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GINNA LAPORT, MD Palo Alto, USA • Professor, Blood and Marrow Transplantation (BMT) at Stanford University School of Medicine • Dr. Ginna Laport, MD is also Director of Clinical Research and the Biostatistical Core of the BMT Division. She was previously a faculty member in the Division of Hematology/Oncology at the University of Pennsylvania and at the University of Chicago. Dr. Laport is the current Chair of the Steering Committee of the BMT Clinical Trials Network and is a member of the Lymphoma Steering Committee of the National Cancer Institute. She is co-chair of the Lymphoma Working Committee of the Center for International Blood and Marrow Transplant Research (CIBMTR) and is a member of the Executive Committee of the American Society for Blood and Marrow Transplantation.
Transcript of 4 ginna laport
GINNA LAPORT, MDPalo Alto, USA
• Professor, Blood and Marrow Transplantation (BMT) at Stanford University School of Medicine
• Dr. Ginna Laport, MD is also Director of Clinical Research and the Biostatistical Core of the BMT Division. She was previously a faculty member in the Division of Hematology/Oncology at the University of Pennsylvania and at the University of Chicago. Dr. Laport is the current Chair of the Steering Committee of the BMT Clinical Trials Network and is a member of the Lymphoma Steering Committee of the National Cancer Institute. She is co-chair of the Lymphoma Working Committee of the Center for International Blood and Marrow Transplant Research (CIBMTR) and is a member of the Executive Committee of the American Society for Blood and Marrow Transplantation.
Hematopoietic Cell Transplantation for Multiple Myeloma: Optimal Timing
Ginna G. Laport, MDProfessor of Medicine
Division of Blood and Marrow TransplantationStanford University School of Medicine
• Current Trends in Autologous SCT
• Transplant vs No Transplant
• Optimal Induction Regimen for Transplant-
Eligible Patients
– Depth of Response
• Maintenance Therapy after SCT
Outline
Multiple Myeloma
Current trends in the role of hematopoietic cell
transplantation in the era of novel agents
Trends in Autologous HCT for Myeloma in Europe
0
5000
10000
15000
20000
25000
30000
1991-1995 1996-2000 2001-2005 2006-2010
Auner HW et al. Bone Marrow Transplant 2014
Nu
mb
er
of
Tra
nsp
lan
ts
Time Period
0
500
1000
1500
2000
2500
3000
3500
4000
1991-1995 1996-2000 2001-2005 2006-2010
65-69
>70
Trends in Autologous HCT for Myeloma in Europe: Elderly Patients
Nu
mb
er
of
Tra
nsp
lan
ts
Time Period
> 70 years
Autologous HCT in Europe, 1991-2010:Overall Survival
Auner HW et al. Bone Marrow Transplant 2014;
Months after Transplant
65 – 69 years
ASCT vs Conventional Chemotherapy: Results of Randomized Studies
Patients(n)
CR(%)
EFS(months)
OS(months) P Value
IFM90[1] CTAuto Tx
100100
522
1827
37NR
0.03
MAG91[2] CTAuto Tx
9694
46
1925*
4848
MRC7[3] CTAuto Tx
200201
844
2032
42.354.1
0.03
IMMSG[4] CTAuto Tx
9995
625
1628
4358+
<0.001
PETHEMA[5] CTAuto Tx
8381
1130
3342
6661
1. Attal M et al. N Engl J Med. 1996;335:91.2. Fermand JP et al. J Clin Oncol. 2005;23:9227.
3. Child A et al. N Engl J Med. 2003;348:1875.4. Palumbo A et al. Blood. 2004;104:3052.
5. Blade J et al. Blood. 2005;106:3755.
*P=0.07
CT = chemotherapy
Problem
All these studies are old. None include novel agents such
IMiDs or proteasome inhibitor therapy
R
VD ± DCEP ASCT1 ± ASCT2
± Len cons. Len maint.
VAD ± DCEP ASCT1 ± ASCT2
± Len cons. Len maint.
IFM 2005-1
R
PAD ASCT1 ± ASCT2
Bort maint.
VAD ASCT1 ± ASCT2
Thal maint.
HOVON-65/GMMG-HD4
R
VTD ASCT1 + ASCT2
+ VTD cons. Dex maint.
TD ASCT1 + ASCT2
+ TD cons. Dex maint.
GIMEMA MM-BO2005
R
VTD ASCT1
CHT + Bort ASCT1
PETHEMA GEM05MENOS65
TD ASCT1 R Thal
VT
IFN
Meta-Analysis: Phase 3 Studies Comparing Bortezomib-
Based vs Nonbortezomib-Based Induction Before
Autologous SCT
Sonneveld P, et al. J Clin Oncol 2013;31:3279
100
80
0
Progression-Free Survival
20
60
Time (months)
12 24 36 42 48 54 60
p=0.0001
A
40
6 18 30
Non-bortezomib
based
Bortezomib based
100
80
0
Overall Survival
20
60
Time (months)
12 24 36 42 48 54 60
p=0.0402
B
40
6 18 30
Non-bortezomib based
Bortezomib based
Meta-Analysis: Phase 3 Studies Comparing Bortezomib-
Based vs Nonbortezomib-Based Induction
Before Autologous SCT
Sonneveld P, et al. J Clin Oncol 2013;31:3279
MM06-04-12_1.ppt
Effect of Pre-transplant Salvage Therapy Prior to Autologous Transplant
in Patients Not Responding to Initial Induction for Multiple Myeloma (MM)
.
Vij R, et al. Biol Bone Marrow Transplant (in press 2015)
Methods (1995 – 2010)
< PR to
induction
Salvage
Chemotherapy
Autologous
Transplant
Diagnosis and
Initial Induction
Autologous
Transplant
12 months from diagnosis to AHCT
Salvage Cohort
No Salvage Cohort
AHCTDiagnosis
Vij R, et al. Biol Bone Marrow Transplant (in press 2015)
Outcomes with/without Pre-HCT Salvage
Years
0 2 4 1086
100
0
20
40
60
80
90
10
30
50
70
SALVAGE(n=324)
NO SALVAGE(n=251)
Progression-Free Survival
Years
0 2 4 1086
0
100
20
40
60
80
90
10
30
50
70
SALVAGE(n=324)
NO SALVAGE(n=251)
Overall Survival
P= 0.35 P= 0.2622
Vij R, et al. Biol Bone Marrow Transplant (in press 2015)
Probability of Survival based on Response to Initial Chemotherapy
Years
0 2 4 1086
100
0
20
40
60
80
90
10
30
50
70
<PR to induction
therapy (n=575)
CR/PR to induction
therapy (n=2326)
Progression-Free Survival
Years
0 2 4 1086
0
100
20
40
60
80
90
10
30
50
70
<PR to induction
therapy (n=575)
CR/PR to
induction therapy
(n=2326)
Overall Survival
p=0.0001 P = 0.0007
Vij R, et al. Biol Bone Marrow Transplant (in press 2015)
Autologous SCT vs No Transplant with
Maintenance Therapy
Gay et al ASH 2014, abstr 198
2007-20092009-2013
Gay et al ASH 2014, abstr 198
Gay et al ASH 2014, abstr 198
Prognostic Factors for PFS and Overall Survival
• Karnofsky performance status > 80%
• ISS stage 1 disease
• >VGPR after lenalidomide-dexamethasone induction
• Absence of del 17 or t(4;14)
Gay et al ASH 2014, abstr 198
Autologous SCT +Maintenance Therapy
N Engl J Med 2012
May 10 issue
American- CALGB
French - IFM
Lenalidomide: 10–15 mg/d until relapse
Placebo until relapse
First-line
ASCT<65 years
Lenalidomide: 25 mg/d Days 1–21/month2 months
Primary end point: PFS
≤6 monthsNo PD
N=614
Lenalidomide: 25 mg/d Days 1–21/month2 months
Consolidation
Phase 3 IFM 2005-02: Lenalidomide as Consolidation/Maintenance Post-ASCT
NEJM 2012; 366: 1759-1769
-Stage 1–3, -<70 years-Therapy at least 2 cycles -Stable disease or better
Placebo
Lenalidomide10 mg/d with ↑↓ (5–15 mg)
CRPRSD
Mel 200
ASCT
CALGB 100104: Lenalidomide as Consolidation/Maintenance Post-ASCT
McCarthy PL et al. NEJM 2012
Lenalidomide Placebo p value
Prog-Free Survival 43% 22% <.001
Median PFS 41 m 23 m <.0001
4 yr Overall Survival 73% 75%
NEJM 2012; 366: 1759-1769
Lenalidomide Placebo p value
Risk of Progression 37% 58%
Time to Progression 46 m 27 m <.001
3 yr OS 88% 80% .03
Median OS Not reached Not reached
CALGB - American
IFM -French
CALGB French
Len Placebo Len Placebo
Hematologic 8 1 13 5
Solid Tumor 10 5 10 4
Skin (non melanoma) 4 3 5 3
TOTAL 22 9 28 12
Secondary Cancers
Lenalidomide maintenance after HCT:- Improved progression free survial- Mixed results with overall survival- Increased risk of secondary cancers- Death from myeloma significantly higher than
death from secondary cancer- Benefits of lenalidomide vs cost/risk?
Early vs Late Transplant
IFM/DFCI 2009 Study
Newly Diagnosed MM Pts (SCT candidates)
Lenalidomide 12 mos
VRD x 3
VRD x 2
VRD x 5
Lenalidomide 12 mos
Melphalan
200mg/m2* +
ASCT
Induction
Consolidation
Maintenance
CY (3g/m2)
MOBILIZATIONGoal: 5 x106 cells/kg
VRD x 3
CY (3g/m2)
MOBILIZATIONGoal: 5 x106 cells/kg
Randomize, stratification ISS & FISH
Collection
SCT at relapse
Summary
• Number of SCT for myeloma increasing esp in older population
• Response to initial induction regimen predicts longer term
outcomes
• Bortezomib-based regimens induce
– Higher remission rates prior to SCT
– Improve survival after SCT
• Maintenance therapy with lenalidomide improves PFS and OS
• Whether early or late, once or twice , HCT remains an active
agent that can be extremely effective in all stages of the patients
disease journey.
