Consolidation and Maintenance Therapy for Multiple Myeloma ... · Novel Agent-Containing...
Transcript of Consolidation and Maintenance Therapy for Multiple Myeloma ... · Novel Agent-Containing...
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Consolidation and Maintenance Therapy for Multiple Myeloma:
Is it the New Standard?
Paul G. Richardson, MD RJ Corman Professor of Medicine,
Harvard Medical School
Jerome Lipper Multiple Myeloma Center,
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
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1. True
2. False
True/False: Consolidation post-SCT has been
associated with PFS, RR, but no OS advantage
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1. True
2. False
True/False: Maintenance post-SCT has been
associated with PFS, RR, and OS benefit
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Current Paradigm of Initial Treatment
Adapted from Ludwig H, et al. Oncologist. 2012;17(5):592-606.
Richardson PG, et al. Br J Haematol. 2011;154(6):755-762.
Transplant
eligibility
Initial therapy
Autotransplant Consolidation
Continue initial therapy
MaintenanceOR
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Treatment Goals Following Induction Therapy for Multiple Myeloma
• Improve progression-free survival (PFS) and overall survival (OS)
• Does improved PFS result in improved OS?
• Is a risk adapted approach justified?
• Continued therapy following Induction
– Timing, duration, intensity & toxicity
(to avoid treatment fatigue)
– Easy to deliver, convenient, improves PFS and OS
Mihelic R, et al. Leukemia. 2007;21(6):1150-1157. Richardson PG, et al. Br J Haematol. 2011;154(6):755-762.
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ConsolidationMaintenance
Transplant Eligible
ASCT Induction
ASCT Induction
Maintenance until PD
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ConsolidationMaintenance
Transplant Eligible
Supportive care
ASCT Induction
ASCT Induction
Maintenance until PD
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Consolidation/Maintenance: Deciding Therapy/Risk Factors
• Age
• Performance status/co-morbidities– PS matters more than age
– Renal failure (bortezomib-containing regimen (BCR)
Sonneveld P, et al. J Clin Oncol. 2012;30(24):2946-2955.
• International scoring system– Stage II or III Greipp PR, et al. J Clin Oncol. 2005;23(15):3412-3420.
• Cytogenetics/molecular testing– CD138 selection of marrow aspirate
– Metaphase karyotyping: del(13) (BCR)
Jagannath S, et al, Leukemia. 2007;21(1):151-157.
– FISH: t(4: 14), (14:16) del(1p), +(1q), del(17p) (BCR)
Munshi NC, et al. Blood. 2011;117(18):4696-4700.
– Molecular: GEP 70, EMC-92 (validation and what to do with high risk pts)
Shaughnessy JD Jr, et al. Br J Haematol. 2007;137(6):530-536. Kuiper R, et al. Leukemia. 2012;26(11):2406-2413.
• Other disease features– Extra-medullary disease, plasma cell leukemia, high LDH
Adapted from McCarthy PL, et al. Hematology Am Soc Hematol Educ Program. 2013:496-503.
Adapted from Ludwig H, et al. Oncologist. 2012;17(5):592-606.
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Novel Agent-Containing Consolidation Therapy Improves Depth of Response and Prolongs PFS
• Bortezomib monotherapy
(Nordic Myeloma Study Group [NMSG 15/05] trial)1
– Significant improvement in PFS with bortezomib consolidation
compared to control: 27 months vs 20 months, P = .05
• VTD versus TD (GIMEMA trial)2
– VTD consolidation significantly increased CR and CR/nCR
rates versus TD
– Median PFS significantly longer for VTD versus TD:
62 months vs 48 months, P = .001
1. Mellqvist UH, et al. Blood. 2013;121(23):4647-4654. 2. Cavo M, et al. Blood. 2012;120(1):9-19.
Cavo M. Presented at: IMW 2013, oral presentation (S15 consolidation / maintenance)
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Straka C, et al. J Clin Oncol. 2015;33(Suppl): Abstract 8511.
• Bortezomib 1.3 mg/m2 16 weekly doses over 20 weeks vs observation
PFS: Consolidation vs Observation
• Median PFS: 33.6 months (bortezomib vs 27.8 months (observation)
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Induction treatment = VRD cycles 1,2 and 3 every 21 days
Lenalidomide 25mg/d (days 1 to 14)
Bortezomib 1.3mg/m2 (days 1, 4, 8, 11)
Oral dexamethasone 40mg/d (days 1, 8, 14)
Stem cell collection
ASCT
Consolidation treatment
VRD cycles 4 and 5 every 21 days
Maintenance therapy for 12 months
Lenalidomide 10mg/d for 3 months then 15mg/d if well tolerated
Immunophenotypic analysis
Immunophenotypic analysis
Immunophenotypic analysisResponse assessment
Response assessment
Response assessment
Response assessment
Response assessment
IFM 2008: Phase II Study
in Newly Diagnosed MM Patients <65 Years
Roussel M, et al. J Clin Oncol. 2014;32(25):2712-2717.
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IFM 2008: Response Rates (ITT)(VRD x 3 - Transplant - VRD x 2 - Rev 1 year)
After
induction After ASCT
After
consolidation
After
therapy
n (%) n = 31 n = 30 n = 30 n = 31
MRD negative 4/25 (16) 14/26 (54) 15/26 (58) 21/30 (68)
sCR + CR 7 (23) 14 (45) 15 (48) 18 (58)
≥VGPR 18 (58) 21 (68) 26 (84) 26 (84)
Roussel M, et al. J Clin Oncol. 2014;32(25):2712-2717.
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IFM 2008: PFS• Median follow up: 39 months (range, 36-42 months), no death
• Estimated 3-year PFS 77% (CI 95%, 57%-88%) and OS 100%
• 10 patients MRD + : 7 relapses
• 21 patients MRD - : No relapse
Roussel M, et al. J Clin Oncol. 2014;32(25):2712-2717.
PFS (ITT) and according to MRD status
IFM, Intergroupe Francophone du Myélome
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IFM/DFCI 2009: VGPR Rate During Each Treatment Phase
RVD arm
N = 350
Transplant arm
N = 350P value
Post induction 47% 50% NS
At C4 or post transplant 55% 73% <.0001
Post consolidation 71% 81% <.006
Post maintenance 78% 88% <.001
Attal M. et al. Blood. 2015;126: Abstract 391. IFM, Intergroupe Francophone du Myélome
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Maintenance for fixed time
or not if in CR
Maintenance until PD
ASCT
Transplant Eligible
Induction
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Maintenance for fixed time
or not if in CR
Maintenance until PD
ASCT
Transplant Eligible
Induction
Supportive Care
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Bortezomib and Zoledronate Maintenance Following ASCT
Adapted from: McCarthy PL, et al. J Natl Compr Canc Netw. 2013;11(1):35-42.
Maintenance vs no maintenance
N Initial dose PFS OSBenefit?EFS/OS
Sonneveld P, et al. J Clin Oncol. 2012; 30(24):2946-2955.
827
Bortezomib: 1.3 mg/m2 IV,
every 2 weeks for 2 years
OR
Thalidomide 50 mg daily for
2 years
(V after PAD vs T after VAD)
Med PFS
35 vs 28 months
(P = .002)
Median FU 41 months
OS (MV analysis)
HR 0.77
(95% CI, 0.60-1.00)
P = .049
+/+
Landmark analysis
PFS 45 vs 38% (P = .05)
5-year OS
61 vs 55% (P = .07)+/+
Rosiñol L, et
al Blood.
2012;120(8):
1589-1596.
386
Bort 1.3 mg/m2 IV, d 1, 4, 8, 11 every 3 mo + Thal 100 mg/dOR Thal 100 mg/d aloneORInterferon-α 3 million units SC3 times weekly(VTD vs T vs IFN-α)
2 year PFS
56.2 vs 28.2 vs 35.3
(P = .01)
OS not significantly
different+/NA
Morgan GJ,
et al. Lancet.
2010;376(975
7):1989-1999
1960 (ITT)
Zoledronic acid 4 mg IV every 3-4 weeks ORClodronic acid 1600 mg daily
IT Median PFS
19.5 vs 17.5 months
(P=.07)
Med OS IT
NR vs 62.5 months
P = .0854
NA/trend+
Median OS all pats
50 vs 44.5 mos
P = .04
+
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Randomization
MM stage II or III, age 18–65
CAD + GCSF
3 x VAD
CAD + GCSF
3 x PAD
MEL 200 + PBSCT
Depending on local
policy for patients PR
MEL 200 + PBSCT
MEL 200 + PBSCT
Depending on local
policy for patients PR
MEL 200 + PBSCT
Thalidomide
50 mg/day for
2 years
maintenance
Allogeneic
Tx
Bortezomib
1.3 mg/m2 / 2 weeks
for 2 years
maintenance
Phase III: PAD vs VAD induction, High-Dose Melphalan (HDM) and
Bortezomib or Thalidomide Maintenance (HOVON 65 MM / GMMG-HD4 )
Sonneveld P, et al. J Clin Oncol. 2012;30(24):2946-2955.
n = 371n = 373
n = 744, median age 57
VAD: vincristine,
doxorubicin, and
dexamethasone
PAD: bortezomib,
doxorubicin, and
dexamethasone
CAD: cyclophosphamide,
doxorubicin, dexamethasone
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Scheid C, et al. Haematologica. 2014;99(1):148-154.
PFS and OS According to Treatment Arm According to Baseline Creatinine and Treatment Arm
PFS OS
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Scheid C, et al. Haematologica. 2014;99(1):148-154.
PFS and OS According to Treatment Arm According to Baseline Creatinine and Treatment Arm
PAD B PAD B
PFS OS
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Scheid C, et al. Haematologica. 2014;99(1):148-154.
PFS and OS According to Treatment Arm According to Baseline Creatinine and Treatment Arm
VAD T
VAD T
PAD B PAD B
PFS OS
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PFS and OS for Thalidomide (Arm A) vs Bortezomib (Arm B) Induction and Maintenance by Cytogenetic Risk
del(17p)
t(4;14)
del(13/13q)
Sonneveld P, et al. J Clin Oncol. 2012;30(24):2946-2955.
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PFS and OS for Thalidomide (Arm A) vs Bortezomib (Arm B) Induction and Maintenance by Cytogenetic Risk
del(17p)
t(4;14)
del(13/13q)
PAD B PAD B
Sonneveld P, et al. J Clin Oncol. 2012;30(24):2946-2955.
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PFS and OS for Thalidomide (Arm A) vs Bortezomib (Arm B) Induction and Maintenance by Cytogenetic Risk
del(17p)
t(4;14)
del(13/13q)
VAD T
PAD B PAD B
VAD T
Sonneveld P, et al. J Clin Oncol. 2012;30(24):2946-2955.
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McCarthy P, et al. N Engl J Med. 2012;366(19):1770-1781.
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CALGB 100104 Schema
• Stratification based on registration -2M level and prior thalidomide and lenalidomide
use during Induction.
• Primary Endpoint: Powered to determine a prolongation of TTP from 24 months to
33.6 months (9.6 months)
• The study was un-blinded at a median 18 months and 86/128 placebo patients without
progressive disease chose to cross over to receive lenalidomide.
Lenalidomide
10 mg/d with
↑↓ (5–15 mg)
n = 460
D-S Stage 1-3, ≤70 years
≥2 cycles of induction
Attained SD or better
≤1 year from start of therapy
≥2 x 106 CD34 cells/kg
Placebo
n = 229
Restaging
days 90-100
Registration
CR
PR
SD
Mel 200
ASCT
Randomization
McCarthy P, et al. N Engl J Med. 2012;366(19):1770-1781. Updated: Holstein SA, et al. J Clin Oncol. 2015;22(suppl):
Abstract 8523.
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Lenalidomide Improves TTP and OS
Median: 53 vs 26 mos
Hazard ratio 0.54
(P<.001)
Median: NR vs 76 mos
Hazard ratio 0.60
(P = .001)
Holstein SA, et al. J Clin Oncol. 2015;22(suppl): Abstract 8523.Intent-to-treat analysis, data cut-off Nov 2014
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Subgroup Analysis of TTP and OS
Holstein SA, et al. J Clin Oncol. 2015;22(suppl): Abstract 8523.
Intent-to-treat analysis, data cut-off Nov 2014
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The Cumulative Incidence Risk (CIR) for Progression, Death and Second Primary Malignancy (SPM) During Maintenance Therapy: Placebo Versus Lenalidomide
SPM vs PD/Death SPM vs Death SPM Death vs Death
Holstein SA, et al. J Clin Oncol. 2015;22(Suppl): Abstract 8523.
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The Cumulative Incidence Risk (CIR) for Progression, Death and Second Primary Malignancy (SPM) During Maintenance Therapy: Placebo Versus Lenalidomide
The CIR of developing a SPM (p=0.005) or dying from an SPM (p=0.02) is higher with Len
compared with placebo. The CIR of PD (p<0.001) or death (p<0.001) is higher for placebo as
compared with Len.
SPM vs PD/Death SPM vs Death SPM Death vs Death
Holstein SA, et al. J Clin Oncol. 2015;22(Suppl): Abstract 8523.
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• ITT Analysis; median follow-up from transplant ~48 months
• Median TTP: 50 months versus 27 months P < .001
• Median OS: Not reached versus 73 months P = .008
McCarthy P, et al, Presented at: IMW 2013.
146/229 events (64%) on placebo
104/231 events (45%) on lenalidomide
CALGB 100104: Updated TTP/OS
Estimated HR=0.51
(95% CI = 0.39 to 0.66)
49% reduction in risk of
progression
69/229 (30%) deaths on placebo
47/231 (20%) deaths on lenalidomide
Estimated HR=0.61
(95% CI = 0.41 to 0.87)
39% reduction in the risk of death
[86 of 128 non-progressing
placebo pts received lenalidomide
at study un-blinding in Jan 2010]
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Lenalidomide Maintenance Therapy: CALGB 100104 Update
• Cumulative incidence of second primary cancers greater in lenalidomide group (P = .034)
• Cumulative incidence of risk of PD (P = .004) and death (P<.001) greater in placebo group
Lenalidomide arm Placebo arm P
Median PFS 47 mos 27 months <.001
McCarthy P, et al, Presented at: IMW 2013 and ASH 2013.
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Attal M, et al. N Engl J Med. 2012;366(19):1782-1791. Attal M, et al. Blood. 122: Abstract 406.
• PFS benefit: 42 vs 24 months overall; benefit seen in low and high risk
cytogenetic populations
• del17p: 29 vs 14 months; t(4;14): 27 vs 15 months. (Avet L’Oiseau H, et al. Blood. 2010;116: Abstract 1944)
• IMW 2014: PFS for t(4:14) 27 vs 24 mos.
• Maintenance stopped at a median of 2 years (range 1-3) due to SPM concern
IFM 2005-02: PFS and OS From Randomization(Study Unblinded 1/2010)
Maintenance Following ASCT
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• 402 patients (younger than 65 years) randomized from 62 centers• Patients: Symptomatic disease, organ damage, measurable disease
Treatment Schedule
*MPR vs MEL 200; R maintenance vs no maintenance; Anti-thrombotic substudy: Aspirin vs Low molecular weight heparin
Rd (R: 25 mg/d, days 1-21; d: 40 mg/d, days 1,8,15,22); MPR (M: 0.18 mg/Kg/d, days 1-4; P: 2 mg/Kg/d, days 1-4; R: 25 mg, d 1-21), MEL 200 (M:
200 mg/m2 day -2); R maint (R: 10 mg/day, days 1-21); # One course MEL 200 if patients achieves VGPR after cycle 1; R: lenalidomide; MEL200:
melphalan 200 mg/m2 and autologous stem cell transplant; MPR: melphalan-prednisone-lenalidomide; NDMM: newly diagnosed multiple myeloma.
Rdfour 28-day courses
MEL 200Two courses#
NO MAINTENANCE
R MAINTENANCE28-day courses until PD
MPRsix 28-day courses
R MAINTENANCE28-day courses until PD
NO MAINTENANCE
*Randomization (2 x 2 design)
MPRsix 28-day courses
MEL 200Two courses#
Palumbo A, et al. N Engl J Med. 2014;371(10):895-905.
MPR, melphalan-prednisone-lenalidomide
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0
25
50
75
100
0 10 20 30 40 50 60 70
MEL200-R
MEL200
MPR-R
MPR
Months
100
0 10 20 30 40 50 60 70
0
25
50
75
MEL200-R
MEL200
MPR-R
MPR
Months
Progression-free survival Overall survival
MEL200, melphalan 200 mg/m2; R, lenalidomide maintenance
MPR vs MEL200 vs MPR-R vs MEL200-R
Palumbo A, et al. N Engl J Med. 2014;371(10):895-905.
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R maintenance vs No maintenance
Median PFS
R maint. 37 months
No maint. 26 months
5-year OS
R maint. 75%
No maint. 58%
HR 0.52, 95% CI 0.40-0.67, P <.0001
Months
HR 0.62, 95% CI 0.42-0.93, P =.02
Months
0
25
50
75
100
0 10 20 30 40 50 60 70
0
25
50
75
100
0 10 20 30 40 50 60 70
R, lenalidomide
Progression-free survival Overall survival48% reduced risk of progression 38% reduced risk of death
Palumbo A, et al. N Engl J Med. 2014;371(10):895-905.
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Lenalidomide Maintenance Therapy Meta-Analysis
Singh M, et al. Blood. 2013;122: Abstract 407.
There was
significant
prolongation of
both PFS (HR 0.49,
95% CI, 0.41–0.58,
P<.001) and OS (HR
0.77, 95% CI, 0.62–
0.95, P = .013) with
LM vs. placebo/no
maintenance
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• N=1209, median follow up 6.6 years
• OS benefit with LEN vs control: Not reached vs 86 months
− HR = 0.74; 95% CI, 0.62-0.89; log-rank P = .001
• 5 yr, 6 yr, and 7 yr OS longer with LEN
• LEN maintenance benefited all subgroups after ASCT
Attal M, et al. J Clin Oncol. 2016;34(suppl): Abstract 8001
Lenalidomide Maintenance Therapy Meta-Analysis: Updated OS
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Consolidation and Maintenance Therapy Post-Transplant With Lenalidomide, Bortezomib and
Dexamethasone (RVD) in High Risk Patients
1. Stringent CR 51%, 96% VGPR
2. Median PFS 32 months
3. Three-year OS 93%
Nooka AK, et al. Leukemia. 2014;28(3)690-693.
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N = 256, all patients received RVD
All received 3 drug maintenance
Minimal exposure to alkylators
Nooka AK, et al. Leukemia. 2014;28(3)690-693.
Early Versus Late Transplant in High Risk MM
P = .044; logrank
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RVDx3
RVD x 2
RVD x 5
Revlimid until PD
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
Revlimid until PD
SCT at relapse
Calibration
MRD
MRD
MRD
MR
D @
CR
MR
D @
CR
IFM/DFCI 2009; DFCI #10-106; CTN 1304
“The Determination Trial”
Newly Diagnosed MM (N = 1,360)
*Primary objective = 7-color Flow, secondary objective = molecular
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P-value : p<0.0001
Negative (<10-6)
PositivePositive
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Patients
without pro
gre
ssio
n (
%)
51 51(0) 51(0) 51(0) 47(3) 36(9) 26(5) 6(9) 3(0)MRD positive
80 80(0) 80(0) 80(0) 80(0) 73(3) 57(3) 33(5) 9(0)MRD neg (<10-6)
N at risk(events)
06
1218
2430
3642
48
Months since randomization
MRD at post-maintenance in CR patients
IFM 2009: 375 CR/sCR, 131 MRD Patients
83%
30%
Avet-Loiseau H, et al. Blood. 2015;126: Abstract 191.
P value: <.0001
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Ixazomib Maintenance Following Ixazomib-Lenalidomide-Dexamethasone Induction in Untreated Multiple Myeloma
29 29
48
10
10
19
33
519
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Best response toinduction
Best response overall
sCRCRnCRVGPRPRMRSD
n = 5
n = 2
10 (48%) patients improved their response during maintenance:
2 VGPR to nCR, 5 VGPR to CR, 1 VGPR to sCR, and 2 CR to sCR
n=2
n=1
Kumar SK, et al. Blood. 2011;118.
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Conclusions: Post-Transplant ConsolidationEmerging as a Key Component of Initial Treatment
Autotransplant
Initial therapy Maintenance
Consolidation
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Conclusions: Post-Transplant ConsolidationEmerging as a Key Component of Initial Treatment
Autotransplant
Initial therapy Maintenance
Consolidation
Bortezomib1
VTD2
Lenalidomide3
RVD4
CTD5
Post-transplant consolidation
improves depths of response
(VGPR and CR)
Mellqvist UH, et al. Haematologica. 2011;96(Suppl1):S31. Cavo M, et al. Blood. 2012;120: Abstract 4210. Attal M, et al.
Haematologica. 2011;96(Suppl1):S23. Roussel M, et al. Blood. 2011;118: Abstract 1872. Sonneveld P, et al. Blood.
2012;120: Abstract 333. Adapted from: Jakubowiak AJ, Poznan 2014. EU /US Perspectives in MM.
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Conclusions: Post-Transplant ConsolidationEmerging as a Key Component of Initial Treatment
Autotransplant
Initial therapy Maintenance
Consolidation
Bortezomib1
VTD2
Lenalidomide3
RVD4
CTD5
Post-transplant consolidation
improves depths of response
(VGPR and CR)
Benefits of Consolidation Emerging
Mellqvist UH, et al. Haematologica. 2011;96(Suppl1):S31. Cavo M, et al. Blood. 2012;120: Abstract 4210. Attal M, et al.
Haematologica. 2011;96(Suppl1):S23. Roussel M, et al. Blood. 2011;118: Abstract 1872. Sonneveld P, et al. Blood.
2012;120: Abstract 333. Adapted from: Jakubowiak AJ, Poznan 2014. EU /US Perspectives in MM.
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Conclusions: Post-Transplant Maintenance
ThalidomidePFS prolonged (6/6)
OS prolonged (3/6)
LenalidomidePFS prolonged (2/2)
OS prolonged (1/2)
Bortezomib +/- ThalidomideMay contribute to
prolonged PFS (2/2)
prolonged OS (1/2)
Autotransplant
Initial therapy Maintenance
Consolidation
Adapted from Jakubowiak AJ, Poznan 2014; EU/US Perspectives in MM.
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Conclusions: Post-Transplant Maintenance
ThalidomidePFS prolonged (6/6)
OS prolonged (3/6)
LenalidomidePFS prolonged (2/2)
OS prolonged (1/2)
Bortezomib +/- ThalidomideMay contribute to
prolonged PFS (2/2)
prolonged OS (1/2)
Autotransplant
Initial therapy Maintenance
Consolidation
Lenalidomide associated with increased SPM post SCT/HD Mel but OS benefit seen
USA: lenalidomide most commonly used agent based on favorable risk/benefit ratio
Updated TTP Updated OSIncludes pts crossing over
McCarthy, IMW 2013
Adapted from Jakubowiak AJ, Poznan 2014; EU/US Perspectives in MM.
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Conclusions/Future Directions• New directions in prognostication / risk adapted therapy:
– Minimal residual disease measurements
PCR, Flow Cytometry, NGS
– Cytogenetic testing
CD138 selection with cytogenetic analysis
– Molecular gene expression profiling
• Disease control with less toxicity will likely result in improved
PFS and OS
• Addition of next generation novel agents
– Carfilzomib
– Anti-CD38 antibodies (DARA, ISA), anti-CS-1/SLAM F7 (ELO)
– Ixazomib
– Vaccines
– HDACIs
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Conclusions/Future Directions
• Transplant eligible
– Bortezomib for 2 years following ASCT is a standard primarily
for those presenting in renal failure and those patients with
chromosome del(17p)
– Lenalidomide until PD is a standard of care following ASCT
– Second primary cancer risks is increased with lenalidomide
maintenance after HD MEL, but cumulative incidence risk of
relapse and death are worse without lenalidomide
maintenance
• Consolidation/maintenance for transplant eligible multiple
myeloma patients as part of clinical trials a key priority
• Identify target pathways for testing new agents with curative
intent (eg, checkpoint inhibition)
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Thank You!!
Slide Courtesy of Phil McCarthy, MD
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