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Consolidation and Maintenance therapy
María-Victoria Mateos, MD, PhDUniversity Hospital of Salamanca, Spain
University of Salamanca
Disclosure form• MVM has served as member of advisory boards or received honoraria from lectures for Takeda, Celgene, Janssen, BMS, Amgen.
Definition and Aims of consolidation and maintenance therapy
Consolidation• Improve response/induce deeper response following therapy
– by administration of treatment for a limited period
Maintenance• Maintain response achieved following therapy
– by administration of treatment for a prolongedperiod
Overall goal: • Improve the quality of response• Sustain MRD-/+• Extend progression free survival• Prolong survival
MRD-negative (n = 316) median PFS: 58 monthsCR (n = 128) median PFS: 24 monthsnCR (n = 96) median PFS: 21 monthsPR (n = 199) median PFS: 26 months< PR (n = 38) median PFS: 9 months
MRD-negative (n = 316) median OS: 145 monthsCR (n = 128) median OS: 59 monthsnCR (n = 96) median OS: 63 monthsPR (n = 199) median OS: 59 months< PR (n = 38) median OS: 32 months
Progression-free survival (%)
Time from response assessment (months)
MRD-negative vs CR: p < 0.001CR vs nCR: p = 0.127
Overall survival (%)
Time from response assessment (months)
MRD-negative vs CR: p < 0.001CR vs nCR: p = 0.657
p < 0.001 p < 0.001
GEM2000, GEM2005MENOS65, GEM2005MAS65, GEM2010MAS65 (n = 777)
Lahuerta JJ, et al. manuscript under review.
The true value of CR relies on the MRD status, and CR w/o MRD is no better than PR
nCR, near complete response;; OS, overall survival;; PFS, progression-free survival;; PR, partial response.
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00 24 48 72 96 120 144 168 192 0 24 48 72 96 120 144 168 192
MRD-positive
All levels of MRD are usually associated with unsustained remissions
1. Flores-Montero J, et al. manuscript under review.2. Avet-Loiseau H, et al. Blood. 2015;;126:abstract 191. As presented at ASH 2015.
IFM 2009 trial: patients who received either 8 cycles of VRD (arm A) or 3 VRD cycles, high-dose melphalan, followed by 2 consolidation VRD cycles (arm B). All patients received a lenalidomide maintenance dose for 12 months.
Heterogeneous patient population (not enrolled in clinical trials)
NGF, next-generation flow.
Progression-free survival (%
)
Time from MRD assessment (months)
Next-generation flow1
NGF-negative (n = 37), 75% PFS: NR*
NGF-positive/2ndgen-negative (n = 16), 75% PFS: 10 months
NGF-positive/2ndgen-positive (n = 26), 75% PFS: 12 months
p = 0.04
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20
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0
0 5 10 15 20 25 30
Next-generation sequencing2
p value (trend) < 0.0001
[10-6;; 10-5][10-5;; 10-4]
³ 10-40.2
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0.5
0.6
0.7
0.8
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1.0
Patientswithoutprogression(%)
0 6 12 18 24 30 36 42 48
Months since randomization
MRD at post-maintenance
<10-6
Undetectable MRD can be associated withoperational cure
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0
Presentation
PR
VGPR
CR
sCR
Total number of tumourcells
MRD
Undetectable MRD
(Operational cure)
Time to progression
-
-
-
-
-
-
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-
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-Diagnosis End of therapy
108
Mateos MV, et al. Blood Rev. 2015;;29:387-403.CR, complete response;; MRD, minimal residual disease;; PR, partial response;; sCR, stringent CR;; VGPR, very good PR.
Rationale for maintenance would be based on the continuous control of MRD, negative or even positive
Pessoa de Magalhães RJ, et al. Haematologica. 2013;;98:79-86. As presented at ASH 2011.
Long-term survival is possible for a few MRD-positive patients with a unique immune profile
Dcs, dendritic cells;; MO, monocyte;; NK, natural killer;; TAMs, tumour associated macrophages;; T-Reg, T-regulatory cell.
Time from MRD assessment (months)
Time to progression (%)
p = 0.001
Median TTP: NR
Median TTP: 16 m
Median TTP: NR
Prognostic value of immune reconstitution in patients with persistent MRD
Paiva B, et al. Blood. 2016;;127:3165-74. As presented at ASH 2015.
PCA3
PCA1
Normal PCsClonal PCs
B-precursors
Erythroblasts
MRD-positive high normal PC recovery and favourable immune
profile
MRD-negativeMRD-positive
Individual patients’ immune signatures
Single 8-colour combination (CD45, CD138, CD38, CD56, CD27, CD19, CD117, CD81):enumeration of 15 different BM cell populations
Patients with favourable immune profile are characterized by an increased compartment of mature B cells
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50403020100
BM, bone marrow;; PCA, principal component analysis;; PCs, plasma cells.
Transplant Candidate: Consolidation/Maintenance
What are the options?
Consolidation
• High-dose chemotherapy + transplant, single or tandem
• Regimens based on
– Bortezomib
– Thalidomide
– Lenalidomide
Maintenance
• Interferon-alpha
• Steroids
• Thalidomide
• Bortezomib
• Lenalidomide
IFM 2009: PFS and OS
P<0.001
0
10
20
30
40
50
60
70
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90
100
Patients (%)
350 296 228 128 24no HDT350 309 261 153 27HDT
N at risk
0 12 24 36 48
Months of follow-up
HDTno HDT
P NS
0
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30
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Patients (%)
350 338 320 244 56no HDT350 328 309 226 55HDT
N at risk
0 12 24 36 48
Months of follow-up
HDTno HDT
PFS OS
RVD arm vs Transplant arm• CR: 49% 59%• ≥ VGPR: 78% 88%
Attal M. ASH 2015
PFS
VMP arm vs Transplant arm after VCD x 3 cycles• CR: 43% 42%• ≥ VGPR: 73% 85%
Cavo M. ASCO 2015
EMN02/HO95 MM trial: study design (n = 1192)
0,00
0,50
1,00
Progression-free survival (%)
497 383 230 74 10 0VMP695 570 349 108 5 0ASCT
Number at risk
0 12 24 36 48 60Time (months)
ASCT VMP
ASCT VMP
PFS median, mos NR 44
PFS at 3 yrs, % 66.1 57.5
HR (95% CI): 0.73 (0.59-0.90);; p = 0.003
Superior PFS with ASCT vs VMP was retained across prespecified subgroups of patients at low (NR vs 46m) and high risk (42 vs 32m)
Double ASCT after bortezomib-based induction as consolidation therapy
PFS and OS in patients with 2 adverse variables
Cavo M et al. Blood 2013;;122:767.
PFS and OS for pts with high-risk cytogenetics and who failedCR after bortezomib-based induction regimens
Double ASCT Single ASCT PPFS 41 months 20 months 0.003OS 67 months 31.5 months <0.001
PFS OS
Consolidation Therapy
Induction Regimen
Response Post-Induction
Response Post-ASCT
Response Post-Consolidation
CR (%) CR (%) CR (%)
VTD1 22.5 48.7 61
RVD2 23 42 48
KTD3 33 38 67
KRd4 10 25 70
1. Cavo M et al. Blood. 2012;; 120:9.2. Roussel M et al. Blood. 2011;;118: Abstract 1872.
3. Sonneveld P et al. Blood. 2015;;125:449.4. Zimmerman TM et al. J Clin Oncol. 2015;;33. Abstract 8510.
Consolidation upgraded response in approximately 30%.
Lenalidomide maintenance†
Lenalidomide maintenance†
Phase III BMT CTN 0702 Trial: SCHEMA
Register and randomize
ASCT MEL 200 mg/m2 RVD × 4*
Lenalidomide maintenance*
ASCT MEL 200 mg/m2*Bortezomib 1.3 mg /m2 days 1, 4, 8, 11
Lenalidomide 15 mg days 1–15 Dexamethasone 40 mg days 1, 8, 15†Lenalidomide 15 mg daily × 3 years
https://clinicaltrials.gov/ct2/show/NCT01109004.
-
Transplant Candidate: Consolidation/Maintenance
What are the options?
Consolidation
• High-dose chemotherapy ± transplant, single or tandem
• Regimens based on
– Bortezomib
– Thalidomide
– Lenalidomide
Maintenance
• Interferon-alpha
• Steroids
• Thalidomide
• Bortezomib
• Lenalidomide
Thalidomide maintenance studiesSignificant improvement in PFS with maintenance
therapy
Significant improvement in OS with maintenance
therapySurvival after relapse
Spencer2009 Yes Yes
(3-year follow-up) Similar in all groups
Attal2006 Yes
Yes (at 39 months),but OS advantage
disappeared with longer follow-up (5.7 years)
Similar in all groups
Barlogie2006, 2008, 2010 Yes Yes
(7.2-year follow-up)Reduced OS after
thalidomide exposure
Lokhorst2010 Yes No Reduced OS after
thalidomide exposure
Morgan2012 Yes No Reduced OS after
thalidomide exposure
Stewart2013 Yes No Reduced OS after
thalidomide exposure
• Toxicity, particularly neurological, leads to discontinuation rates up to 60%, and worse QoL• Worse OS in patients with adverse FISH
Attal M, et al. Blood. 2006;;108:3289-94. Barlogie B, et al. N Engl J Med. 2006;;354:1021-30. Barlogie B, et al. Blood. 2008;;112:3115-21. Barlogie B, et al. J Clin Oncol. 2010;;28:1209-14.
Lokhorst HM, et al. Blood. 2010;;115:1113-20. Morgan GJ, et al. Blood. 2012;;119:7-15.Spencer A, et al. J Clin Oncol. 2009;;27:1788-93. Stewart AK, et al. Blood. 2013;;121:1517-23.
This table is provided for ease of viewing information from multiple trials. Direct comparisons across trials is not intended and should not be inferred.FISH, in situ fluorescence hybridization;; QoL, quality of life.
Studies included in meta-analysis (N = 1,209)
Target population of patients with NDMM who received LEN maintenance or placebo/no maintenance after ASCT
CALGB 100104(accrual 8/2005–11/2009)
INDUCTIONASCT
1:1 RANDOMIZATION“NO EVIDENCE OF PD”
LEN MNTCa(n = 231)
PLACEBO(n = 229)
INTERIM ANALYSIS AND UNBLINDINGDec 2009
CROSSOVER BEFORE PD ALLOWED
CONTINUEDTREATMENT
IFM 2005-02(accrual 6/2006–8/2008)
INDUCTIONASCT
1:1 RANDOMIZATION“NO EVIDENCE OF PD”
LEN: 2 COURSES
LEN MNTCa(n = 307)
PLACEBO(n = 307)
ALL TREATMENT DISCONTINUED
Jan 2011
CONTINUED TREATMENTNO CROSSOVER
BEFORE PD ALLOWED
INTERIM ANALYSIS AND UNBLINDINGDec 2009 Jan 2010
GIMEMA (RV-MM-PI-209)(accrual 11/2007–7/2009)
MPR: 6 COURSES
2 × 2 DESIGNLEN + DEX × 4 INDUCTION
LEN MNTCb(n = 67)
NO TREATMENT(n = 68)
LEN MNTCb
NO TREATMENT
ASCT
CONTINUED TREATMENT
CONTINUED TREATMENT
PRIMARY ANALYSIS
a Starting dose of 10 mg/day on days 1–28/28 was increased to 15 mg/day if tolerated and continued until PD. b Patients received 10 mg/day on days 1–21/28 until PD.
The PFS in the LEN arm was doubled vs placebo arms(41-46 months vs 21-23 months) in all studies
Attal M, et al. J Clin Oncol. 2016;;34 Suppl:abstract 8001.DEX, dexamethasone;; LEN, lenalidomide;; MNTC, maintenance;;NDMM, newly diagnosed multiple myeloma;; PD, progressive disease.
Lenalidomide maintenance: OS meta-analysis
00 10 20 30 40 50 60 70 80 90 100 110 120
0.2
0.4
0.6
0.8
1.0
26% reduction in risk of death, representing an estimated 2.5-year increase in median survivala
605 578 555 509 474 431 385 282 200 95 20 1 0604 569 542 505 458 425 350 271 174 71 10 0
Overall survival (months)
Survival probability
Patients at risk
7-year OS
62%
50%N = 1209 LEN CONTROL
Median OS(95% CI), months
NE(NE–NE)
86.0(79.8–96.0)
HR (95% CI)p value
0.74 (0.62–0.89)0.001
a Median for LEN treatment arm was extrapolated to be 116 months based on median of the control arm and HR (median 86 months;; HR = 0.74).
CA, cytogenetic abnormality;; ISS, International Staging System;; NE, not estimable.
N = 1,209
LEN maintenance after ASCT can be considered a standard of care
Median follow-up: 80 months
The OS benefit was observed in all investigated subgroups of patients (except high-risk CA and ISS stage III)
Attal M, et al. J Clin Oncol. 2016;;34 Suppl:abstract 8001.
Bortezomib maintenance therapyStudy details n Treatment Outcome
PFS OSHOVON 65 MM/ GMMG-HD41
Median follow-up:91 months
413
414
PAD x 3 à HDM à bortezomibevery 2 weeks for 2 years
VAD x 3 à HDM à thalidomide daily for 2 years
34 months
28 monthsp = 0.001
90
83 monthsRMS8y
(4.8 months)p = 0.04
PETHEMA/GEM2
Median follow-up:34.9 months
89
87
90
VT (1 cycle bortezomib every 3 months, thalidomide daily) for 3 years
Thalidomide (daily for 3 years)
Interferon-a2b (3 x per week for 3 years)
Significant PFS benefit for VT
p < 0.0009
OS not significantly different
between arms
1. Sonneveld P, et al. Blood. 2015;;126:abstract 27. Presented at ASH 2015.2. Rosinol L, et al. Blood. 2012;;120:334. Presented at ASH 2012.
Bortezomib administered at 1.3 mg/m2 i.v. in both studies
HOVON 65 MM→ PAD x3 → tandem HDM → bortezomib maintenance: benefit for patients with del(17p)
Bortezomib maintenance after double ASCT is effective in patients with del(17p)
HDM, high-dose melphalan;; i.v., intravenous;; PAD, bortezomib, doxorubicin, dexamethasone;; RMS8y,restricted mean survival time at 8 years;; VAD, vincristine, doxorubicin, dexamethasone.
Ixazomib: oral proteasome inhibitor
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 S, et al. Lancet Oncol. 2014 (13):1503-12.
Ixazomib maintenance promising but data from phase 3 trial are pendingIRd, ixazomib, lenalidomide, dexamethasone;; nCR, near partial response.
Best response to treatment in phase 2 patients receiving maintenance with ixazomib after IRd as induction (N = 21)
29 29
48
10
10
19
33
519
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Best response to induction Best response overall
sCR
CR
nCR
VGPR
PR
n = 5
n = 2
Non-Transplant Candidate: Consolidation/Maintenance
What are the options?
Consolidation
No trials
Maintenance
• Thalidomide
• Bortezomib
• Lenalidomide
GEM2016FIT: Consolidation
2
aDuring the first cycle (6 weeks), bortezomib is given on D1, 4, 8, 11, 22, 25, 29, and 32.; GAH: J Geriatr Oncol. 2015 Sep;;6(5):353-61;; R1: first randomization;; R2: second randomization ;; IMF imnunofenotipic response NGF ( next generation flow)
NDMM patientsNS CTC >65 yn= 462 elderly Fit
Patients(GHA) ARM 2a KRd .N=154
CFZ: 20/70 mg/m2, d1, 8, 15 LEN: 25 mg, d1–21 DEX: 20/10 mg, d1, 2, 8, 9, 15, 16, 22, 23
18 28-day cyclesN=159
ARM 1 VMP N=154Mel: 9mg/m2 D1-4Pred: 60mg/m2 D1-4BTZ: 1.3mg/m2 D1, 8,15,22ªOne 6 week cycle followedby eight 4-week cycleN=159
Rd
LEN: 25 mg, d1–21 DEX: 20/10 mg, d1, 2, 8, 9, 15, 16, 22, 23
Nine 28-day cycles
(R1) Induction 18 cycles (R2) MaintenanceConsolidation
RdLEN: 25 mg, d1–21 DEX: 20/10 mg, d1, 2, 8, 9, 15, 16, 22, 23Dara 16 mg/Kg Days 1, 8, 15, 22 of cycles 1-‐2; Days 1 and 15 of cycles 3 and 4
Four 28-day cycles
Dara 16 mg/Kg IV Day 1 of cycles 1-‐24
+R 15 mg, d1–21 Until progresion
No maintenance
MRD9 cy
MRD18 cy
MRD22 cy
Dara 16 mg/Kg IV Day 1 of cycles 1-‐24
+R 15 mg, d1–21 Until progresionARM 2b KRD- DARA n=154
CFZ: 20/70 mg/m2, d1, 8, 15LEN: 25 mg, d1–21 DEX: 20/10 mg, d1, 2, 8, 9, 15, 16, 22, 23Dara 16 mg/Kg IV Days 1, 8, 15, 22 of cycles 1-‐2; Days 1 and 15 of cycles 3 and 4; Day 1 of cycles 5 to 18
No maintenance
Primary endpoint immonuphenotipic complete response Secondary exploratory outcome: PFS
MRD+
MRD-
Directly to the R2 maintenance fase
*
*
* Patientes in Biological relapsewill be rechallenge by Dra + R
20
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80
60
40
00 6 12 18 24 30 36 42 48 54 60
HR
Rd vs MPT: 0.78;; p = 0.017 (È 22% risk of death with Rd)
Rd vs Rd18: 0.90;; p = 0.307Rd18 vs MPT: 0.88;; p = 0.184
FIRST trial: lenalidomide as continuous therapy
DP, disease progression;; m, months;; MPT, melphalan, prednisolone, thalidomide;; Rd18, lenalidomide and low-dose dexametasone for 18 cycles.
Median PFSRd (n = 535) 25.5 mRd18 (n = 541) 20.7 mMPT (n = 547) 21.2 m
HRRd vs MPT: 0.72;; p = 0.0006Rd vs Rd18: 0.70;; p = 0.0001 Rd18 vs MPT: 1.03;; p = 0.70349
100
80
60
40
20
00 6 12 18 24 30 36 42 48 54 60
Facon T, et al. N Engl J Med. 2014;;371:906-17.
Continuous Rd reduced the risk of DP and death by 28% and 22% vs MPT, respectively. Rd as continuous therapy is a standard of care
Rd until DP vs Rd for 18 cycles vs MPT x 18 cycles, N = 1,623 patients
4-year OS
Rd (n = 535) 59.4%
Rd18 (n = 541) 55.7%
MPT (n = 547) 51.4%
PFS OS
Patients (%)
Patients (%)
Months Months
Progression-free survivalLandmark analysis
Progression-free survivalLandmark analysis
Time (months)
VT MaintenanceVMPT Off therapy
4-years PFS Median PFS
VMPT-VT 33% 31.5 months
VMP 16% 17.8 months
0.00
0.25
0.50
0.75
1.00
0 10 20 30 40 50 60 700.00
0.25
0.50
0.75
1.00
0 10 20 30 40 50 60 70
Patients (%)
Overall Survival (OS)30% Reduced Risk of DeathOverall Survival (OS)30% Reduced Risk of Death
Patients (%)
Time (months)
0.00
0.25
0.50
0.75
1.00
0 10 20 30 40 50 60 70 80 90
0.00
0.25
0.50
0.75
1.00
0 10 20 30 40 50 60 70 80 90
5-years OS Median OS
VMP
VMPT-VT
51% 60.6 months
61% Not reached
5-years OS Median OS
VMP
VMPT-VT
51% 60.6 months
61% Not reached
HR 0.70, 95% CI, 0.52-0.92, P = 0.01
Off therapyVT MaintenanceVMPT
Bortezomib as maintenance:VMPT→ VT x 2 y vs VMP with no maintenance
(GIMEMA-MM-03-05;; N = 511)
Time to next therapy: 46.6 vs 27.8 months and OS from relapse identical
Palumbo A, et al. J Clin Oncol. 2014;;32:634-40.
Bortezomib as maintenance is feasible during a fixed timey, years.
Progression-free survivalLandmark analysis
Overall survival30% reduced risk of death
HR 0.70, 95% CI 0.52–0.92, p = 0.01
VT maintenanceVMPTVT maintenanceVMPT
Summary (I)
• Maintenance therapy seems to benefit patients with MM after ASCT
and as continuous therapy in non-ASCT candidates.
However,…...... Some questions remain open:
• What is the optimal duration of maintenance?
• Can we personalize the maintenance?
Maintenance therapy after ASCT: futureSponsor/cooperative group Treatment
Lenalidomide-basedIFM/DFCI 2009 Lenalidomide x 1 year vs lenalidomide until DPMyeloma XI Lenalidomide vs lenalidomide + vorinostat vs no maintenance
GEM14MAIN Lenalidomide vs lenalidomide + ixazomib for up to 2 yearsPatients with MRD will continue 3 additional years
GMMHD6 Lenalidomide-dexamethasone vs lenalidomide-dexamethasone + elotuzumab
GIMEMA Lenalidomide vs lenalidomide + carfilzomibSWOG Lenalidomide vs lenalidomide + ixazomib until DP
US Cooperative group trials(pick the winner)
Lenalidomide vs lenalidomide + vaccination/lenalidomide x 2 years vs lenalidomide until DPLenalidomide vs lenalidomide + ixazomib
ECOG-ACRIN study Lenalidomide x 2 years vs lenalidomide until DP
AFT-40 Lenalidomide vs lenalidomide + durvalumab vs lenalidomide + daratumumab vs lenalidomide + ACY-241Other
C16019 Ixazomib for up to 2 years vs placebo HOVON-IFM Daratumumab vs placeboCCT-PNK-004-mmy001 Human cord blood derived, cultured and expanded NK cells
NK, natural killer.
Maintenance therapy in transplant-ineligible patients
Sponsor/cooperative group Treatment
C16019 Takeda Millennium Ixazomib for up to 2 years vs placebo
Myeloma XI LEN vs LEN + vorinostat vs no maintenance
Future new standards of care
LEN-DEX + daratumumab until DPLEN-DEX + elotuzumab until DPLEN-DEX + ixazomib until DPLEN-DEX + carfilzomibLEN-DEX + bortezomib followed by LEN-DEX
Transplant-ineligible patients benefit from CT until DPSome studies are investigating maintenance therapy
Will it be possible to personalize maintenance?
• Personalization of maintenance type:– standard risk versus high risk, based on cytogenetic abnormalities, ISS, LDH, etc.- Single agent for standard risk patients, len or ixa?- PI & IMiDs for high risk or just PI?
– toxicity during maintenance, QoL
• Personalization of maintenance duration– response status at start of maintenance: MRD-negative versus MRD-positive
– MRD status during maintenance – biomarkers: which maintenance drug or drug combination will my individual patient benefit most from?
– MRD only at the Bone Marrow level, or combine MRD by NGS/NGF with PET-CT??
ISS, International Staging System;; LDH, lactate dehydrogenase;; MRD, minimal residual disease;; QoL, quality of life.
• European trial investigating different durations of maintenance– MRD negative: 2 years– MRD positive: up to 5 years
PETHEMA GEM 2014 study
R
NCT02406144 at www.clinicaltrials.gov.
Len + dex
Len + dex+ Ixazomib
Len + dexup to 3 years
End of treatment
MRD negative
MRD positive
MRD evaluation at 2 years
GEM
2012MENOS65
n = 316
Annual MRD
PFS
dex, dexamethasone;; Len, lenalidomide;; R, randomization.
GEM2016FIT: Consolidation
2
aDuring the first cycle (6 weeks), bortezomib is given on D1, 4, 8, 11, 22, 25, 29, and 32.; GAH: J Geriatr Oncol. 2015 Sep;;6(5):353-61;; R1: first randomization;; R2: second randomization ;; IMF imnunofenotipic response NGF ( next generation flow)
NDMM patientsNS CTC >65 yn= 462 elderly Fit
Patients(GHA) ARM 2a KRd .N=154
CFZ: 20/70 mg/m2, d1, 8, 15 LEN: 25 mg, d1–21 DEX: 20/10 mg, d1, 2, 8, 9, 15, 16, 22, 23
18 28-day cyclesN=159
ARM 1 VMP N=154Mel: 9mg/m2 D1-4Pred: 60mg/m2 D1-4BTZ: 1.3mg/m2 D1, 8,15,22ªOne 6 week cycle followedby eight 4-week cycleN=159
Rd
LEN: 25 mg, d1–21 DEX: 20/10 mg, d1, 2, 8, 9, 15, 16, 22, 23
Nine 28-day cycles
(R1) Induction 18 cycles (R2) MaintenanceConsolidation
RdLEN: 25 mg, d1–21 DEX: 20/10 mg, d1, 2, 8, 9, 15, 16, 22, 23Dara 16 mg/Kg Days 1, 8, 15, 22 of cycles 1-‐2; Days 1 and 15 of cycles 3 and 4
Four 28-day cycles
Dara 16 mg/Kg IV Day 1 of cycles 1-‐24
+R 15 mg, d1–21 Until progresion
No maintenance
MRD9 cy
MRD18 cy
MRD22 cy
Dara 16 mg/Kg IV Day 1 of cycles 1-‐24
+R 15 mg, d1–21 Until progresionARM 2b KRD- DARA n=154
CFZ: 20/70 mg/m2, d1, 8, 15LEN: 25 mg, d1–21 DEX: 20/10 mg, d1, 2, 8, 9, 15, 16, 22, 23Dara 16 mg/Kg IV Days 1, 8, 15, 22 of cycles 1-‐2; Days 1 and 15 of cycles 3 and 4; Day 1 of cycles 5 to 18
No maintenance
Primary endpoint immonuphenotipic complete response Secondary exploratory outcome: PFS
MRD+
MRD-
Directly to the R2 maintenance fase
*
*
* Patientes in Biological relapsewill be rechallenge by Dra + R
Summary
• Maintenance therapy seems to benefit patients withMM after ASCT and as continuous therapy in non-ASCT candidates.
• Understanding the role of MRD and immune reconstitution should allow us to further improve the optimal maintenance therapy, duration, … to prolong OS
• Developing early endpoints as surrogate markers for long-term outcomes and OS is critically important;; otherwise, trials may continue for 10 years or longer
