexamethasone; Rd18, Rd for 18 cycles.

Avet-Loiseau H, et al. Impact of Cytogenetics on Outcomes of Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma Treated With Continuous Lenalidomide Plus Low-Dose

Dexamethasone in the FIRST (MM-020) Trial. ASH 2015, abstract #730.

• 762 of 1623 pts (47%) had validated FISH results

– 142 pts (19%) had t(4;14), t(14;16), and/or del(17p) and were

categorized as high risk

– The remaining 620 pts (81%) were categorized as non-high risk

Pts With Validated

FISH Results

Rd

Continuous

(n = 248)

Rd18

(n = 261)

MPT

(n = 253)

Total

(n = 762)

High risk, n (%) 43 (17) 52 (20) 47 (19) 142 (19)

t(4;14) 22 (9) 23 (9) 25 (10) 70 (9)

t(14;16) 7 (3) 11 (4) 10 (4) 28 (4)

del(17p) 16 (6) 20 (8) 16 (6) 52 (7)

Non-high risk, n (%) 205 (83) 209 (80) 206 (81) 620 (81)


Response

a Numbers may not sum due to rounding.

CR, complete response; MPT, melphalan, prednisone, and thalidomide; ORR, overall response rate; PR, partial response; Rd, lenalidomide plus low-dose dexamethasone; Rd18, Rd for 18 cycles;

VGPR, very good partial response.



ORRa:

77%

Pati

en

ts (

%)

ORRa:

67%

ORRa:

68%

ORRa:

81%

ORRa:

80% ORRa:

71%

CR

VGPR

PR

High Risk Non-High Risk

30%

35%49%

11%47%

Odds Ratio (95% CI) High Risk Non-High Risk

Rd continuous vs MPT 1.55 (0.61-3.95) 1.75 (1.10-2.77)

Rd continuous vs Rd18 1.60 (0.64-4.00) 1.07 (0.66-1.74)

39%


Progression-Free Survival

cont, continuous; HR, hazard ratio; MPT, melphalan, prednisone, and thalidomide; pt, patient; Rd, lenalidomide plus low-dose dexamethasone; Rd18, Rd for 18 cycles.



Pts at risk:

Non-

High

Risk

Rd cont 205 159 132 115 96 78 68 51 30 11 1 0

Rd18 209 168 136 114 65 48 32 19 11 7 1 0

MPT 206 152 127 108 84 58 38 27 10 4 0

High

Risk

Rd cont 43 27 17 9 6 2 1 1 1 0

Rd18 52 29 20 14 7 5 3 3 1 1 0

MPT 47 32 22 16 8 3 1 0

n

3 Yr,

%

HR (95% CI)

(Rd cont vs)

Rd cont 205 45 –

Rd18 209 20 0.61 (0.48-0.79)

MPT 206 26 0.68 (0.53-0.88)

Rd cont 43 3 –

Rd18 52 10 1.52 (0.94-2.44)

MPT 47 3 1.27 (0.81-2.01)

High

Risk

Non-

High

Risk

0 6 12 18 24 30 36 42 48 54 60 66 72

100

80

60

40

20

0

Pati

en

ts (

%)

Progression-Free Survival (mos)

High Risk

Non-High

Risk


Overall Survival

cont, continuous; HR, hazard ratio; MPT, melphalan, prednisone, and thalidomide; pt, patient; Rd, lenalidomide plus low-dose dexamethasone; Rd18, Rd for 18 cycles.



n

3 Yr,

%

HR (95% CI)

(Rd cont vs)

Rd cont 205 77 –

Rd18 209 71 0.85 (0.62-1.18)

MPT 206 65 0.66 (0.48-0.91)

Rd cont 43 41 –

Rd18 52 40 0.90 (0.55-1.47)

MPT 47 47 0.95 (0.57-1.59)

High

Risk

Non-

High

Risk

0 6 12 18 24 30 36 42 48 54 60 66 72

100

80

60

40

20

0

Pati

en

ts (

%)

Overall Survival (mos)

High

Risk

Non-High

Risk

Pts at risk:

Non-

High

Risk

Rd cont 205 189 179 174 165 154 145 104 70 31 3 0

Rd18 209 197 189 177 163 152 139 100 63 35 8 0

MPT 206 182 174 162 148 139 122 97 58 25 4 0

High

Risk

Rd cont 43 36 32 30 27 20 17 13 10 5 1 0

Rd18 52 48 36 32 27 21 18 14 6 3 1 0

MPT 47 40 34 33 28 25 20 10 4 2 0

FIRST (MM-020): Frailty Analysis

Frailty Algorithm

1. Palumbo A, et al. Blood. 2015;125:2068-2074.

IMWG, International Myeloma Working Group; pt, patient.

Facon T. A Frailty Scale Predicts Outcomes in Patients With Newly Diagnosed Multiple Myeloma Who Are Ineligible for Transplant Treated With

Continuous Lenalidomide Plus Low-Dose Dexamethasone in the FIRST Trial. ASH 2015, abstract 4239.

• Pts were categorized into 3 severity groups (fit, intermediate, or frail) as described by a

proxy algorithm based on the IMWG frailty scale1

IMWG Frailty Scale1 Proxy for MM-020 Analysis Score

Age Age

≤ 75 yrs ≤ 75 yrs 0

76-80 yrs 76-80 yrs 1

> 80 yrs > 80 yrs 2

Activity of Daily Living score EQ-5D: Self Care score

> 4 1 (no problem) 0

≤ 4 2-3 (moderate or severe problem) 1

Instrumental Activity of Daily Living score EQ-5D: Usual Activities score

> 5 1 (no problem) 0

≤ 5 2-3 (moderate or severe problem) 1

Charlson Comorbidity Index score Charlson Comorbidity Index score

≤ 1 ≤ 1 0

≥ 2 ≥ 2 1

Total

0: Fit

1: Intermediate

≥ 2: Frail


Breakdown of Severity Group by Treatment Arm

cont, continuous; MPT, melphalan, prednisone, and thalidomide; Rd; lenalidomide and low-dose dexamethasone; Rd18, Rd for 18 cycles.

Facon T. A Frailty Scale Predicts Outcomes in Patients With Newly Diagnosed Multiple Myeloma Who Are Ineligible for Transplant Treated With Continuous Lenalidomide Plus Low-Dose

Dexamethasone in the FIRST Trial. ASH 2015, abstract 4239.


Treatment Breakdown by Severity Group With ISS Stage

cont, continuous; ISS, International Staging System; MPT, melphalan, prednisone, and thalidomide; Rd; lenalidomide and low-dose dexamethasone; Rd18, Rd for 18 cycles.


Dexamethasone in the FIRST Trial. ASH 2015, abstract 4239

• Fit pts were classified as ISS stage I vs II/III; intermediate and frail pts were classified by

stage I/II vs III


PFS and OS by Severity Group With ISS Stage

HR, hazard ratio; Int, intermediate; ISS, International Staging System; NR< not reached; OS, overall survival; PFS, progression-free survival; pt, patient; Tx, treatment.



Severity n

Median PFS, mos

(95% CI) HR (95% CI)

Fit + ISS I 84 34.1 (25.6-43.7)0.71 (0.50-0.99)

Fit + ISS II/III 171 23.3 (21.2-30.2)

Int + ISS I/II 298 27.7 (24.6-30.4)0.63 (0.49-0.80)

Int + ISS III 150 19.2 (17.6-21.3)

Frail + ISS I/II 437 23.0 (20.5-25.8)0.69 (0.58-0.82)

Frail + ISS III 377 17.1 (14.1-19.0)

00.0

0.2

0.4

0.6

0.8

1.0

20 40 60 80

PFS By Investigator, mos

Surv

ival P

robability

Severity n

Median OS, mos

(95% CI) HR (95% CI)

Fit + ISS I 84 NR0.57 (0.33-1.00)

Fit + ISS II/III 171 NR

Int + ISS I/II 298 63.1 (58.2-NR)0.43 (0.32-0.59)

Int + ISS III 150 44.3 (33.5-56.1)

Frail + ISS I/II 437 58.9 (49.5-NR)0.57 (0.47-0.69)

Frail + ISS III 377 35.6 (32.5-40.6)

00.0

0.2

0.4

0.6

0.8

1.0

20 40 60 80

OS, mosS

urv

ival P

robability

• No Tx effects were seen in these groups, likely due to small pt numbers


PFS by Severity Group (Data Cutoff: March 3, 2014)

HR, hazard ratio; MPT, melphalan, prednisone, and thalidomide; NR, not reached; PFS, progression-free survival; pt, patient; Rd, lenalidomide and low-dose dexamethasone; Tx, treatment.



Severity

Median PFS, mos

(95% CI)

Fit 28.1 (23.0-32.0)

Intermediate 24.5 (22.1-26.7)

Frail 20.0 (18.7-22.1)

00.0

0.2

0.4

0.6

0.8

1.0

20 40 60 80

Fit vs frail: HR = 0.67 (95% CI, 0.56-0.80)

Fit vs intermediate: HR = 0.83 (95% CI, 0.68-1.01)

Intermediate vs frail: HR = 0.81 (95% CI, 0.70-0.94)

Surv

ival

Pro

bab

ility

00.0

0.2

0.4

0.6

0.8

1.0

20 40 60 80

HR = 0.56 (95% CI, 0.38-0.84)

00.0

0.2

0.4

0.6

0.8

1.0

20 40 60 80

HR = 0.62 (95% CI, 0.46-0.85)

PFS by Investigator, mos

Surv

ival

Pro

bab

ility

00.0

0.2

0.4

0.6

0.8

1.0

20 40 60 80

HR = 0.79 (95% CI, 0.64-0.97)

PFS by Investigator, mos

Fit Pts

Median PFS, mos

(95% CI)

Rd

continuous43.7 (30.1-NR)

MPT 23.9 (21.2-32.0)

Intermediate

Pts

Median PFS, mos

(95% CI)

Rd

continuous31.1 (23.0-45.0)

MPT 22.6 (19.4-27.5)

Frail Pts

Median PFS, mos

(95% CI)

Rd

continuous20.3 (17.7-25.3)

MPT 20.2 (17.1-23.0)

PFS by Severity Group for All Tx Arms PFS for Rd Continuous vs MPT in Fit Pts

PFS for Rd Continuous vs MPT in Intermediate Pts PFS for Rd Continuous vs MPT in Frail Pts

PFS by Investigator, mos PFS by Investigator, mos

Intermediate

Pts

Median OS, mos

(95% CI)

Rd continuous NR (56.7-NR)

MPT 52.0 (46.8-NR)


OS by Severity Group (Data Cutoff: March 3, 2014)

HR, hazard ratio; MPT, melphalan, prednisone, and thalidomide; NR, not reached; OS, overall survival; pt, patient; Rd, lenalidomide and low-dose dexamethasone; Tx, treatment.



Severity

Median OS, mos

(95% CI)

Fit NR (NR-NR)

Intermediate 63.1 (56.1-NR)

Frail 44.7 (41.4-50.3)

00.0

0.2

0.4

0.6

0.8

1.0

20 40 60 80

Fit vs frail: HR = 0.42 (95% CI, 0.32-0.54)

Fit vs intermediate: HR = 0.67 (95% CI, 0.51-0.89)

Intermediate vs frail: HR = 0.62 (95% CI, 0.52-0.75)

Surv

ival

Pro

bab

ility

00.0

0.2

0.4

0.6

0.8

1.0

20 40 60 80

HR = 0.52 (95% CI, 0.29-0.96)

00.0

0.2

0.4

0.6

0.8

1.0

20 40 60 80

HR = 0.72 (95% CI, 0.49-1.06)

OS, mos

Surv

ival

Pro

bab

ility

00.0

0.2

0.4

0.6

0.8

1.0

20 40 60 80

HR = 0.80 (95% CI, 0.64-1.01)

OS, mos

Fit Pts

Median OS, mos

(95% CI)

Rd

continuousNR (NR-NR)

MPT NR (49.0-NR)

Frail Pts

Median OS, mos

(95% CI)

Rd

continuous52.3 (41.4-57.4)

MPT 41.4 (35.4-45.7)

OS by Severity Group for All Tx Arms OS for Rd Continuous vs MPT in Fit Pts

OS for Rd Continuous vs MPT in Intermediate Pts OS for Rd Continuous vs MPT in Frail PtsOS, mos OS, mos

Benefits of continuous treatment

extend across drug classes and

patient populations

0

25

50

75

100

0 10 20 30 40 50 60 70 800 10 20 30 400

25

50

75

100

MPR-R vs MPR vs MP VMPT-VT vs VMPRd vs Rd18 vs MPT

Palumbo A, et al. N Engl J Med. 2012;366:1759-69. Palumbo A, et al. J Clin Oncol 2010;28:5101-9.

Time (months) Time (months)

Median

Rd 26.0 months

Rd18 21.0 months

MPT 21.9 months

Median

MPR-R 31 months

MPR 14 months

MP 13 months

Median

VMPT-VT 35.3 months

VMP 28.8 months

MP, melphalan, prednisone; MPR, MP, lenalidomide; MPR-R, MPR followed by lenalidomide maintenance; MPT,

melphalan, prednisone, thalidomide; Rd, lenalidomide plus low-dose dexamethasone; Rd18, Rd for 18 cycles; VMPT,

bortezomib, melphalan, prednisone, thalidomide; VMPT-VT, VMP followed by bortezomib plus thalidomide maintenance.

Continuous vs fixed duration: PFS advantage

0 12 24 36 48 60 72

1.0

0.8

0.6

0.4

0.2

0

Su

rviv

al

pro

ba

bil

ity

Time (months)

72

we

eks

Facon T, et al. J Clin Oncol. 2015;33

Suppl:abstract 8524.

Rd is a new standard of care for

transplant-ineligible NDMM

2014: EMN guidelines2

VMP or MPT are the standards of care for transplant-ineligible patients.

Rd is also an effective option for these patients.

1. Ludwig H et al., Leukemia. 2014;28:981-92. 2. Engelhardt M, et al. Haematologica. 2014;99:232-42. 3. NCCN Guidelines Multiple Myeloma. Version 4.2015. 4.

Moreau P, etl al. Blood. 2015;125:3076-84.

2014: IMWG guidelines1

“Recommended treatments for patients not eligible for high-dose therapy, or in

case the transplant procedure is not available, include MPT, VMP and CTD. In

addition, other regimens such as […] Rd present effective options."

2015: NCCN guidelines3

Rd, MPR, MPT, VMP are category 1 primary treatment options for transplant-

ineligible patients with multiple myeloma

33

CTD, cyclophosphamide, thalidomide, and dexamethasone; EMN, European Myeloma Network; IMWG, International Myeloma Working Group; MPT, melphalan, prednisone,

and thalidomide; MPV, melphalan, prednisone, and bortezomib; NCCN, National Comprehensive Cancer Network.

2015: Moreau P, Attal M, Facon T. Blood. 20154

Recommended first treatment options for transplant-ineligible patients with

multiple myeloma: VMP, Rd, or MPT

Treatment of MM in Elderly Patients –

Landscape and Perspectives

MP

VMP

MPT

MPR-R

# Vd

MPT-T

<

<

<

Rd

?

<

VMP – Daratumumab1

VRD

Rd – Ixazomib2

Rd – Elotuzumab3

Rd – Daratumumab4

MP – Carfilzomib5

Alternating

regimens6 ?

1MMY3007; 2 Tourmaline 2, clinical trial.gov ref: NCT01850524. Accessed June 2014; 3 Eloquent 1, clinical trial.gov ref: NCT01335399.

Accessed June 2014; 4MMY3008; 5 Clarion, clinical trial.gov ref: NCT01818752. Accessed June 2014; 6 Mateos et al. Blood. 2014;122: abs 403.

•

•

35

•

•

•

•

36

MaintenanceLEN

PFS and OS of High-Risk del(17p) Patients

receiving RVD Maintenance Post-ASCT

ASCTRVD Maintenance)

(up to 3 years)

RVD, lenalidomide, bortezomib, low-dose dexamethasone

Len 10mg/d on days 1-21 of a 28-day cycle, bortezomib 1.3mg/m2 per week SC/IV.

39

OS

Nooka AK, et al. Leukemia. 2014;28:690-3.

PFS

3-year OS

All high-risk patients: 93%

del(17p) patients: 94%

P = 0.51

Median PFS

All high-risk patients: 32 mos

del(17p) patients: 28 mos

P = 0.86

1.0

0.8

0.6

0.4

0.2

0

0 10 20 30 40 50

Time (months)

Cu

mu

lati

ve s

urv

ival

All high-risk patients

del(17p) patients

1.0

0.8

0.6

0.4

0.2

0

0 10 20 30 40 50

Time (months)

Cu

mu

lati

ve s

urv

ival

All high-risk patients

del(17p) patients

Best response with VRD; sCR 51%, VGPR 96%

RVDx3

RVD x 2

RVD x 5

Revlimid until PD (US)

Revlimid for 1 yr (IFM)

Melphalan

200mg/m2* +

ASCT

Induction

Consolidation

Maintenance

CY (3g/m2)

MOBILIZATIONGoal: 5 x106 cells/kg

RVDx3

CY (3g/m2)

MOBILIZATIONGoal: 5 x106 cells/kg

Randomize

Collection

Revlimi until PD (US)

Revlimid for 1 yr (IFM)ASCT at relapse

IFM/DFCI 2009/CTN 1304/Alliance

Parallel Phase 3 Study

“The Determination Trial”

Newly Diagnosed MM (SCT candidates; overall n= 1360; USA 660; France 700)

IFM 2009: PFS (9/2015)

P<0.001

0

10

20

30

40

50

60

70

80

90

100

Pa

tient

s (%

)

350 296 228 128 24no HDT350 309 261 153 27HDT

N at risk

0 12 24 36 48

Months of follow-up

HDT

no HDT

IFM 2009: PFS.

0.20

0.97

0.53

0.69

Overall 158 / 350 204 / 350

<60 years 84 / 185 123 / 196

>=60 years 74 / 165 81 / 154

Stage I 44 / 118 58 / 115

Stage II 81 / 171 103 / 170

Stage III 33 / 61 43 / 65

Standard 87 / 213 118 / 212

High Risk 28 / 46 31 / 44

At least VGPR 93 / 180 122 / 190

PR SD PD 60 / 164 77 / 154

Transplant better RVD better

1.4 .6 .8 1 1.2 1.4

Response after induction

Cytogenetics

ISS

Age

Nb of events / Nb of patients

Transplant RVD Arm Hazard Ratio for

Progression or death

p-value for

interaction

IFM/DFCI 2009: PFS according to MRD (FCM) post consolidation (9/2015).

P<0.001

0

10

20

30

40

50

60

70

80

90

100

Pa

tie

nts

(%

)

172 166 151 86 17MRD neg65 57 43 30 4MRD pos

N at risk

0 12 24 36 48

Months of follow-up

MRD pos

MRD neg

RVD Arm Transplant Arm

P<0.001

0

10

20

30

40

50

60

70

80

90

100

Pa

tie

nts

(%

)

140 135 113 72 14MRD neg89 75 54 22 2MRD pos

N at risk

0 12 24 36 48

Months of follow-up

MRD pos

MRD neg

P NS

0

10

20

30

40

50

60

70

80

90

100

Patie

nts

(%)

350 338 320 244 56no HDT350 328 309 226 55HDT

N at risk

0 12 24 36 48

Months of follow-up

HDT

no HDT

IFM 2009: OS (9/2015)

45

Phase 3 ELOQUENT-1 (CA204-006): ERd vs Rd in

TNE NDMM

NCT01335399. Available from: www.clinicaltrials.gov. Accessed 8 October 2013.

EudraCT 2010-022445-20

ERdELO: 10 mg/kg, d1, 8, 15, 22 (cycles 1–2); d1, 15

(cycles 3–18); 20 mg/kg, d1 (cycles ≥ 19)

LEN: 25 mg, d1–21

DEX: 28mg orally d1, 8, 15, 22 (cycles 1–2);

d1, 15 (cycles 3–18); d1 (cycles ≥ 19)

28-day cycles, until PD

Rd

LEN: 25 mg, d1–21

DEX: 40 mg, d1, 8, 15, 22

28-day cycles, until PD

n=375

n=375

Stratified by

ISS stage,

age and

ECOG

234 sites

21 countries

Follow-UpSurvival every

16 weeks

Tumor assessments: every 4 weeks from Day 1 until progression

Ran

do

miz

ati

on

• Primary endpoint: PFS (EBMT)

– Primary endpoint analysis expected Q4 2018

• Secondary endpoints: ORR, OS

46

ELOQUENT-2 Update: A Phase 3, Randomized,

Open-Label Study of Elotuzumab in Combination

with Lenalidomide/Dexamethasone in Patients with

Relapsed/Refractory Multiple Myeloma – 3-Year

Safety and Efficacy Follow-up

Meletios Dimopoulos,1 Sagar Lonial,2 Darrell White,3 Philippe Moreau,4 Antonio Palumbo,5 Jesus San Miguel,6

Ofer Shpilberg,7 Kenneth Anderson,8 Sebastian Grosicki,9 Ivan Spicka,10 Adam Walter-Croneck,11 Hila Magen-

Nativ,12 Maria-Victoria Mateos,13 Andrew Belch,14 Donna Reece,15 Meral Beksac,16 Eric Bleickardt,17 Valerie

Poulart,18 Jessica Katz,19 Anil Singhal,20 Paul Richardson8

1National and Kapodistrian University of Athens, Athens, Greece; 2Winship Cancer Institute, Emory University School of Medicine, Atlanta, USA; 3QEII

Health Science Center and Dalhousie University, Halifax, Canada; 4University Hospital, Nantes, France; 5A.O.U. San Giovanni Battista di Torino - Ospedale

Molinette, Torino, Italy; 6Clinical Universidad de Navarra, Pamplona, Spain; 7Assuta Medical Centers, Tel-Aviv, Israel; 8Dana-Farber Cancer Institute,

Boston, MA; 9Silesian Medical University, Katowice, Poland; 10Charles University Hospital, Prague, Czech Republic; 11Medical University of Lublin, Lublin,

Poland; 12Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, and Tel Aviv University, Ramat Aviv, Israel; 13University Hospital of Salamanca-

IBSAL, Salamanca, Spain; 14Cross Cancer Institute and University of Alberta, Edmonton, Canada; 15Princess Margaret Cancer Center, Toronto, Canada; 16Ankara University, Ankara, Turkey; 17Bristol-Myers Squibb, Wallingford, CT; 18Bristol-Myers Squibb, Braine-l'Alleud, Belgium; 19Bristol-Myers Squibb,

Princeton, NJ; 20AbbVie Biotherapeutics Inc. (ABR), Redwood City, CA

American Society of Hematology (ASH) Annual Meeting & Exposition;

December 5–8, 2015; Orlando, Florida

28

47

Extended Progression-Free Survival

E-Ld Ld

HR 0.73 (95% CI 0.60, 0.89); p=0.0014

Median

PFS

(95% CI)

19.4 mos

(16.6,

22.2)

14.9 mos

(12.1, 17.2)

PFS benefit with E-Ld was maintained over time (vs Ld):

• Overall 27% reduction in the risk of disease progression

or death

• Relative improvement in PFS of 44% at 3 years

0.0

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

480 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

No. of patients at risk:

E-Ld

Ld

321

325

293

266

259

215

227

181

171

130

144

106

125

80

107

67

94

60

85

51

59

36

34

15

19

7

8

3

PFS (months)

Pro

bab

ilit

y p

rog

ressio

n f

ree

3

0

195

157

E-LdLd0.1

1-year PFS 2-year PFS 3-year PFS

0

0

68%

41%

26%

57%

27%

18%

ELOQUENT-2

48

Placebo + LEN

(25 mg) + DEX (40 mg)*

28-day cycles for 18 months

Ixazomib (4.0 mg) +

LEN (25 mg) + DEX(40 mg)

28-day cycles for 18 months

Placebo + LEN (10 mg)

Until progression

Ixazomib (3.0 mg) +

LEN (10 mg)

Until progression

N ~ 700

Phase 3 TOURMALINE-2: Oral Ixazomib-Rd vs.

Placebo-Rd in NDMM

* 20 mg for patients > 75 years of age. NCT01850524. Available from: www.clinicaltrials.gov.

Millennium C16014 / IFM 2013-07

Ra

nd

om

iza

tio

n

• Primary endpoint: PFS


• Secondary endpoints: CR, OS, pain relief

49

Ixazomib, an Oral Proteasome Inhibitor,

in Combination with Lenalidomide and

Dexamethasone (IRd), Significantly Extends

Progression-Free Survival for Patients with

Relapsed and/or Refractory Multiple Myeloma:

The Phase 3 TOURMALINE-MM1 Study

(NCT01564537)

Philippe Moreau,1 Tamás Masszi,2 Norbert Grzasko,3 Nizar J. Bahlis,4

Markus Hansson,5 Ludek Pour,6 Irwindeep Sandhu,7 Peter Ganly,8 Bartrum W.

Baker,9 Sharon Jackson,10 Anne-Marie Stoppa,11 David Simpson,12 Peter Gimsing,13

Antonio Palumbo,14 Laurent Garderet,15 Michele Cavo,16 Shaji Kumar,17

Cyrille Touzeau,1 Francis K. Buadi,17 Jacob P. Laubach,18 Deborah Berg,19

Jianchang Lin,19 Alessandra Di Bacco,19 Ai-Min Hui,19 Paul G. Richardson18

1University Hospital Hôtel Dieu, Nantes, France; 2St. István and St. László Hospital of Budapest, Budapest, Hungary; 3Medical

University of Lublin and St. John's Cancer Center, Lublin, Poland; 4Southern Alberta Cancer Research Institute, University of

Calgary, Alberta, Canada; 5Skåne University Hospital, Lund University, Lund, Sweden; 6University Hospital Brno, Brno, Czech

Republic; 7University of Alberta, Edmonton, Canada; 8Christchurch Hospital, Christchurch, New Zealand; 9Palmerston North

Hospital, Palmerston North, New Zealand; 10Middlemore Hospital, Auckland, New Zealand; 11Institut Paoli-Calmettes,

Marseille, France; 12North Shore Hospital, Auckland, New Zealand; 13University Hospital Rigshospitalet, Copenhagen,

Denmark; 14University of Torino, Torino, Italy; 15Hôpital Saint Antoine, Paris, France; 16Bologna University School of Medicine,

Bologna, Italy; 17Mayo Clinic, Rochester, MN; 18Dana-Farber Cancer Institute, Boston, MA; 19Millennium Pharmaceuticals, Inc.,

Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

50

Final PFS analysis:

A significant, 35% improvement in PFS with

IRd vs placebo-Rd

Number of patients at risk:

IRd

Placebo-Rd

360 345 332 315 298 283 270 248 233 224 206 182 145 119 111 95 72 58 44 34 26 14 9 1 0

362 340 325 308 288 274 254 237 218 208 188 157 130 101 85 71 58 46 31 22 15 5 3 0 0

1.0

0.8

0.6

0.4

0.2

0.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Pro

ba

bil

ity o

f p

rog

res

sio

n-f

ree

su

rviv

al

Time from randomization (months)

Log-rank test p=0.012

Hazard ratio (95% CI): 0.742 (0.587, 0.939)

Number of events: IRd 129; placebo-Rd 157

Median PFS:IRd: 20.6 months

Placebo-Rd: 14.7 months

Median follow-up: ~15 months

51

Phase 3 MMY3008: DARA-Rd vs Rd in TNE NDMM

Stratified by:

• IISS (I vs. II vs. III)

• Region (North America

vs. Other)

• Age (<75 vs. ≥75)

NCT02252172. Available from: www.clinicaltrials.gov.

Rd

LEN: 25mg PO Day 1-21

DEX: 40mg PO Day 1, 8, 15,22

28-day cycles until PD

DARA-Rd

DARA: 16mg/kg Q1Wk for 8

weeks, then Q2Wk for 16 weeks,

thereafter Q4Wk

LEN: 25mg PO Day 1-21

DEX: 40mg PO Day 1, 8, 15, 22

28-day cycles until PD (DARA)

or up to 2 yrs (Rd)

End-of-

Treatment

Visit

(30 days

after last

dose)

Long

Term

Follow-

up

Screening

Within 21

days of

randomization

Planned enrollment:

730 Subjects

Ran

do

miz

ati

on

1:1

• Primary endpoint: PFS


• Secondary endpoints: sCR/CR, ORR, MRD, PFS2, OS, QoL

52

2015 2016 2017 2018 2019 2020+

Source: Trialtrove, Biomed Tracker, ClinicalTrials.gov

Changing Landscape NDMM TNE Patients

Expected Readouts Selected Phase III Trials

Ixazomib+RdTNE

EU: est Q2 ‘19

KMP vs. VMPCLARIONQ1 2017

ECOG KRd vs RVd TNE

Est Q2 2016

Elo Rd in NDMM TNE

EU: est. Q4 ‘18

Elo Rd TNEELOQUENT-1 Est, Q2 2017

TOUR2 Ixa+RdQ4 ‘17

D+VMP vs VMP Ph III TNE Q2 ‘18

MMY3008 DRd vs Rd Ph III TNE

Q4’19

KMP vs. VMPCLARION TNEEU: est. Q3 ‘18

D+VMP Ph III TNE

DRd vs Rd Ph III TNE

Data Readouts

Approvals

SWOG RVD vs Rd Q2 ‘15

IXA

BO

R

T

CF

ZE

LO

DA

R

A

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