consolidation and* maintenance therapy...thalidomidemaintenancestudies significant*improvement*...

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.

100

90

80

70

60

50

40

30

20

10

0

100

90

80

70

60

50

40

30

20

10

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

80

100

60

20

40

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

0.3

0.4

0.5

0.6

0.7

0.8

0.9

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

107

106

105

104

103

102

101

10

0

Presentation

PR

VGPR

CR

sCR

Total number of tumourcells

MRD

Undetectable MRD

(Operational cure)

Time to progression

-­

-­

-­

-­

-­

-­

-­

-­

-­

-­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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0

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

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10

20

30

40

50

60

70

80

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

10

20

30

40

50

60

70

80

90

100

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

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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

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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