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Transcript of Thierry FACON Lille University Hospital, Lille, France On behalf of IFM Strategies for front-line...
Thierry FACON
Lille University Hospital, Lille, France
On behalf of IFM
Strategies for front-line treatment of Strategies for front-line treatment of Multiple MyelomaMultiple Myeloma
1962 1983 1986 1996 1999 2000+
BisphosphonatesBisphosphonates
Oral melphalan and prednisone
Oral melphalan and prednisone
VADVAD
High-dose dexamethasone
High-dose dexamethasone
High-dose therapy with autologous stem cell
support
High-dose therapy with autologous stem cell
support
Proteasome inhibitors
(Bortezomib)Other immuno-
modulatory agents(Lenalidomide)
Proteasome inhibitors
(Bortezomib)Other immuno-
modulatory agents(Lenalidomide)
Historical Perspective of Multiple MyelomaHistorical Perspective of Multiple Myeloma
High-dose melphalan
1984
Thalidomide
ABMTABMT
Period estimates of 10-year survival of patients with Period estimates of 10-year survival of patients with MM by major age groups in defined calendar periods MM by major age groups in defined calendar periods
from 1984-1986 to 2002-2004from 1984-1986 to 2002-2004
Brenner et al; Blood 2008; 111:2521-26
Front-line treatment in multiple myeloma Front-line treatment in multiple myeloma patients not eligible for stem cell patients not eligible for stem cell
transplantationtransplantation
Age- and Sex- Incidence Rates per 100 000/year for MM in the South Thames Area (1999-
2000)
Phekoo et al; BJH 2004; 127: 299-304
16-24 25-34 35-44 45-54 55-64 65-74 75-84 85+
60.00
50.00
40.00
30.00
20.00
10.00
0.00
Rat
e pe
r 100
,000
Age (years)
MalesFemalesFemales and Males combined
0.0
0.2
0.4
0.6
0.8
1.0
surv
ival pro
port
ion
814 621 480 289 143trt = MPT868 654 465 265 122trt = MP
Number at risk
0 12 24 36 48months
trt = MP
trt = MPT
Overall survival - All
Median 32.7 months (30.5-36.6)
Median 39.3 months(35.6-44.6)
HR=0.83 in favour of MPT, P=.005Cox model for treatment, with analysis sratified by study using a random effects (frailty) model
MRC Myeloma IX non intensive pathwayMRC Myeloma IX non intensive pathwayOlder less fit patients (approximately > 65 y)Older less fit patients (approximately > 65 y)
Morgan et al. Blood 2007; 110:1051a(abs 3593)
Morgan et al. Blood 2008; 112:245 (abs 656)
VISTA: VELCADE as Initial Standard Therapy in multiple VISTA: VELCADE as Initial Standard Therapy in multiple myeloma: Assessment with MPmyeloma: Assessment with MP
• Randomized, international, phase III trial of VMP vs MP in 682 previously untreated patients with symptomatic MM who were not candidates for HDT-ASCT due to age (≥65 yrs) or co-morbid conditions
• Stratification: β2-microglobulin, albumin, region
VMPCycles 1–4Bortezomib 1.3 mg/m2 IV: d 1,4,8,11,22,25,29,32Melphalan 9 mg/m2 and prednisone 60 mg/m2: d 1–4
Cycles 5–9Bortezomib 1.3 mg/m2 IV: d 1,8,22,29Melphalan 9 mg/m2 and prednisone 60 mg/m2: d 1–4
MPCycles 1–9 Melphalan 9 mg/m2 and prednisone 60 mg/m2: d 1–4
RANDOMIZE
9 x 6-week cycles (54 weeks) in both arms
• Primary end point: TTP
• Secondary end points: CR rate, ORR, time to response, DOR, time to next therapy (TNT), OS, QoL (PRO)
San Miguel et al. N Engl J Med 2008;359:906–17
VISTA:Efficacy dataVISTA:Efficacy data
ORR: VMP 71%, MP 35% CR: VMP 30%, MP 4%
Time to progression Overall survival
Pat
ient
s w
ithou
t ev
ent
(%)
VMP: 24.0 monthsMP: 16.6 monthsP < .000001
0
20
40
60
80
100VMPMP
Time (months)
• Only 5% “true” non-responders• 43% of MP patients received bortezomib upon progression• 3-y OS VMP 68.5% vs MP 54%, median OS VMP not reached vs MP 43.1 mo.
after a median FU 36.7 mo. Mateos et al.JCO,2010;28:2259-2266
Median follow-up: 25.9 months3-year OS: VMP: 72% MP: 59%P = .0032
VMPMP
Time (months)0 3 6 9 12 15 18 21 24 27
0
20
40
60
80
100
0 4 8 12 16 20 24 28 32 36 40
MPV, an evolving standard of careFrom twice weekly to once weekly regimens
Spanish MPV; Mateos et al.Lancet Oncology 2010 Epub August 24.
Induction 6 cycles; one 6-week cycle, bortezomib 2x weekly, five 5-week cycles, bortezomib 1x weekly. Maintenance VT or VP
Italian MPV; Palumbo et al.JCO 2010 Epub October 12.Bringhen et al.Blood 2010 Epub August 31.
Induction Nine 5-week cycles, bortezomib 1x weekly.No maintenance in MPV but VT maintenance in VMPT
One-weekly schedule reduces the incidence of PN and decreases the rate of discontinuation without any reduction in efficacy
Randomized, placebo-controlled, double-blind trial in 51 centres in Europe, Australia, and Israel (N = 450)
Primary end-point: PFS
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)
Up to 9 courses in the absence of disease progression or unacceptable adverse events; treatment in 28-day cycles
Trial NCT00405756. Available from: www.clinicaltrials.gov.
Patientswith newly diagnosed,untreated
MM who arenot eligible for a
transplant
Melphalan 0.18 mg/kg, days 1–4Prednisone 2 mg/kg, days 1–4Lenalidomide 10 mg/day p.o., days 1–21
Melphalan 0.18 mg/kg, days 1–4Prednisone 2 mg/kg, days 1–4Lenalidomide 10 mg/day p.o., days 1–21
Melphalan 0.18 mg/kg, days 1–4Prednisone 2 mg/kg, days 1–4Placebo days 1–21
Melphalan 0.18 mg/kg, days 1–4Prednisone 2 mg/kg, days 1–4Placebo days 1–21
LenalidomideLenalidomide
PlaceboPlaceboMelphalan 0.18 mg/kg, days 1–4Prednisone 2 mg/kg, days 1–4Lenalidomide 10 mg/day p.o., days 1–21
Melphalan 0.18 mg/kg, days 1–4Prednisone 2 mg/kg, days 1–4Lenalidomide 10 mg/day p.o., days 1–21
PlaceboPlacebo
MM-015: phase III trial of MPR vs MP for long-term control in newly diagnosed MM
RANDOMIZATION
0 5 10 15 20 25 30 35 400
25
50
75
100
Time (months)
Pat
ient
s (%
)
Progression-Free SurvivalAll Patients
HR 0.423 Log rank P < .001
HR 0.850Log rank P = .307
No. at Risk
MPR-R 152 115 89 66 35 17 2 – –MPR 153 120 90 36 17 7 – – –MP 154 112 85 43 19 2 – – –
2-Year PFS Median PFS
MPR-R 55% Not reached
MPR 24% 14.1 months
MP 16% 13.0 months
0 5 10 15 20 25 30 35 400
25
50
75
100
Time (months)
Pat
ient
s (%
)
Progression-Free Survival 65 - 75 Years of Age
HR 0.315 Log rank P < .001
HR 0.675Log rank P = .031
No. at Risk
MPR-R 116 91 75 57 31 15 2 – –MPR 116 97 77 31 16 7 – – –MP 116 82 62 29 13 1 – – –
2-Year PFS Median PFS
MPR-R 61% Not reached
MPR 27% 14.7 months
MP 10% 12.4 months
Treatment – Initial 9 cyclesTreatment – Initial 9 cycles
MPRa MP
Discontinuation rateb, %
65 - 75 years of age 17 10
> 75 years of age 34 16
Cumulative dose intensityc, %
65 - 75 years of age 88 97
> 75 years of age 56 97
a MPR includes MPR-R and MPR for the initial 9 cycles.b Discontinuation due to AEs or withdrawal of consentc Cumulative dose intensity of melphalan and lenalidomide/placebo
Len. + high-dose Dexx 4 cycles (cycle length : 28 d)
Rev. 25 mg/d, days 1-21 Dex. 40 mg/d, days 1-4, 9-12, 17-20
Len. + low-dose Dexx 4 cycles
Rev. 25 mg/d, days 1-21 Dex. 40 mg/d, days 1, 8, 15, 22
ECOG E4A03 Trial DesignECOG E4A03 Trial Design
Newly diagnosedMM patients
(n = 445)
Primary objective:response rate and toxicity
Len + high-dose Dex vs Len + low-dose DexLen + high-dose Dex vs Len + low-dose Dexin newly diagnosed patients with myelomain newly diagnosed patients with myeloma
Rajkumar et al. Lancet Oncology 2010;11:29-37
ECOG/E4A03 Adverse eventsECOG/E4A03 Adverse events
Type (≥ Grade3) RD
(N=223)Rd
(N=220)P
DVT/PE 26 % 12 % 0.0003
Infection/Pneumonia 16 % 9 % 0.04
Cardiac ischemia 3 % 0.5 % 0.07
Any non Hem toxicity (Grade ≥ 3)
65 % 48 % 0.0002
Toxicity of any type (Grade ≥ 4)
21 % 14 % 0.0002
Early deaths (< 4 mo. All pts) 5 % 0.5 % 0.003
Rajkumar et al. Lancet Oncology 2010;11:29-37
FIRST: Lenalidomide + LD-dex vs. MPT(IFM 07-01)
RR
LD (28-day cycle)
Oral dexamethasone on day 1, 8, 15, 22
Oral lenalidomide once daily on days 1-21
LD (28-day cycle; up to 18 cycles)
Oral dexamethasone on day 1, 8, 15, 22
Oral lenalidomide once daily on days 1-21
MPT (6-wk cycle; up to 12 cycles)
Oral melphalan and prednisone on days 1-4
Oral thalidomide once daily on days 1-42
MMTreatment until
progressive disease (PD)
• Pts: Previously untreated MM pts >65 yrs old or not a candidate for ASCT
• Primary Endpoint: Progression-free survival (PFS)
Treatment selection: elderly patients
Treatment should be selected based on:
Biological age, comorbidities, overall clinical impression
Dose adjustments:
Standard schedules for fit patients requiring quick relief from symptoms
Less intense treatment approach for frail patients and those with comorbidities (heart, lung, kidney, liver, diabetes) or aged >75 years
Need to do what is best for an average elderly MM patient
Newly diagnosed frail elderly patients with MMNewly diagnosed frail elderly patients with MM
Symptomatic treatments remain essential
Highest doses of drugs are not optimal
Dexamethasone
MP+ studies
Avoid excessive toxicity
careful treatment monitoring
dose reduction guidelines
particularly in early stages of treatment
Need to consider Quality of life as factor
New options for patients eligible for New options for patients eligible for
transplantationtransplantation
Induction regimens in the era of novel agentsInduction regimens in the era of novel agents
IFM 2005/01 GIMEMA HOVON-GMMG PETHEMA/GEM
Harousseau
VD vs VAD
(n=197 vs 184) (ASH
2008, joint
ASH/ASCO
symposium)
Cavo
VTD vs TD
(n=226 vs 234)
(IMW 2009;
Abstract 451)
Sonneveld
PAD vs VAD
(n=150 vs 150)
(IMW 2009;
Abstract 152)
Rosinol
VTD vs VBCMP/VBAD+V vs TD
(n=61 vs 58 vs 61)
(IMW 2009; Abstract 160)
Results post-ASCT
CR 18% vs 10%* 41% vs 20%* 15% vs 4%* 48% vs 43% vs 23%
CR + nCR 40% vs 22%* 54% vs 29%* n/a n/a
≥VGPR 61% vs 44%* 75% vs 53%* 59% vs 47% n/a
CR + PR 91% vs 91% n/a 92% vs 77%* 77% vs 70% vs 62%
Summary of post-transplant results in Phase III Summary of post-transplant results in Phase III bortezomib trialsbortezomib trials
Bortezomib induction regimen results in high CR/nCR and VGPR rates post-transplant
*significantly different
n/a: not available
Phase III VD vs vTD as induction prior to ASCTPhase III VD vs vTD as induction prior to ASCTIFM 2007/02IFM 2007/02
Harousseau et al. ASH 2009 (Abstract 354)
RANDOMIZE
Bortezomib 1.3 mg/m2 d1, 4, 8, 11Dex 40 mg d1–4 and 8–11 (c3+4 only)
Bortezomib 1.0 mg/m2 d1,4,8,11Thal 100 mg dailyDex 40 mg d 1–4 and 8–11 (c3+4 only)
VD
vTD
4 x 21-day cycles
Patients with <PR after cycle 2 could have bortezomib increased to 1.3 mg/m2 and thal increased to 200 mg in the absence of PN
Stratified by β2M and del(13) by FISH
Primary Objective: Induction CR rate
Secondary Objectives: ≥VGPR, ≥PR, toxicity (including PN)
FISH, fluorescent in situ hybridization
IFM 2007/02: VD vs vTD as induction IFM 2007/02: VD vs vTD as induction treatment prior to ASCT treatment prior to ASCT
Harousseau et al. ASH 2009, abs 354Harousseau et al. ASH 2009, abs 354
• 205 patients from Mar. 2008 to Jan. 2009 (191 pts evaluable)
vTD should be considered as a new standard for induction treatment prior to ASCT
Response (%)
VD vTD
CR 12 14
VGPR* 36 50
PR 81 91
*P=0.047
Toxicity (%)
VD vTD
Treatment reduction
17 7
PN gr 2* 28 14
PN gr 3 6 2
*P=0.02
Phase I/II: bortezomib, lenalidomide, dex (VRD) Phase I/II: bortezomib, lenalidomide, dex (VRD) in newly diagnosed MMin newly diagnosed MM
CR/nCR (%) ≥VGPR (%) ≥PR (%)
All patients (n=66)
Response at cycle 4 6 11 74
Response at cycle 8 23 53 95
Best response 39 67 100
• TreatmentTreatment– Up to 8 3-week cycles: Bortezomib 1.0/1.3 mg/mUp to 8 3-week cycles: Bortezomib 1.0/1.3 mg/m22, Len 15–25 mg, Dex 40/20 mg , Len 15–25 mg, Dex 40/20 mg
• ResultsResults
• Median follow-up: 21 months• Median PFS not reached
• Estimated 18-month PFS rate: 75%• No difference in PFS for pts
undergoing ASCT or not• Median OS not reached
• Estimated 18-month OS rate: 97%
• Most common AEs: • Sensory PN (80%), fatigue (64%),
constipation (61%), edema limb (45%), muscle pain (44%)
• Grade 3 PN: 7%, no grade 4• Overall rate of DVT/PE: 6%• No treatment-related mortality
Richardson et al. Blood 2010;116;679-686
Post-Transplant MaintenancePost-Transplant Maintenance
• Transplant settingTransplant setting 5/5 studies showed significant improvement in PFS5/5 studies showed significant improvement in PFS 2/5 studies showed significant improvement in OS2/5 studies showed significant improvement in OS
• Non-transplant settingNon-transplant setting 2/2 studies showed significant improvement in PFS2/2 studies showed significant improvement in PFS No significant improvement in OSNo significant improvement in OS
Thalidomide maintenance studies / SummaryThalidomide maintenance studies / Summary
ConsiderationsConsiderations
- Short survival following relapse in some studies
- Worse outcome in patients with poor cytogenetics
IFM 2005-02: IFM 2005-02: Lenalidomide as maintenance therapy Lenalidomide as maintenance therapy After ASCT for MMAfter ASCT for MM
Lenalidomide 10 -15 mg/day p.o., continuous dosing
until relapse
Lenalidomide 10 -15 mg/day p.o., continuous dosing
until relapse
Patients < 65 years, with non-progressive disease, 6 months after ASCT in first line
Placebo until relapsePlacebo until relapse
Primary end-point : PFSSecondary end-points: CR rate, OS, feasibility of long-term lenalidomide.
Ongoing phase III randomized, placebo-controlled trial
ConsolidationLenalidomide 25 mg/day p.o., days 1-21 of
every 28 days for 2 months
ConsolidationLenalidomide 25 mg/day p.o., days 1-21 of
every 28 days for 2 months
RandomizeRandomize
IFM 2005-02 : PFS from randomization 0.0
00.2
50.5
00.7
51.0
0
0 6 12 18 24 30 36
Placebo Revlimid
p<10-7
P < 10-7
Lenalidomide
Placebo
Randomization
MM Stage II or III, Age 18–65
CAD + GCSF
3 x VAD
MEL 200 + PBSCT
Depending on local
policy for patients PR MEL 200 + PBSCT
Thalidomide 50 mg/day for
2 years maintenance
Allogeneic TxAllogeneic Tx
HOVON 65 MM / GMMG-HD4HOVON 65 MM / GMMG-HD4
CAD + GCSF
3 x PAD
MEL 200 + PBSCT
Depending on local policy for patients
PR MEL 200 + PBSCT
Bortezomib 1.3 mg/m2/2 weeks for 2 years maintenance
Accrual goal: 800 patients
IFM 2009/ DFCI TrialIFM 2009/ DFCI Trial
Major question: Can early SCT prolong EFS of at least 9 months? (1000 pts)
VRD x 3
SC collection
VRD x 5
Rev maintenance
(HDM + ASCT at relapse)
Mel 200 + ASCT
VRD x 2
Rev maintenance
Jean-Paul FermandPhilippe MoreauThierry Facon