Impact of Novel Therapies In Multiple Myeloma

Jean-Luc Harousseau

Intergroupe Francophone du Myélome

Impact of novel agents in younger patients

VAD TD VD RD TAD PAD VTD

Summary of novel agent induction trials (randomized studies)

Post-inductionPost-transplant

≥ VGPR rates post-induction and post-transplant

Harousseau et al. ASH/ASCO symposium during ASH 2008Rajkumar et al. ASCO 2008 (Abstract 8504); ASH/ASCO symposium during ASH 2008

Lokhorst et al. Haematologica 2008;93:124–7Sonneveld et al. ASH 2008 (abstract 653); IMW (abstract 152) Cavo et al. ASH 2008 (abstract 158); IMW 2009 (abstract 451)

*Post-transplant data not available

15-16%

30-35%

39% 33% 45%62%

42%

44-50%45-55%

57%49%

71%

76%

*

IFM 2005-01Impact of achieving at least VGPR after

induction ≥ VGPR vs PR

β2 mic (3mg/L)

t(4;14) ± del (17p)

≥ VGPR vs PR

RR

1.54

1.32

1.44

p. Value

0.01

0.23

0.038

median

≥ VGPRN=117

41m

PRN=145

33m

PFS

p=0.0015

VAD vs Vel/Dex induction for t(4;14) patients OS

treatment VAD Vel/Dex pvalue (logrank)

Patients 106 107

0.0004Deaths 70 20

Median OS (years) [IC 95%]

2.87[1.76 ; 3.48]

---*[3.60 ; ---*]

Vel/Dex

VADp=.0004

t(4;14) with BortezomibEFS of 507 patients treated with Vel/Dex induction

t(4 ;14) neg pos pvalue (logrank)

Patients 396 106

0.0178Relapses 141 43

Median EFS (years) [IC 95%]

2.90[2.74 ; 3.53]

2.32[1.49 ; 2.95]

p<.02

t(4;14) pos

t(4;14) neg

Avet-Loiseau et al., JCO online

Impact of Novel Agentsin the ASCT paradigm

Induction Treatment • Impact of CR/VGPR after Induction• Induction with BTZ appears to partly overcome poor prognosis

related to t(4,14)• The impact of 3-4 cycles of Len/Dex is less clear (no randomized

study)• Triple combinations appears more effective

( VCD,PAD, VTD…VRD) with VGPR rates up to50% before and 75% after ASCT

VTD is currently the best induction regimen andits neurotoxicity is reduced by lower doses (Moreau ASCO 2010)

Stage 1-3, <70 yearsTherapy at least 2 cycles Stable Disease or better≤1 year from Rx initiation2 x 106 CD34 cells/kg

Placebo

Lenalidomide*10 mg/d with ↑↓ (5–15 mg)

RestagingDays 90–100

Registration

CALGB trial

CRPRSD

Stratification based on Diagnostic B2M and IMiD Use during Induction

Mel 200

ASCT

*

Randomization

Median Follow up is 12 monthsCALGB 100104, Nov 2009

Median TTP: Not yet reached

Median TTP 25.5 mo

IFM 2005-02: Study design

Arm A=Placebo(N=307)

until relapse

Patients < 65 years, with non-progressive disease, ≤ 6 months after ASCT in first line

Arm B=Lenalidomide

(N=307)10-15 mg/d until

relapsePrimary end-point: PFS.Secondary end-points: CR rate, TTP, OS, feasibility of long-term lenalidomide….

bConsolidation:Lenalidomide alone 25 mg/day p.o.

days 1-21 of every 28 days for 2 months

Randomization: stratified according to Beta-2m, del13, VGPR

IFM 2005-02 : PFS from randomization0.

000.

250.

500.

751.

00

0 6 12 18 24 30 36

Placebo Revlimid

p<10-7

P < 10-7

Impact of Novel Agentsin the ASCT paradigm

Best Intensive Approach

• Induction- 3 or 4 courses of VTD (RVD ?)

• Maintenance with Lenalidomide

Questions for the near future

• Will longer PFS with lenalidomide maintenance translate into longer OS ? Survival after relapse ?

• Optimal duration of maintenance ?- until progression- fixed duration- until best response (immunophenotypic remission?)

• Role of consolidation ?- maintenance with/without consolidation- novel agents or second TX ?

PRE POST p value

CR (IF -) 13 % 19 % <0.0001

≥ VGPR 58 % 68 % <0.0001

ATTAL ASCO 2010

IFM 2005 02 : Response during consolidation(n= 572)

Consolidation with VTD• Patients: (n=39) with ≥VGPR after ASCT• Treatment:

– 4 cycles VTD, started within 6 months• Bortezomib: 1.6 mg/m2, days 1, 8, 15, 22• Thalidomide: initial dose 50 mg/day, with increments up to 200 mg• Dex: 20 mg/day, days 1-4, 8-11, 15-18

• Results: at 32 month median follow up CR increased from 15% post-auto to 49% post-conso, MR from 3% to 18%

Ladetto et al. JCO 2010

• Six patients achieved molecular remission; none had clinical relapse

• 50 month PFS: 100% for patients with MR vs 62% for patients with no MR

SCHEMA: BMT CTN

Register

and Randomize

MEL

200mg/m2

Lenalidomide

Maintenance

VRD x 4

MEL

200mg/m2

Lenalidomide Maintenance

Lenalidomide

Maintenance

No Consolidation

Questions for the near future

Key Question• With novel agents (MPT,MPV,Rd,RVD) it is

now possible to achieve up to 30%CR and up to 70% VGPR

• In published trials median PFS are comparable to those achieved in the past with ASCT (24-28 months)

• With prolonged treatment the CR/VGPR rate continues to increase (especially with Len which is well tolerated and administered orally)

Phase I/II study on RVD innewly diagnosed MM

• Overall response rate (66pts) 100%• CR 29 % (37 % for 35pts in the Phase II part)• CR+ VGPR 67% (74% in Phase II part)• 2-yr PFS 68% (no difference in 41 pts with ASCT) • 2-yr OS 95%

Up to eight 21-day cycles *

1 2 4 5 8 9 11 12 14 21

Lenalidomide

Bz Bz Bz Bz

Dex Dex Dex Dex

MPD Len 25mg Vel 1.3mg Dex 20mg in Phase II (35 pts)

ASCT plus novel agentsPFS

0

10

20

30

40

50

60

70

80

90

100

IFM 90MRC7LdMPT FaconMPT PalumboMPVRVDGIMEMA

Attal NEJM 1996. Facon Lancet 2007. Child NEJM 2003. Palumbo Blood 2008. San Miguel NEJM 2008. Rajkumar lancet 2010

IFM/DFCI Trial

VRD x 3

SC collection

VRD x 5 Mel 200 + ASCT

VRD x 2

Rev 1 year Rev 1 year

(HDM + ASCT atrelapse)

Impact of novel agents in elderly patients

Frontline therapy in elderly patients

• MP is no longer the standard of care

• New standards- MPT > MP (1,2,3)

- MPV > MP (4)

- Len/dex > Len /dex (5)

• Maintenance therapy prolongs PFS- Low-dose lenalidomide (MM015 Palumbo ASH 2009)- Velcade-based combinations (Mateos ASH 2009, BoccadoroASCO 2010)

• Weekly velcade is better tolerated than bi-weeklyVMPT-VT vs VMP (Mateos ASH 2009, Boccadoro ASCO 2010)

Facon Lancet Oncol 2007, Palumbo Blood 2008, Hulin JCO 2009San Miguel NEJM 2008, Rajkumar Lancet Oncology 2010

MPR-R vs MPR47% reduced risk in PFS

MPR-RMPR

Median PFSNot reached13.2 months

HR 0.530 95% CI 0.350–0.802Log-rank p = 0.002

100

75

50

25

00 5

PFS duration (months)10 15 20 25 30

Patie

nts

with

out e

vent

(%)

Number at riskMPR-R 152 115 70 36 11 2 1MPR 153 122 78 20 5 1 1 Palumbo A, et al. Blood. 2009;114:[abstract 613]; updated data presented at ASH 2009.

VMPT-VT vs VMP

VMP VMPT-VT P-value

Nb of pts 257 254

Med age 71 71

CR 24% 38% 0.008

CR+VGPR 50% 59% 0.03

3-yr PFS 40% 54% 0.006

3-yr OS 84% 86% 0.6

Frontline therapy in elderly patients

• MP is no longer the standard of care

• New standards- MPT > MP (1,2,3)

- MPV > MP (4)

- Len/dex > Len /dex (5)

• Maintenance therapy prolongs PFS- Low-dose lenalidomide (MM015 Palumbo ASH 2009)- Velcade-based combinations (Mateos ASH 2009, BoccadoroASCO 2010)

Questions for the near future

- Will better PFS obtained with maintenance translate into longer OS ?

- Is maintenance necessary after all induction treatments (MPT, MPV, Ld) ?

- Optimal duration of maintenance ?- Role of alkylating agents

MPT 12 cycles MP at 6-week interval + Thal at 200 mg/day, stopped at end of MP

Rev + low-dose Dex.Rev 25mg/day, days 1-21 ; Dex 40

mg/day, days 1,8,15, 2218 cycles at 4-week interval

Rev + low-dose Dex.same schedule as above

Given until progessive disease

N = 1590 Primary endpoint:

PFS

1

1

1

MPT vs Revlimid-low dose Dexamethasone in Newly Diagnosed Myeloma Patients, Aged >65 Years

Phase III international study / MM-020, IFM 2007-01, FIRST study

General Questions

1) Role of novel agents in poor-risk cytogenetics

General Questions

1 Role of novel agents in poor-risk cytogenetics2 Which level of CR is needed to achieve long-term

remission?

78726660544842363024181260

1,0

,9

,8

,7

,6

,5

,4

,3

,2

,1

0,0

Impact of immunophenotypingat 3 months post-ASCTR

elap

se-fr

ee s

urvi

val

— <0.01% MM-PC

— ≥ 1% MM-PC

Months from immunophenotypical analysis

Updated Paiva et al Blood 2008

RFS

p=0.0001

40m

23m

— 0.01% to 1% MM-PC NR

General questions

1 Role of novel agents in poor-risk cytogenetics2 Which level of CR is needed to achieve long-term

remission?3 Which treatment at relapse when novel agents have

been used upfront ?

Pomalidomide

Lenalidomide

NNHO O

O

NH2

Structurally similar but functionally different, both qualitatively and quantitatively

NN

O

O

O

O

Thalidomide Pomalidomide (CC-4047)

N

O

O

NH

O

O

NH2

Teo SK, et al. Drug Discov Today. 2005;10:107-14.

Phase II of Pom/Dex in patients refractory to Lenalidomide

• 35 patients - Median age 62 y - 15 pts with mSMART high-risk- Median number of prior Tt 6- 100% Len , 100% Btz , 77% SCT

• Best response- VGPR 5 (14%)- PR 6 (17%)- MR 8 (23%)

• Median PFS 8 months Lacy M ASCO 2010

Carfilzomib

Carfilzomib is the first in a new class of selective and irreversible proteasome inhibitors that are associated with prolonged target suppression, improved antitumor activity

and low neurotoxicity

Tetrapeptide

0

50

100 CRVGPRPRMRSD

ORR:57%

ORR:18%

ORR:35.5%

AllSubjects(N = 31)

BortezomibNaive

(N = 14)

BortezomibExposed(N = 17)

PDNE (TLS)

14%

29%

36%

14%

7%

6%

18%

18%

59%45%

26%

6.5%3%

10%

3%

6.5%

% o

f sub

ject

s

90% of responses occurred by the end of Cycle 2

Phase II study of Carfilzomib

0

50

100 CRVGPRPRMRSD

ORR:57%

ORR:18%

ORR:35.5%

AllSubjects(N = 31)

BortezomibNaive

(N = 14)

BortezomibExposed(N = 17)

PDNE (TLS)

14%

29%

36%

14%

7%

6%

18%

18%

59%45%

26%

6.5%3%

10%

3%

6.5%

% o

f sub

ject

s

90% of responses occurred by the end of Cycle 2

PX-171-004: Response Summary

37

Panobinostat + Bortezomib Best ResponseDose escalation B2207 study in Relapsed MM pts

Clinical benefit (≥ MR) in 13/17 at cohort 3 and 6 levelN

umbe

r of p

atie

nts

PAN mgBTZ mg/m2

101.0

20 1.0

201.3

301.3

251.3

201.3

PAN panobinostat; BTZ bortezomib

CR, IF-negative CR; VGPR, very good PR; PR, partial response; MR, minor response; SD, stable disease; PD, progress. disease; NA, no assessment

0123456789

10

Co.1 Co. 2 Co. 3 Co. 4 Co. 5 Co. 6

NAPDSDMRPRVGPRCR

Panobinostat + Bortezomib EfficacyResponses including in Bortezomib-Refractory Patients

0102030405060708090

100

All (n=47) BTZ refractory (n=15)

MR

PR

VGPR

CR

Res

pons

e ra

te (%

)

39

Total Patients (%)Lenalidomide-Naїve

Patients (%)

Total (intent to treat)

28 22

ORR (≥ PR) 23 (82) 21 (95)

CR 1 (4) 1 (5)

VGPR 7 (25) 6 (27)

PR15 (54) 14 (64)

SD 4 (14) 1 (5)

PD 1 (4) 0

Phase 1b Elotuzumab plus Len/dexLonial ASCO 2010

General questions

1 Role of novel agents in poor-risk cytogenetics2 Which level of CR is needed to achieve long-term

remission?3 Which treatment at relapse when novel agents have

been used upfront ?4 What is the best strategy ?

- all active agents upfront ?- sequential use of active agents ?

General Questions

SEARCHING FOR CURE …

General Questions

SEARCHING FOR CURE

… OR TREATING MM LIKE A CHRONIC DISEASE

General Questions

SEARCHING FOR CURE

… OR TREATING MM LIKE A CHRONIC DISEASE

The answer to this question may depend on your definition of cure !!