Getting Clear Answers to Complex Treatment …ºs F. San-Miguel, MD, PhD Unsure Patient Case 3, Treatment VRD x 4 induction – Achieved VGPR (M -component: 4 g/dL) ASCT (mel200) –

Friday, December 8, 2017Atlanta, Georgia

Getting Clear Answers to Complex Treatment Challenges in Multiple Myeloma: Case Discussions

Friday Satellite Symposium preceding the 59th ASH Annual Meeting & Exposition.

This activity is supported by educational grants from Amgen, Celgene Corporation, Janssen, Karyopharm, Takeda Oncology, and The Binding Site.

Image: Copyright©2017 DNA Illustrations. All Rights Reserved

Discussion 3Transplant, Consolidation, and Maintenance:

The Role of MRD in Monitoring

Presented by Philippe Moreau, MD

Presenting Faculty

Philippe Moreau, MDProfessor of Clinical HematologyHead, Hematology Department University Hospital Hôtel-DieuNantes, France

Philippe Moreau, MD, has disclosed that he has received consulting fees from Amgen, Bristol-Myers Squibb, Celgene, Janssen, Novartis, and Takeda.

Program Director

Brian G.M. Durie, MDCo-Chair Myeloma Committee, SWOG Chairman, International Myeloma FoundationSpecialist in Multiple Myeloma and Related Disorders Cedars-Sinai Outpatient Cancer CenterLos Angeles, California

Brian G.M. Durie, MD, has disclosed that he has received consulting fees from Celgene, Johnson & Johnson, Amgen, and Takeda.

Patient Case 3

A 61-year-old male presents with bone pain and fatigue

He is diagnosed with multiple myeloma – IgG, M-spike 46 g/L

– Bone marrow aspirate: 32% plasma cells

– FISH: t(11;14)

– Creatinine: 80 mcM/L, Ca: 2.24 mM/L,

– β2-microglobulin: 3.8 mg/L, albumin: 38 g/L ISS2

– MRI: diffuse bone lesions

What is the optimal treatment plan for this patient?

Expert RecommendationBrian G.M. Durie, MD VRD x 4/ASCT (mel200)/VRD x 2 consolidation + len maintenance

Philippe Moreau, MD VRD x 4/ASCT (mel200)/VRD x 2 consolidation + len maintenanceVTD x 4/ASCT (mel200)/VTD x 2 consolidation/len maintenance

Bruno Paiva, PhD VRD x 4/ASCT (mel200)/VRD x 2 consolidation + len maintenance

S. Vincent Rajkumar, MD VRD x 4/ASCT (mel200)/VRD x 2 consolidation + len maintenance

Jesús F. San-Miguel, MD, PhD VRD x 4/ASCT (mel200)/VRD x 2 consolidation + len maintenance

Eligibility for ASCT

Yes No

First option: VMP, Rd, VRD

Second option: VCD, MPT

Other options: BP, CTD, MP

Induction: 3-drug regimensVTDVCDRVDPAD

200 mg/m2 Melphalan followed by ASCT

MaintenanceLenalidomide

Moreau P, et al. Ann Oncol. 2017;28 (Suppl 4):iv52-iv61.

FRONTLINE THERAPYESMO guidelines

Moreau et al, Ann Oncol 2017.

De Novo MM, Transplant Eligible

• Issues:

• Consolidation: YES or NO?

• Single vs tandem ASCT?

• How to improve?

• How to monitor?

Design of EMN02/HO95 Trial Sonneveld et al. ASH 2016. Abstract 242.

4 × VCD +Stem cell apheresis

R1

4 × VMP HDM 1/2

2 × VRD None

Lenalidomide Lenalidomide

HDM/ASCT at 1st relapse

RegistrationInduction

Stem cell mobilization in all pts

Consolidation

Maintenanceuntil relapse

R2 MRD

Early or late ASCT, once or twice

https://clinicaltrials.gov/ct2/show/NCT01208766 [Accessed March 2015]

EMN02/HO95: Progression-Free Survival

no consolidationVRDCox LR P=0.045 (adjusted for 1st random.)

N435450

F137115

no consolidation

VRD

At risk:435450

336371

187196

4952

no consolidation

VRD

0

25

50

75

100

Cum

ulat

ive p

erce

ntag

e

months0 12 24 36

Sonneveld et al. ASH 2016. Abstract 242.

Stadtmauer E, et al. ASH 2016. Abstract LBA-1.

Stadtmauer E, et al. ASH 2016. Abstract LBA-1.

Single vs Tandem ASCT Frontline TherapyEMN02 Trial

PFS PFS by Cytogenetic Risk OS

Cavo, et al. ASH 2017. Abstract 401.Oral presentation Sunday 10, 10.30

How to improve?

Cassiopeia

1080 patients enrolled, completed, ASH 2018?

Courtesy Dr JakubowiakEHA 2016. Abstract S101.

VRD +/- Daratumumab + ASCT

KRD +/- Daratumumab + ASCT

Maintenance Following ASCT

GEM

12m

enos

65

R

Arm ALena/dexaLena 15 mg/d x 21dDexa 20 mg d 1-4 y 9-12

Arm BLena/dexa + IXAZOMIB

Lena/dexa + MLN9708 4mg d 1,8,15

2 ye

ars

MRD pos

StopMRD neg

Lena/dexaX 3 years

GEM14

EUDRACT registry ID: 2014-000554-10.

Patient Case 3, Treatment

VRD x 4 induction– Achieved VGPR (M-component: 4 g/dL)



ASCT (mel200)– Achieved sCR




MRD was assessed using flow cytometry, 8-color, 2 tubes (EUROFLOW)– After ASCT: MRD negative 10-5

Would you prefer to use next generation sequencing (NGS) or next generation flow (NGF)? Expert RecommendationBrian G.M. Durie, MD NGFPhilippe Moreau, MD UnsureBruno Paiva, PhD NGFS. Vincent Rajkumar, MD UnsureJesús F. San-Miguel, MD, PhD Unsure




– After ASCT: MRD negative 10-5

VRD x 2 consolidation– Maintained sCR





VRD x 2 consolidation– Maintained sCR

– After consolidation (premaintenance): MRD negative 10-6

Are you using PET-CT?

Expert RecommendationBrian G.M. Durie, MD Yes, at diagnosis and before maintenancePhilippe Moreau, MD Yes, at diagnosis and before maintenanceBruno Paiva, PhD Yes, at diagnosis and before maintenanceS. Vincent Rajkumar, MD NoJesús F. San-Miguel, MD, PhD Yes, at diagnosis and before maintenance

Are you using both NGS/NGF and PET-CT?

Expert RecommendationBrian G.M. Durie, MD YesPhilippe Moreau, MD YesBruno Paiva, PhD YesS. Vincent Rajkumar, MD NoJesús F. San-Miguel, MD, PhD Yes


VRD x 4 induction

– Achieved VGPR (M-component: 4 g/dL)

ASCT (mel200)

– Achieved sCR


VRD x 2 consolidation

– Maintained sCR


Lenalidomide maintenance for 3 years, discontinued due to fatigue, GI toxicity

Patient Case 3, Treatment VRD x 4 induction

– Achieved VGPR (M-component: 4 g/dL)

ASCT (mel200)

– Achieved sCR


VRD x 4 consolidation

– Maintained sCR


Lenalidomide maintenance for 3 years, discontinued due to fatigue, GI toxicity– 1 year post maintenance: negative 10-6

– End of maintenance: negative 10-6

This patient remained MRD negative at 3 years post maintenance. Do you consider this patient cured?Expert RecommendationBrian G.M. Durie, MD UnsurePhilippe Moreau, MD UnsureBruno Paiva, PhD UnsureS. Vincent Rajkumar, MD NoJesús F. San-Miguel, MD, PhD Unsure

How to monitor?

Techniques Available to Measure MRD in MM

Next-generationflow NGS PET-CT

Availability High Limited Intermediate

Diagnostic sample Important but not mandatory Mandatory Important but not

mandatory

Applicability Universal (~100%) High (~90%) ~100%

Time 2-3 hours ≥7 days 2 hours

Cost ~350 USD ~700 USD ~2000 USD

Sensitivity 10−5–10−6 10−6 High (4 mm)

Quantitative Yes Yes Yes

Fresh sample Needed Not needed NA

Patchy sample Impacts Impacts No impact

Global cell characterisation Yes No No

Standardization Ongoing (EuroFlow) Not reported No

Adapted from Paiva B, et al. Blood. 2015;125:3059-68.

IFM DFCI 2009 Trial700 patients < 66y,

Newly diagnosed symptomatic MM

3 RVD

5 RVD MEL200 + ASCT

2 RVD

12 months’ Lenalidomide maintenance

MRD*

MRD*

MRD*

MRD** Primary objective = 7-color Flow, Secondary objective = Molecular

Attal M et al. NEJM 2017;376(14):1311-1320.

MRD by NGS; Threshold 10-6; Progression-Free Survival

Avet-Loiseau et al. ASH 2017. Abstract 435. Minimal Residual Disease in Multiple Myeloma: Final Analysis of the IFM2009 TrialOral presentation, Sunday at 12:30.

Indu

ctio

nVR

D x

6

R

Mel-200

Bu-Mel

Con

solid

atio

n

VRDx 2

MRD MRD MRD

Newly Diagnosed MM Patients Transplant Candidates

Primary endpoint: PFS comparing Mel-200 vs Bu-Melhttps://www.clinicaltrials.gov/ct2/show/NCT01916252

GEM12MENOS65

https://www.clinicaltrials.gov/ct2/show/NCT01916252

Impact of Next-Generation Flow (NGF) Minimal Residual Disease (MRD) Monitoring in Multiple Myeloma (MM): Results From the Pethema/GEM2012 Trial

Paiva, et al. ASH 2017. Abstract 905. Oral presentation, Monday 11, at 7:15pm

IFM/DFCI 2009 StudyNewly Diagnosed MM Pts (SCT Candidates)

RVDx3

RVD x 2

RVD x 5

Lenalidomide

Melphalan 200mg/m2* +

ASCT

CY (3g/m2) MOBILIZATIONGoal: 5 x106 cells/kg

RVDx3

CY (3g/m2)MOBILIZATIONGoal: 5 x106 cells/kg

Randomize

Lenalidomide

ASCT at relapse

PET-CT/MRD evaluation



PFS for Patients withNegative PET-CT and Negative MRD by Flow

(47.7% of patients) pre-maintenance vs others, P = 0.05

Moreau et al. J Clin Oncol 2017;35:2911-2918.

Pts with Negative PET-CT and Negative MRD by Flow

Other Pts

Validated points Open issues

MRD negativity is a surrogate for PFSMRD negativity is a surrogate for OS

MRD by NGS is standardizedMRD by NGF (EuroFlow) is standardized

MRD by NGS or NGF and PET-CT are complementary

MRD useful to compare treatment options

Moreau, Zamagni. Blood Cancer J, 2017

Validated points Open issues

MRD negativity is a surrogate for PFSMRD negativity is a surrogate for OS

MRD by NGS is standardizedMRD by NGF (EuroFlow) is standardized

MRD by NGS or NGF and PET-CT are complementary

MRD useful to compare treatment options

Optimal threshold for PFS and/or OS prediction by NGS or NGF?

Need for both NGS and NGF?

Time interval to define sustained MRD negativity?Definition of loss of MRD-negative status?Optimal timing for MRD assessment during and after treatment?Meaning of MRD negativity in specific subgroups (ie, high-risk cytogenetics)?

Standardization of MRD by PET-CT?Best tracer for PET-CT?

MRD to alter therapy: duration of maintenance, change treatment, add agents…

Blood-based MRD assessment?MRD and detection of clonal evolution?MRD and MGUS-like profile?MRD as a valid endpoint for drug approval?

Moreau, Zamagni. Blood Cancer J, 2017

SCR

EEN

FOLL

OW

-UP

RAN

DO

MIZ

EVTD + DARA

x 4 cycles

VTDx 4 cycles St

em c

ell m

obili

zatio

n/C

ondi

tioni

ng a

nd A

SCT

Induction

VTD + DARAx 2 cycles

VTDx 2 cycles

Consolidation

RAN

DO

MIZ

E

DARA Q8W for 2 years

Observation

Maintenance

Part 1 Part 2

≥PR

www.clinicaltrials.gov; NCT02541383

CASSIOPEIA trialPET/FLOW/NGS PET/FLOW/NGS



Indu

ctio

nVR

Dx6 R

Mel-200

Bu-Mel

Con

solid

atio

n

GEM12MENOS65

VRDx 2

MRD MRD MRD

Newly diagnosed MM patients transplant candidates

Primary end-point: PFS comparing Mel-200 vs Bu-Melhttps://www.clinicaltrials.gov/ct2/show/NCT01916252

Rosinol L, et al. ASH 2017. Abstract 2017. Sat 9, 5.30 pm


GEM

12m

enos

65

R

Arm ALena/dexaLena 15 mg/d x 21dDexa 20 mg d 1-4 y 9-12

Arm BLena/dexa + Ixazomib 4mg d 1,8,15

MR

D a

t 2 y

ears

MRD pos

StopMRD neg

Lena/dexaX 3 years

GEM14

MRD annual

Maintenance



KRd Study Design: Forte

Newly diagnosed multiple myeloma

patients eligible for autologous

transplantation (ASCT)

N= 425

Endpoints:• Primary: VGPR• Secondary: ORR,

DoR, TTNT, OS, MRD

Arm A: CRd• Carfilzomib 36 mg/m2 IV Days 1, 2, 8,

9, 15, 16• Lenalidomide 25mg/day Days 1 - 21• Dexamethasone 20mg PO Days 1, 2,

8, 9, 15, 16, 22, 23

Arm A: CRd• Carfilzomib 36 mg/m2 IV Days 1, 2, 8,

9, 15, 16• Lenalidomide 25mg/day Days 1 - 21• Dexamethasone 20mg PO Days 1, 2,

8, 9, 15, 16, 22, 23

Arm B: CCyd• Carfilzomib 20/36 mg/m2 IV Days 1, 2,

8, 9, 15, 16• Cyclophosphamide 300mg/m2 Days

1, 8, 15• Dexamethasone 20mg PO Days 1, 2,

8, 9, 15, 16, 22, 23

Arm B: CCyd• Carfilzomib 36 mg/m2 IV Days 1, 2, 8,

9, 15, 16• Cyclophosphamide 300mg/m2 Days

1, 8, 15• Dexamethasone 20mg PO Days 1, 2,

8, 9, 15, 16, 22, 23

Study Schema: One cycle = 28 days

Arm C: CRd• Carfilzomib 36 mg/m2 IV Days 1, 2, 8, 9, 15, 16• Lenalidomide 25mg/day Days 1 - 21• Dexamethasone 20mg PO Days 1, 2, 8, 9, 15, 16, 22, 23

Induction (4 cycles) Consolidation (4 cycles)

Lenalidomide 10mg Days 1-21

MaintenanceOne cycle = 28 days

Lenalidomide 10mg Days 1-21

Carfilzomib 27 mg/m2 IV Days 1, 2, 15, 16

R R To Progression or Intolerance

ASCT

Total 12 Cycles

One cycle = 28 days

NGS/NGFPET

NGS/NGFPET

NGS/NGFPET

NGS/NGF

Gay et al. ASH 2017. Abstract 4541. Monday 11, 6 pm

Standard-Risk Patients, Eligible for Frontline ASCT

Negative

MRD PositiveFurther therapy+ maintenance

Triplet/quadrupletinduction4 cycles

Triplet/quadrupletconsolidation

2 cycles

PET or DWI+ NGF/NGS

ASCT

PET or DWI+ NGF/NGS

MRD Negative Maintenance 2/3 yrs

MRD MRD MRD

Reappearance= relapse? therapy ?

Anderson K, et al. Clinical Cancer Research 2017;23:3980-3993.

® stop vs continue

Thank you

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Documents

Getting Clear Answers to Complex Treatment …ºs F. San-Miguel, MD, PhD Unsure Patient Case 3, Treatment VRD x 4 induction – Achieved VGPR (M -component: 4 g/dL) ASCT (mel200) –