Management of Multiple Myeloma in the ElderlyManagement of Multiple Myeloma in the Elderly Xavier Leleu ServicedesMaladies du Sang Hôpital Huriez, CHRU, Lille, France INSERM U837,

Management of Multiple Myeloma in the ElderlyMyeloma in the Elderly

Xavier Leleu

Service des Maladies du Sang

Hôpital Huriez, CHRU, Lille, France

INSERM U837, équipe 3

IRCL, CHRU, Lille, France

IMPRT

Institut de Médecine Prédictive et de Reherches Thérapeutique

IFR 114

Conflict of Interests

Lecture fees – Research grants – Boards

Janssen, Celgene, LeoPharma, Amgen, Novartis, Onyx

Period estimates of 10Period estimates of 10--year survival of patients with year survival of patients with MM by major age groups in defined calendar periods MM by major age groups in defined calendar periods

from 1984from 1984--1986 to 20021986 to 2002--20042004

Brenner et al; Blood 2008; 111:2521-26

Age- and Sex- Incidence Rates per 100 000/year for MM in the South Thames Area (1999-

2000)2000)

60.00 Males

50.00

Females

Females and Males combined

40.00

30.00

te p

er 10

0,000

20.00

10.00

Ra

16-24 25-34 35-44 45-54 55-64 65-74 75-84 85+0.00

Phekoo et al; BJH 2004; 127: 299-304

Age (years)

Current platform Future platform

Platform Mel Pred

MPV (IV)MPV (IV)

MPT

Other alkylating agents

BP

CTD

Platform Dexamethasone

TD

Rd

C. cyclophosphamide; T. thalidomide; V. bortezomib; P. prednisone; M. melphalan; R. lenalidomide; D. low dose dexamethasone; B. bendamustine

MPT vs MP: Meta-analysis of 1685 individual-patient data from 6 randomized trials

PFSOS

1.0

MPMPT

HR=0.67 in favor of MPT, p<0.0001

1.0

M di 39 3

HR=0.83 in favor of MPT, p=0.005*

MPMPT

40.

60.

8 p

ropo

rtio

n MP

Median 20.3 mos (18.8-21.6)

0.6

0.8

Median 32 7 mos

Median 39.3 mos(35.6-44.6)

MP

00.

20.

4Su

rviv

al

Median 14.9 mos (14.0-16.6)

00.

20.

4 Median 32.7 mos (30.5-36.6)

0.0

0 12 24 36 48months

0.0

0 12 24 36 48months

Fayers et al. Blood 2011, accepted for publication 30 May 2011

MP MP vsvs MPTMPT : : PFSPFS and OSand OS

GIMEMA1,2 IFM 99-063 IFM 01-014 NMSG5 HOVON6

PFS (med,mo.)( , )MPMPTP

14.521.80004

1827.5

< 0001

18.524001

1415NS

9*

13< 001P

OS (med,mo.)MPMPT

.0004

47.645

<.0001

3351 5

.001

2944

NS

3229

<.001

3140MPT

P45NS

51.5.0006

44.028

29NS

40.05

* Event-free survival

• In 4/5 studies, MPT was superior to MP in terms of PFS.• In 3/5 studies, MPT was superior to MP in terms of OS.

1. Palumbo et al, Lancet 2006; 367:825-831

2. Palumbo et al. Blood 2008; 112:3107-14

3. Facon et al. Lancet 2007;370:1209-1218

4. Hulin et al. JCO 2009 ;27:3664-3670

5. Waage et al. Blood Epub May 6, 2010

6. Wijermans et al. JCO Epub June 1, 2010

MP vs MPT Studies : Patient characteristics and MPT

regimensGIMEMA1,2 IFM 99-063 IFM 01-014 NMSG5 HOVON6

No.pts (MPT) 331 (167) 447 (125) 232 (113) 363 (182) 333 (165)

Agemedian 72 69 78.5 74.5 (mean) 72range 60-85 65-75 75-89 49-92 NA

WHO 3/4 (%) 5 8 7 30 4

MPT regimenMPT regimenNo. Cycles 6 12 12 Until plateau Until plateauM dosing 4 mg/m2

d1-70.25 mg/kg

d1-40.2 mg/kg

d1-40.25 mg/kg

d1-40.25 mg/kg

d1-5Thal. dosing 100 up to 400 100 up to 400 200

Maintenance + - - + +

1. Palumbo et al, Lancet 2006; 367:825-831

2. Palumbo et al. Blood 2008; 112:3107-14

3. Facon et al. Lancet 2007;370:1209-1218

4. Hulin et al. JCO 2009 ;27:3664-3670

5. Waage et al. Blood Epub May 6, 2010

6. Wijermans et al. JCO Epub June 1, 2010

Len + high-dose Dex vs. Len + low-dose Dexin newly diagnosed patients with myeloma

ECOG E4A03 Trial DesignECOG E4A03 Trial Designin newly diagnosed patients with myeloma

Len. + high-dose Dexx 4 cycles (cycle length: 28 d)

Rev 25 mg/d days 1-21Rev. 25 mg/d, days 1-21 Dex. 40 mg/d, days 1-4, 9-12, 17-20

Newly diagnosed Primary objective

Len. + low-dose Dex

MM patients(n = 445) response rate and toxicity

x 4 cyclesRev. 25 mg/d, days 1-21

Dex. 40 mg/d, days 1, 8, 15, 22

VU University Medical CenterAmsterdam The Netherlands

Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.

High dose dexamethasone results inHigh dose dexamethasone results in early mortality

1.0

0.8RD

Rd

80

100

0.6

0.4urvi

val 3-Year OS rate 75%

RD

Patie

nts

(%)

40

60

0.2

0 0

Su

High-doseLow-dose

Log-rank p = 0.46 Pepe-Fleming p = 0.01

20

0.0

Months24181260

Time (months)

00 6 12 18 24 30 4236

Number at riskHigh-dose 223 179 103 37 0Low-dose 221 192 103 37 0

RD 223 208 195 184 173 123 78 7Rd 222 217 212 201 192 146 83 9


Low dose 221 192 103 37 0 Rd 222 217 212 201 192 146 83 9


ECOG/E4A03 Adverse eventsECOG/E4A03 Adverse events

RD RdType (≥ Grade 3) RD(N=223)

Rd(N=220) P

DVT/PE 26% 12% 0.0003

Infection/Pneumonia 16% 9% 0.04

Cardiac ischaemia 3% 0.5% 0.07

Any non-haem toxicity (Grade ≥ 3) 65% 48% 0.0002

Toxicity of any typeToxicity of any type (Grade ≥ 4) 21% 14% 0.0002

Early deaths (< 4 mo. All pts) 5% 0.5% 0.003



MM-015: phase III trial of MPR vs MP for long-term control in newly diagnosed MM

Randomized, placebo-controlled, double-blind trial in 51 centres in Europe, Australia, and Israel (N = 450)

R

Up to 9 courses in the absence of disease progression or unacceptable adverse events; treatment in 28-day cycles

Melphalan 0.18 mg/kg, days 1–4Melphalan 0.18 mg/kg, days 1–4L lid idL lid id

A

N

D

Patients

with newly diagnosed,

Prednisone 2 mg/kg, days 1–4

Lenalidomide 10 mg/day p.o., days 1–21



LenalidomideLenalidomide

PlaceboPlaceboMelphalan 0.18 mg/kg, days 1–4

P d i 2 /k d 1 4

Melphalan 0.18 mg/kg, days 1–4

P d i 2 /k d 1 4

O

M

I

untreated MM who are

not eligible for t l t





PlaceboPlaceboPrednisone 2 mg/kg, days 1–4




PlaceboPlacebo

Z

A

T

Primary end-point: PFS

a transplant Prednisone 2 mg/kg, days 1 4

Placebo days 1–21

Prednisone 2 mg/kg, days 1 4

Placebo days 1–21I

O

N

Secondary end-points: OS, TTP, ORR, TTR, duration of response, and quality of life

All patients receive VTE prophylaxis with aspirin (75–100 mg/day)Trial NCT00405756. Available from: www.clinicaltrials.gov.

Phase III study: MPR in elderly patientsPhase III study: MPR in elderly patients

MPR+R MPR MP

Patients: n=459, ≥65 years

Median age 71 71 71>75 years 24% 24% 25%

18/33/4 21/31/4

MPR+R MPR MP P (MPR+R

Response data

ISS stage I/II/III 18/33/49

21/31/48 18/31/51

MPR+R MPR MP (vs MP)

ORR 77% 67% 49% <0.001CR 18% 13% 5% <0.001≥VGPR 32% 33% 11% <0.001PR 45% 34% 37% –Median time to firstMedian time to first response 1.9 months 1.9 months 2.8 months <0.001

Palumbo et al. ASH 2009 (Abstract 613)

Progression-Free Survival 65 - 75 Years of Age

100

65 - 75 Years of Age2-Year PFS

Median PFS

MPR R 61% N t h d

75

(%)

HR 0 31

MPR-R 61% Not reachedMPR 27% 14.7 monthsMP 10% 12.4 months

50

Patie

nts

( HR 0.315

Log rank P < .001

0

25

P

HR 0.675

Log rank P = .031

0 5 10 15 20 25 30 35 400

Time (months)No. at Ri kRiskMPR-R 116 91 75 57 31 15 2 – –MPR 116 97 77 31 16 7 – – –MP 116 82 62 29 13 1 – – –

FIRST: lenalidomide + low-dose Dex vs MPT (IFM 07-01)( )

Inclusion criteriaInclusion criteriaLenalidomide 25 mg/day, days 1–21; every 28 daysLenalidomide 25 mg/day, days 1–21; every 28 days

Until PD•Previously untreated MM

•Age 65 years

•Previously untreated MM

•Age 65 years

Dexamethasone* 40 mg/day, days 1, 8, 15, 22; every 28 days


Until PD

Lenalidomide 25 mg/day days 1–21; every 28 daysLenalidomide 25 mg/day days 1–21; every 28 days Eighteen g yor not a

candidate for transplantation

No neuropathy

g yor not a

candidate for transplantation

No neuropathy

Lenalidomide 25 mg/day, days 1 21; every 28 days


Lenalidomide 25 mg/day, days 1 21; every 28 days


g4-week cycles

•No neuropathy of grade > 2

•CLCr > 30 ml/min

•No neuropathy of grade > 2

•CLCr > 30 ml/min

Melphalan* 0.25 mg/kg/day, days 1–4, every 42 days

Prednisone 2.0 mg/kg/day, days 1–4, every 42 days

Thalidomide* 200 mg/day, daily through 42-day cycle

Melphalan* 0.25 mg/kg/day, days 1–4, every 42 days

Prednisone 2.0 mg/kg/day, days 1–4, every 42 days

Thalidomide* 200 mg/day, daily through 42-day cycle

Twelve 6-week cycles

N = 1,590

Centres in EU, Switzerland USA

* In patients older than 75 years: dexamethasone 20 mg/day,

melphalan 0.20 mg/kg/day, thalidomide 100 mg/day.

g y y g y yg y y g y y

Switzerland, USA, and Canada Primary end-point: progression-free

survival

H t d fi ?How to define?

DefinitionsC bidit Comorbidity

FrailtyDisability Disability

Age? Social context?


Whi h i t ?Which scoring system?

Clinical impression/feeling not sufficient?

Karnofsky Performance Score ECOG Performance Score

Quality of Life questionnaire

Prognostic Inflammatory and Nutritional Index (PINI index)

Comprehensive Geriatric Assessment Comprehensive Geriatric Assessment

Do we need an onco-geriatric score or just geriatric score?


Comprehensive Geriatric AssessmentComprehensive Geriatric Assessment (CGA)

Comorbidity Functional status Physical performance Physical performance Cognitive status Psychological status

Nutritional status Nutritional status Medication review Social support

Detects unsuspected conditions that may affect the ability to complete cancer treatment in 50% of patients > 65 yearsHowever laborious process: ~100 minutes


However, laborious process: ~100 minutes

D d ti f th ld lDose recommendations for the elderly


Annual IMWG Summit Meeting. London, UK. June 2011.

Current platform Future platform

Platform Mel Pred

MPV (IV)

Platform Melphalan PrednisoneMP +Carfilzomib (Carmysap) MP +MLN9708 (oral)MPV (IV)

MPT

Other alkylating agents

MP +MLN9708 (oral) MP +pomalidomide (oral)MPV (weekly – sub cutaneous)

Pl tf L l d D thBP

CTD

Platform Len-low dose DexamethasoneCRd / CRP (oral)Rd +Carfilzomib (Weekly)

Platform Dexamethasone

TD

Rd +Bortezomib sub cutaneousRd +HDAC inhibiteur (oral)Rd +MLN9708 (oral)

Rd Rd +Elotuzumab (IV)Maintenance to develop

C. cyclophosphamide; T. thalidomide; V. bortezomib; P. prednisone; M. melphalan; R. lenalidomide; D. low dose dexamethasone; B. bendamustine

F t i k t tifi tiFuture risk stratification

IVSC VTE PNP

CytoCGA

Patients older than DM Cardiac History of SC

oralVTE PNP

ygenetics

CGA 75 years of age

complicated diseasey

SPM

CURRENTLY USED FUTURE USECURRENTLY USED FUTURE USE


Thank you very much

Documents

Management of Multiple Myeloma in the ElderlyManagement of Multiple Myeloma in the Elderly Xavier Leleu ServicedesMaladies du Sang Hôpital Huriez, CHRU, Lille, France INSERM U837,