Initial Therapy

Sagar Lonial, MDChair and Professor

Department of Hematology and Medical OncologyChief Medical Officer, Winship Cancer Institute

Emory University School of Medicine

Topics

When to treat? Smoldering vs SymptomaticChoice of Induction regimenRole of HDTRole of consolidation/maintenance

Criteria for Diagnosis of Myeloma

MGUS < 3 g M spike < 10% plasma cells

AND

SMM 3 g M spike 10% plasma cells

Active MM 10% plasma cells M spike +

AND

No anemia, bone lesions,normal calcium, and

kidney function

MGUS = monoclonal gammopathy of unknown significance; SMM = smoldering multiple myeloma. Kyle et al, 2009.

Anemia, bone lesions,high calcium, or

abnormal kidney function

Kyle R et al. N Engl J Med 2007;356:2582-2590

Not all Smoldering patients are the same

27% will convert in 15 yearsRoughly 2% per year

Free Light is Useful for Risk Assessment in AMM

Dispenzeri et al Blood 2008

Updated IMWG Criteria for Diagnosis of Multiple Myeloma

C: Calcium elevation (> 11 mg/dL or > 1 mg/dL higher than ULN)R: Renal insufficiency (creatinine clearance < 40 mL/min or serum creatinine > 2 mg/dL)A: Anemia (Hb < 10 g/dL or 2 g/dL < normal)B: Bone disease ( 1 lytic lesions on skeletal radiography, CT, or PET-CT)

Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

MGUS M-protein < 3 g/dL Clonal plasma cells in BM

< 10% No myeloma defining events

Smoldering Myeloma M-protein 3 g/dL (serum)

or 500 mg/24 hrs (urine) Clonal plasma cells in BM

10% - 60% No myeloma defining events

Multiple Myeloma Underlying plasma cell

proliferative disorder AND

1 or more myeloma defining events including either:

1 CRAB feature(s)OR

1 Biomarker Driven

Biomarker driven (1) Sixty-percent (60%) clonal PCs by BM; (2) serum free Light chain ratio involved:uninvolved 100; (3) >1 focal lesion detected by MRI

ECOG/SWOG: Phase III Asymptomatic Myeloma*(PI: SL)Lenalidomide vs. observation

Observation

Lenalidomide CR/PR/Stable

Prog.anytime

Continue therapytill prog. or toxicity

Off Rx

RANDOMIZATION

Control/standard arm

No Dex to isolate the effect of len

Ongoing Investigations

RD + Dara RD+ Pembro/nivo Vaccine + len + Durva KRD auto transplant KRD KRD + Dara auto KRD Len

PETHEMA Cure with old Drugs

Martinez-Lopez et al, Blood 2011

Functional cure?

Survival outcomes in newly diagnosed myeloma patients with RVD induction among all patients

(at a median follow up of 66 months)

Nooka et al, unpublished

Three Drugs Are Better Than Two

0

10

20

30

40

50

60

70

80

90

100

TD RD VD VTD VCD RVD

ORR

VGPR

Nooka et al. Cancer 2013. DOI: 10.1002/cncr.28325

Induction regimens in MM

Progression Free Survival Overall Survival

Impact of IMIDs on OS and PFS with translocations

Barwick et al

CR and VGPR rates in high risk subgroups of patients

P

Randomized Trial VTD vs VCD Shows superiority of IMID/PI

Moreau et al, Blood 2016

VCD is no longer a reasonable induction choice

RVD is better than VCD

Compass trial, IA9

SWOG S0777 Study Design (continued)

VRd

Rd

After induction

Rd Maintenance Until PD, Toxicity or Withdrawal

Lenalidomide 25 mg PO days 1-21

Dexamethasone 40 mg PO days 1, 8,15, 22

All patients received Aspirin 325 mg/day VRd patients received HSV prophylaxis

17

Durie et al, Lancet 2017

Confirmed Response*: VRd versus Rd

*Assessable patients

VRd RdCR 15.7% 8.4%

VGPR 27.8% 23.4%

PR 38% 39.7%

ORR (PR or better) 81.5% 71.5%

SD 15.7% 24.3%

SD or better 97.2% 95.8%

PD or Death 2.8% 4.2%

1818

Durie et al, Lancet 2016

Progression-Free Survival By Assigned Treatment Arm

Log-rank P value = 0.0018 (one sided)*

*Stratified

19

HR = 0.712 (0.560, 0.906)*

19Durie et al, ASH 2015*Assessable patients 1919D i t l ASH 2015

Durie et al, Lancet 2016

Overall Survival By Assigned Treatment Arm

Log-rank P value = 0.0250 (two sided)*

HR = 0.709 (0.516, 0.973)*

20

*Stratified*Assessable patients

2020

Durie et al, Lancet 2016

Where are we?

Risk stratify Smoldering IMID/PI combination is the standard of care Which PI?

KRD for newly diagnosed Myeloma

Frontline Therapy with Carfilzomib, Lenalidomide, and Dexamethasone(KRd) Induction Followed By Autologous Stem Cell Transplantation,

KRd Consolidation and Lenalidomide Maintenance in Newly Diagnosed Multiple Myeloma (NDMM) Patients:

Primary Results of the Intergroupe Francophonedu Mylome (IFM) KRd Phase II Study

NCT02405364

M. Roussel, V. Lauwers-Cances, N. Robillard, K. Belhadj, T. Facon, L. Garderet, M. Escoffre, B. Pegourie, L. Benboubker, D. Caillot, C. Fohrer, P. Moreau, X. Leleu,

H. Avet-Loiseau, and M. Attal for the IFM

STUDY DESIGNOpen-label, multicenter, phase II study in frontline MM pts < 65 yrs

Induction KRd 1-428-day cycles Carfilzomib/Len/Dex

PBSC harvest:Cyclophosphamide high dose

MaintenanceLenalidomide 10mg D1-21

13 cycles (1 year)

IntensificationHD Melphalan 200 mg/m2

Consolidation KRd 5-828-day cycles Carfilzomib/Len/Dex

KRd Induction

Carfilzomib 20-36mg/m2 D1, 2, 8, 9, 15, 16

Lenalidomide 25 mg D1-21Dexamethasone 20 mg1-2, 8-9, 15-16, 22-23

KRd Consolidation

Carfilzomib 36mg/m2 D1,2, 8, 9, 15, 16

Lenalidomide 25 mg D1-21Dexamethasone 20 mg D1, D8, D15, D22

Mandatory LMWH

MRD evaluation for VGPR pts (CMF/NGS)

RESPONSE RATES at the completion of Consolidation

MRD CMF 10-4/10-5MRD NGS clonoSEQ Adaptive 10-6

N=46 n %

sCR 26 57

4 patients were not evaluable due to toxicities

N=46 n %

sCR 26 57

MRD - CMF 32 70

MRD - NGS 23/34 68

N=46 n %

sCR 26 57

MRD - CMF 32 70

MRD - NGS 23/34

At least CR 28 61

At least VGPR 39 85

ORR 41 89

PD 1 2

RESPONSE RATES

Post Induction

Post ASCT Post

Consolidation Best Response

n n n n %

sCR 9 15 26 32 70

CR+sCR 11 19 28 35 76

VGPR 25 18 11 7 15

VGPR or better 36 37 39 42 91

PR 6 3 2

ORR 42 40 41 46 100

PD 1 1 1

CARDIO-VASCULAR + PULMONARY TOXICITIES all grades

25 CARDIAC AND VASCULAR EVENTS Total No of events No of patients (%)

Cardiac Failure 2 2 (4)Pulmonary Embolism 2 2 (4)Venous Thrombosis 2 2 (4)Intra Cardiac Thrombus 1 1 (2)Superfical Thrombosis 8 8 (17)Bradycardia 2 2 (4)Arrhythmia 1 1 (2)Atrial Fibrillation 1 1 (2)Tachycardia 1 1 (2)Hypertension 5 4 (9)

Cough 11 9 (20)Dyspnea 5 5 (11)

IRD Response Rates

Kumar SK, et al. Lancet Oncol. 2014;15(13):15031512

Ixazomib-Lenalidomide-Dexamethasone (IRd) combination before and after ASCT followed by

Ixazomib maintenance in patients with newly diagnosed multiple myeloma:

a phase 2 study from the Intergroupe Francophone du Mylome (IFM)

P Moreau, C Hulin, D Caillot, G Marit, A Perrot, L Garderet, T Facon,L Benboubker, L Karlin, M Tiab, B Arnulf, JP Fermand, X Leleu,

C Touzeau, M Roussel, L Planche, H Caillon, S Minvielle, MC Bn,H Avet-Loiseau, T Dejoie, M Attal

1- Induction: 3 cycles of Ixazomib RD, every 28 days- Ixazomib 4 mg/d; D1, 8, 15- Lenalidomide 25 mg/d ; D1 to 21- Dexamethasone 40 mg/d; D1, 8, 15, 22

2- PBSC harvestMobilization: Cyclophosphamide 3 g/m2 and G-CSF 5 g/kg

3- Peripheral stem cell transplantationMelphalan 200 mg/m2

4- Early consolidation : 2 cycles of Ixazomib/Len/Dex, every 28 days

5- Late consolidation: 6 cycles of Ixazomib/Len (without Dex), every 28 days

6 Maintenance therapy for 1 year (13 cycles) Ixazomib weekly 4 mg D1, 8, 15, every 28 days

Study design

Responses intent-to-treatPost-induction

N = 42Post-ASCT

N = 42

Post-earlyConsoN = 42

Post-lateConsoN = 42

sCR (%)CR (%)VGPR (%)PR (%)Stable (%)PD (%)NE (%)

> PR (%)> VGPR (%)> CR (%)

2.49.523.842.914.34.82.4

8138.111.9

10.88.1

51.424.35.400

94.670.318.9

275.4

43.221.6

02.70

97.375.732.4

314.8

26.214.3

04.819

76.261.935.7

During induction : 2 PD, 1 RashFeasibility ASCT: 37 / 42 (88%)

ASCT: no toxic death, no PDFeasibility: 37 / 42

Early consolidation : no SAE, 1 PDFeasibility: 37 / 42

Late consolidation: 1 SAE (rash), 1 PDFeasibility 34 / 42 (81%)

Maintenance ongoing : 1 thrombocytopenia precluding maintenance, 2 PD

Intent-to-treat / feasibility

AEs leading to exclusion- During induction : 1 rash- Late consolidation: 1 rash- Before maintenance: 1 thrombocytopenia

12 cases of non-hematologic grade 3-4 toxicities were reported:-infections (8 cases),-abdominal pain (2),-atrial fibrillation (1),-thrombosis (1)

No cardiac failure, no ischemic heart disease, no renal impairment

No grade 3-4 peripheral neuropathy

Safety (excluding ASCT, and maintenance)

ELO+ RVD phase II study

Newly Diagnosed

Multiple Myeloma

4 cycles Elo-RVD

ASCT NO

High Risk:Elotuzumab LenalidomideBortezomib Dexamethasone

Low Risk:ElotuzumabLenalidomideDexamethasone

Stem Cell Mobilization

ASCT YES

4 cycles Elo-RVD

Autologous Stem Cell Transplantation

Induction therapy and Transplant Maintenance28-day cycles

Screening

Follow Up Visits

every 3 months

Follow Up

Laubach et al, ASH 2016

Response After 4 Cycles

Laubach et al, ASH 2016

On-study death and treatment discontinuations due to AEs One patient died on study

Hospitalized due to respiratory failure and sepsis during cycle 2 and subsequently died as a result of these AEs

One patient died > 30 days after discontinuing study therapy Patient became acutely ill during cycle 1, hospitalized for febrile neutropenia and

hypotension related to sepsis, then developed renal failure. Participant was removed from study and died more than 30 days later.

Five additional patients discontinued from treatment due to the following AEs: Grade 3 peripheral neuropathy, discontinues treatment after cycle 3 Grade 3 mood disturbance, discontinues treatment after cycle 3 Grade 4 hyperglycemia, discontinues treatment after cycle 2 Grade 3 orthostatic hypotension and demyelinating polyneuropathy, d/cs treatment after

cycle 4 Grade 3 lung infection, discontinues treatment after cycle 2

Laubach et al, ASH 2016

Where are we?

Risk stratify Smoldering IMID/PI combination is the standard of care Which PI?

Bz has the most data, randomized trials in progress Role of HDT?

Registration

RVD 1 Lenalidomide + Bortezomib + Dexamethasone

25mg/d (d1 to 14) 1.3mg/m2 (d 1, 4, 8, 11) 20mg/d (d1,2,4,5,8,9,11,12)

)

Randomization (stratified on ISS and FISH)

Arm A Arm BRVD 2 and 3

PBSC Collection (cyclophosphamide 3g/m2 and G-CSF)

10mcg/kg/d)ASCT

HDM 200mg/m2 RVD 4 to 8

RVD 4 and 5

Lenalidomide Maintenance 12 months (10-15 mg/d)

RVD 2 and 3

PBSC Collection (cyclophosphamide 3g/m2 and G-CSF)

IFM 2009 : Study Design.

Lenalidomide Maintenance 12 months (10-15 mg/d)

IFM 2009: Best Response.

RVD armN=350

Transplant armN=350 p-value

CR 49% 59%

VGPR 29% 29% 0.02

PR 20% 11%

IFM 2009: PFS (9/2015)

P < 0 .0 01

0

10

20

30

40

50

60

70

80

90

10 0

Pa

tie

nts

(%

)

3 5 0 296 2 28 12 8 24no H D T35 0 309 2 61 15 3 27H D T

N a t risk

0 12 24 36 48

M o n th s o f f o l lo w -u p

H D T

no H D T

P N S

0

10

20

30

40

50

60

70

80

90

10 0

Pat

ient

s (%

)

3 5 0 33 8 3 20 24 4 56no H D T35 0 32 8 3 09 22 6 55H D T

N a t risk

0 12 24 36 48

M o n th s o f f o l lo w -u p

H D T

no H D T

IFM 2009: OS (9/2015)

KRD outcomes by Transplant Status

Jakubowiak et al, EHA 2016

Getting to Minimal Residual Disease (MRD): New Definitions for CR

S.S. Patient

11012

Stringent CR

Molecular/Flow CR?Cure?

Disease burden

Newly diagnosed

1108

1104

0.0

AntibodiesMaintenance

Therapy

CR

MRD

P-value (trend) : p

Where are we?

Risk stratify Smoldering IMID/PI combination is the standard of care Which PI

Bz has the most data, randomized trials in progress Role of HDT

Continues to offer benefit in achievement of MRD- Role of consolidation/Maintenance

Up-front single versus double autologous stem cell transplantation

for newly diagnosed multiple myeloma: an intergroup, multicenter, phase III study

of the European Myeloma Network (EMN02/HO95 MM Trial)

Michele Cavo*, Maria Teresa Petrucci, Francesco Di Raimondo, Elena Zamagni, Barbara Gamberi, Claudia Crippa, Giulia Marzocchi, Mariella Grasso, Stelvio

Ballanti, Donatella Iolanda Vincelli, Paola Tacchetti, Massimo Offidani, Giampietro Semenzato, Anna Marina Liberati, Anna Pascarella, Giulia Benevolo,

Rossella Troia, Angelo D. Palmas, Nicola Cantore, Rita Rizzi, Fortunato Morabito, Mario Boccadoro, and Pieter Sonneveld

On behalf of EMN02/HO95 MM Trial participants* Seragnoli Institute of Hematology, Bologna University School of Medicine, Italy

0.00

0.50

1.00

% P

roba

bilit

y

208 171 132 50 9 0HDM1207 185 145 69 19 1HDM2

Number at risk

0 12 24 36 48 60months

HDM2 HDM1

PFS by randomization 1 (HDM-1 vs HDM-2)

HDM-2 HDM-1PFS median, mos NR NRPFS at 3 yrs, % 73.6 62.2

HR (95% CI): 0.70 (0.49-1.01); p = 0.05

Median follow-up: 32 months (IQR 26-41)

PFS by high-risk cytogenetics

0.00

0.50

1.00

% P

roba

bilit

y

43 34 20 7 1 0HDM138 35 28 9 2 1HDM2

Number at risk

0 12 24 36 48 60months

HDM2 HDM1

HDM-2 HDM-1PFS median, mos 46.8 26.5PFS at 3 yrs, % 64.9 41.4

HR (95% CI): 0.49 (0.24-0.99); p = 0.046

EMN02 / HOVON 95 MMA randomized phase III study to compare Bortezomib,

Melphalan, Prednisone (VMP) with High Dose Melphalan followed by Bortezomib, Lenalidomide,

Dexamethasone (VRD) consolidation and Lenalidomide maintenance in patients with newly

diagnosed multiple myeloma

(NTR2528, Eudract 2009-017903-28)

The European Intergroup Trial of the European Myeloma Network EMN

Design of EMN02 trial

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]

Sonneveld et al. ASH 2016

EMN02 / HO95 MM 51

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

perc

enta

ge

months0 12 24 36

Progression free survival

HR = 0.78 (0.61-1.00)

Progression-free survival

Sonneveld et al. ASH 2016

Stadtmauer et al. ASH 2016

Stadtmauer et al. ASH 2016

Stadtmauer et al. ASH 2016

Where are we? Risk stratify Smoldering IMID/PI combination is the standard of care Which PI

Bz has the most data, randomized trials in progress Role of HDT

Continues to offer benefit in achievement of MRD- Role of consolidation

Limited role, tandem transplant does not offer benefit Role of Maintenance

Overall Survival: Median Follow-Up of 80 Months

0.00 10 20 30 40 50 60 70 80 90 100 110 120

0.2

0.4

0.6

0.8

1.0

There is a 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, mos

Surv

ival

Pro

babi

lity

Patients at risk

7-yr OS

62%

50%N = 1209 LENALIDOMIDE CONTROL

Median OS(95% CI), mos

NE(NE-NE)

86.0(79.8-96.0)

HR (95% CI)P value

0.74 (0.62-0.89).001

a Median for lenalidomide treatment arm was extrapolated to be 116 months based on median of the control arm and HR (median, 86 months; HR = 0.74). HR, hazard ratio; NE, not estimable; OS, overall survival.

0 . 2 5 0 . 5 1 2

5 0 m L / m i n

< 5 0 m L / m i n

N o

Y e s

N o n - L E N

L E N

P R / S D / P D

C R / V G P R

C R

I I I

I o r I I

F e m a l e

M a l e

6 0 y r s

< 6 0 y r s

H R

LENa CONTROLa HR (95% CI)

Age372 375 0.68 (0.54-0.86)233 229 0.83 (0.63-1.10)

Sex322 349 0.65 (0.52-0.83)283 255 0.91 (0.69-1.19)

ISS stage411 440 0.65 (0.52-0.81) 113 90 1.04 (0.72-1.51)

Response after ASCT66 80 0.63 (0.35-1.16)

320 339 0.70 (0.54-0.90)218 210 0.86 (0.65-1.15)

Prior induction therapy147 146 0.48 (0.31-0.75)458 458 0.82 (0.67-1.00)

Adverse-risk cytogeneticsb56 36 1.18 (0.66-2.10)

231 243 0.79 (0.59-1.06)

CrCl after ASCTc33 25 0.73 (0.33-1.60)

379 404 0.74 (0.59-0.92)

Overall Survival: Subgroup Analysis

Favors controlFavors LEN

Suggested Approach for Newly Diagnosed MM

Transplant Eligible

Yes No

RVD

High RIsk Std RIsk

Early Transplant Early vs Delayed Transplant

t(4:14)

Bz Maintenance

Del 17p Other high risk features

RVD Maintenance

Len Maintenance

Std RIsk High RIsk

RVD-liteMPV

t(4:14)

Bz Maintenance

Del 17p Other high risk features

RVD Maintenance

Rd, Vd,

Nooka et al, JOP 2016

Failure to achieve VGPR

Car/Pom/DexMaintenance

Emory OS by Genetics

Nooka et al, Leukemia 2013

N= 256 all patients received RVD

High risk all received 3 drug maintenance

Minimal exposure to alkylators

New directions

IMID/PI is the standard of Care for Newly diagnosed MM, question on optimal PI remains the subject of trials

Transplant continues to have an important role in quest to achieve MRD negativityTandem in US patients not standard

Maintenance is not one size fits all 4 drug induction is on the way

Thanks to:Jonathan KaufmanCharise Gleason Danni CassabourneMelanie Watson Donald HarveyRenee SmithColleen LewisAmelia Langston L.T. Heffner Ebeneezer David Claire TorreS-Y Sun Jing Chen Fadlo Khuri Leon BernalLarry Boise

IMSGolfers Against CancerT.J. Martell Foundation

And Many Others who are part of the B-cell Team

Initial TherapyTopicsCriteria for Diagnosis of MyelomaSlide Number 4Free Light is Useful for Risk Assessment in AMMUpdated IMWG Criteria for Diagnosis of Multiple MyelomaSlide Number 7Ongoing InvestigationsPETHEMA Cure with old DrugsSlide Number 10Three Drugs Are Better Than TwoSlide Number 12Impact of IMIDs on OS and PFS with translocationsSlide Number 14Randomized Trial VTD vs VCD Shows superiority of IMID/PI RVD is better than VCDSlide Number 17Slide Number 18Slide Number 19Slide Number 20Where are we?Slide Number 22Slide Number 23Slide Number 24Slide Number 25Slide Number 26Slide Number 27IRD Response RatesIxazomib-Lenalidomide-Dexamethasone (IRd) combination before and after ASCT followed by Ixazomib maintenance in patients with newly diagnosed multiple myeloma:a phase 2 study from the Intergroupe Francophone du Mylome (IFM)Study designSlide Number 31Intent-to-treat / feasibilitySafety (excluding ASCT, and maintenance)ELO+ RVD phase II studyResponse After 4 CyclesOn-study death and treatment discontinuations due to AEsWhere are we?Slide Number 38Slide Number 39Slide Number 40Slide Number 41Slide Number 42Getting to Minimal Residual Disease (MRD): New Definitions for CRSlide Number 44Where are we?Slide Number 46Slide Number 47Slide Number 48Slide Number 49Design of EMN02 trial Progression-free survivalSlide Number 52Slide Number 53Slide Number 54Where are we?Overall Survival: Median Follow-Up of 80 MonthsOverall Survival: Subgroup AnalysisSlide Number 58Slide Number 59New directionsSlide Number 61