esmo e-learning: treatment of multiple myeloma patients...diagnostic criteria for multiple myeloma...

TREATMENT OF MULTIPLE MYELOMA PATIENTS

Jesus San-Miguel

Universidad Navarra, Spain

In very elderly patients (>80–85 years)… To ensure QoL and avoid additional costs of expensive

treatments

In fit elderly patients (65–80 years) and young ones with severe co-morbidities… Treatment goal

should be to prolong survival and ensure QoL

In young patients (<65 years)… In reference centres and large cooperative groups… To

investigate therapeutic schemes with a cure in the horizon*

WHAT SHOULD BE THE TREATMENT GOAL IN

MULTIPLE MYELOMA (MM) PATIENTS?

To search for an appropriate balance between treatment efficacy, toxicity and costs

*to achieve and maintain the best possible response

Pro

gres

sion

-fre

e su

rviv

al (

%)

Time from diagnosis (months)

CR (n=548) median PFS: 56 months

nCR (n=249) median PFS: 43 months

PR (n=535) median PFS: 33 months

<PR (157) median PFS: 20 months

p<0.001

CR vs nCR: p<0.001

nCR vs PR: p=0.004

PR vs <PR: p<0.001

Ove

rall

surv

ival

(%

)


CR (n=548) median OS: 108 months

nCR (n=249) median OS: 91 months

PR (n=535) median OS: 73 months

<PR (157) median OS: 35 months

p<0.001

CR vs nCR: p=0.09

nCR vs PR: p<0.001

PR vs <PR: p<0.001

100

80

60

40

20

0

0 50 100 150 200

100

80

60

40

20

0

0 50 100 150 200

GEM2000, GEM2005MENOS65, GEM2005MAS65, GEM2010MAS65

PFS OS

PATIENTS ATTAINING CR EXPERIENCE PROLONGED

PFS AND OS… BUT…

Data on file. Adapted by Prof J. San Miguel

PFS

Pro

gres

sion

-fre

e su

rviv

al (

%)


MRD- (n=318) median PFS: 70 months

CR (n=130) median PFS: 36 months

nCR (n=96) median PFS: 32 months

PR (n=207) median PFS: 35 months

<PR (46) median PFS: 20 months

P <.001

MRD- vs. CR: P <.001

CR vs. nCR: P =.131

nCR vs. PR: P =.589

PR vs. <PR: P =.002

Ove

rall

surv

ival

(%

)


MRD- (n=318) median OS: Not reached

CR (n=130) median OS: 71 months

nCR (n=96) median OS: 75 months

PR (n=207) median OS: 67 months

<PR (46) median OS: 46 months

P <.001

MRD- vs. CR: P <.001

CR vs. nCR: P =.657

nCR vs. PR: P =.583

PR vs. <PR: P =.032

100

80

60

40

20

0

0 50 100 150 200

100

80

60

40

20

0

0 50 100 150 200

GEM2000, GEM2005MENOS65,

GEM2005MAS65, GEM2010MAS65

PFS OS

DEPTH OF RESPONSE CORRELATES WITH SURVIVAL

MRD is the best biomarker to predict outcome

Lahuerta JJ, et al. J Clin Oncol, 35(25), 2017: 2900–10. Reprinted with permission. © 2017 American Society of Clinical Oncology. All rights reserved.

The definition of CR is suboptimal and confusing for patients.

If cure is the goal, the risk of undertreating patients by concluding they are in CR may be a serious error

0,0 0,2 0,4 0,6 0,8 1,0 1,2

Overall

Transplant eligible

Transplant ineligible

ISS I

ISS II

ISS III

Standard-risk FISH

High-risk FISH

Reduced risk after MRD–

0,0 0,2 0,4 0,6 0,8 1,0 1,2

Overall

Transplant eligible

Transplant ineligible

ISS I

ISS II

ISS III

Standard-risk FISH

High-risk FISH

Reduced risk after MRD-–

Progression-free survival Overall survival

Lahuerta JJ, et al. J Clin Oncol, 35(25), 2017: 2900–10. Reprinted with permission. © 2017 American Society of Clinical Oncology. All rights reserved

IMPACT OF MRD ACROSS MM PATIENT SUBGROUPS

NGS1

0

20

40

60

80

100

0 12 24 36 48

Time from MRD assessment

after consolidation (months)

Pro

gres

sion

-fre

e su

rviv

al (

%)

Negative MRD, median PFS: not reached

MRD positive ≥2x10-6 to <10-5, median PFS: not reached

MRD positive ≥10-5 to <10-4, median PFS: 31 months

MRD positive ≥10-4, median PFS: not reached

NGF2

1. Republished with permission of American Society of Hematology, from Blood, Perrot A, et al. 132, 23, 2018, permission conveyed through Copyright Clearance Center, Inc, and with permission from Dr Avet Loisseau; 2. Paiva B,

et al. J Clin Oncol. Manuscript in review. With permission from Dr J San Miguel; 3. Reprinted from Clin Cancer Res 2015;21(19):4384–90, Zamagni E, et al. PET/CT Improves the Definition of Complete Response and Allows to

Detect Otherwise Unidentifiable Skeletal Progression in Multiple Myeloma, with permission from AACR; 4. Moreau P, et al. Blood 2015;126: Abstract 395. Presented at ASH 2015

PET3,4

The concept of PET CR......Methionine?

MRD ASSESSMENT (ENDPOINT)

The lower the level of MRD, the longer the survival

MRD in the logarithmic range of 10-6 is clinically relevant

IFM 2009: PET-CT normalisation before maintenance

Impact on PFS and OS (62% normalised)4

PET-CT normalisation before maintenance associated with significant improvement in:

• 30-month PFS rate: 54.4% in PET-CT+ vs. 75.9% in PET-CT– (p=0.0004)

• 30-month OS rate: 69.9% in PET-CT+ vs. 94.6% in PET-CT– (p=0.01)

PFS

PFS and OS in patients in CR after 1st-line therapy3

OS

Response subcategory Response criteria

IMW

G M

RD

neg

ativ

ity

crit

eria

(Req

uir

es C

R a

s d

efin

ed b

elo

w)

Sustained

MRD-negative

MRD negative in the bone marrow (by next-generation flow cytometry or next-generation sequencing) and by

imaging as defined below, confirmed 1 year apart; subsequent evaluations can be used to further specify the

duration of negativity (e.g. MRD negative at 5 years)

Imaging MRD-

negative

MRD negative as defined below (by next-generation flow cytometry or next-generation sequencing) PLUS

Disappearance of every area of increased tracer uptake found at baseline or a preceding PET/CT

Flow MRD-

negative

Absence of phenotypically aberrant clonal plasma cells by next-generation flow cytometry on bone marrow

aspirates using the EuroFlow standard operation procedure for MRD detection in MM (or a validated equivalent

method), with a minimum sensitivity of 1 in 105 nucleated cells or higher

Sequencing

MRD-negative

Absence of clonal plasma cells by next-generation sequencing on bone marrow aspirates in which the

presence of a clone is defined as less than two identical sequencing reads obtained after DNA sequencing of

bone marrow aspirates using the Lymphosight® platform (or a validated equivalent method) with a minimum

sensitivity of 1 in 105 nucleated cells or higher

IMWG CRITERIA FOR MRD IN MULTIPLE MYELOMA

IMWG, International Myeloma Working GroupKumar SK, et al. Lancet Oncology 2016; 17(8):e328–e346

Numerous clinical trials in SMM (~51 in clinicaltrials.gov)

TO CURE THE DISEASE:

• KRD+ASCT+Consol+Maint (Cesar)

• KRD+Dara...... (Ascent)

TO DELAY DISEASE PROGRESSION:

• Len-Dex vs Observation: +PFS and OS

• Len vs Observation: +PFS

• Elo-Rd: Positive results

• Daratumumab: Positive results

• KRd: Positive results

• Ixazomib-Rd: Positive results

• Pembrolizumab; Nivolumab-Rd; Isatuxima

SMOLDERING MYELOMA (HIGH RISK)

To treat the disease early on

• Early detection and intervention is a prerequisite for cure in most malignancies

• Why is the standard of care in MM no treatment until CRAB? Risk of harm: clonal selection, toxicities.

TTP OS

18% vs. 36% patients died

Progression to MM

in 36% vs. 86%

NR vs. 23 m (HR 0.24)

Len-dex vs. Observation (n=119)1,2

Median follow-up: 75 months

Treatment HR 0.28

(95% CI: 0.12, 0.63; p=0.0005)

Len vs. Observation (n=182)3

HR 0,15 in Mayo High Risk 2/20/20

DELAY PROGRESSION IN HIGH RISK SMOLDERING

MULTIPLE MYELOMA

1. Reprinted from The Lancet Oncology, 17(8), Mateos MV, et al. Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): long-term follow-up of a randomised,

controlled, phase 3 trial, 1127-1136 Copyright (2016), with permission from Elsevier; 2. Mateos MV, et al. N Engl J Med 2013;369(5):438–47;

3. Lonial S, et al. J Clin Oncol 2019 37 (suppl): Abstract 8001. Reproduced with permission from Dr S Lonial.

Induction 6 cycles of KRd

ASCT (melphalan 200)

Consolidation (2 cycles of KRd)

Maintenance (Len-dex for 2yrs)

MRD

MRD

MRD

MRD

CESAR

Response category

Induction

(n=88)

HDT-ASCT

(n=83)

ORR 86 (98%) 82 (99%)

sCR/CR 36 (40%) 52 (63%)

MRD –ve 27 (32%) 43/78 (55%)

94% at 28m

PFS

CURATIVE STRATEGY FOR HIGH-RISK SMOLDERING

MULTIPLE MYELOMA

Mateos M-V, et al. EHA 2019; Abstract S871;

Mateos M-V, et al. Blood 2018;132: Abstract 2142. Presented at ASH 2018. By permission of Prof M-V Mateos.

REVISED INTERNATIONAL MYELOMA WORKING GROUP

DIAGNOSTIC CRITERIA FOR MULTIPLE MYELOMA

Clonal BM PC ≥10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the

following myeloma defining events (MDE)

End organ damage (CRAB) that attributed to the PC disorder

◆ Hypercalcemia: >11 mg/dL

◆ Renal insufficiency: CrCl <40 mL/minute or Serum Cr >2 mg/dL

◆ Anaemia: Hb value <10 g/dL or >2 g/dL below the lower limit of normal

◆ Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT

◆ Any one or more of the following new biomarkers of malignancy (Early MM)

◆ ≥60% PC in BM

◆ Involved/uninvolved serum free light chain ratio ≥100

◆ >1 focal lesions on magnetic resonance imaging studies

Rajkumar V et al Lancet Oncol 2014, 15: e538-48Rajkumar V, et al. Lancet Oncol 2014;15:e538-48

MYELOMA TREATMENT

Newly diagnosed

◆ Transplant candidates (Young)

◆ Non-transplant candidates (Elderly)

Relapsed Patients

Gimema: PFS Pethema/GEM05: PFS

LONG-TERM FOLLOW-UP OF VTD VS. TD WITH ASCT –

PFS AT 10 YEARS: GIMEMA AND PETEHMA 05

Rosiñol L, et al. Blood 2018;132: Abstract 126. Presented at ASH 2018. Adapted by Prof J.

San Miguel

24%

17%

24%

15%

Tacchetti P, et al. Blood 2018;132: Abstract125. Presented at ASH 2018

Reproduced with permission from Prof P. Tacchetti

34%

This translates into

prolonged PFS

ORRCR

0

10

20

30

40

50

60

70

80

90

100

VAD TD TAD LD BzD BzCD

VCD

BzTD KRD

Induction Regimen

Per

cent

resp

onse

BzRD

VRD

IRD

WHAT ARE THE OPTIMAL INDUCTION REGIMENS?

Response to induction

Adapted from: How I treat MM in younger patients by Stewart K, Richardson P, San Miguel JF. Blood 2009;114:5436-43.

Mobilisation after 3 cycles of VRD-GEM is highly effective (only 2 failures; median 4.66 x 106/kg, CD34 cells; 86% with only G-CSF)

Toxicity, particularly PN, is remarkably low (3%), neutropenia:11%

Response Inductionx6N (%)

ASCTN (%)

ConsolidationN (%)

≥ CR

• sCR

176 (39%)

28%

227 (49%)

36%

266 (58%)

46%

≥ VGPR 309 (68%) 352 (77%) 358 (78%)

≥ PR ≥386 (84%) 383 (83%) 377 (82%)

MRD –ve (eva) 28%(33%) 42%(53%) 45%(56%)

BORTEZOMIB, LENALIDOMIDE AND DEXAMETHASONE

(VRD-GEM) INDUCTION IN THE TRANSPLANT SETTING

458 patients

Rosiñol L, et al. Blood 2017;130: Abstract:2017. Presented at ASH 2017

Age (years) VRd Rd

<65 48 34

≥65 34 24

>75 34 17

Impact of age on outcomes*

Months from registration

48 m


VS. LENALIDOMIDE AND DEXAMETHASONE

In patients with NDMM without an intent for immediate ASCT: Longer follow-up of

Phase III SWOG S0777

*For all analyses, both SWOG and IRC assessments have been conducted using the fully updated datasets with current data lock in May 2018.Durie BGM, et al. Blood 2018;132: Abstract 1992. Presented at ASH 2018. Reproduced with permission from Dr BGM. Durie

Median PFS (months) Overall survival by age

Using Forest plot technique, other correlates of improved

outcomes (PFS and OS) with VRd are Sβ2M (<4); BMPC

(60%); hemoglobin (>10 GMS/dL); serum creatinine (<2 mg/dL),

ie, predominantly good risk (early disease) risk features

RECENT / ONGOING TRIALS

VTD +/- Dara

VRD +/- Dara

VRD +/- Ixatu

VRD +/- Elo

KRD + Dara

Primary endpoint (sCR* post-cons): 29% D-VTd vs.

20% VTd; p=0.0010; CR: 39% vs. 26%

MRD Negative rate (10-5): 63.7 vs. 43.5%

• Median (range) follow-up: 18.8 (0.0–32.2) months

53% reduction in the risk of progression or death in the D-VTd armD-VTd reduced the risk of progression or death across all subgroups (High risk HR: 0.67)

D-VTd

(n=543)

VTd

(n=542)

Events, n (%) 45 (8) 91 (17)

HR (95% CI) 0.47 (0.33, 0.67)

p-value <0.0001

DARATUMUMAB-VTD VS. VTD EFFICACY

Induction (x4 cycles) + ASCT + Consolidation (x2) + Maintenance (Dx2y vs. observ)

% s

urvi

ving

with

out p

rogr

essi

on

0 3 6 9 12 15 18 21 33302724

Months

0

20

40

60

80

100

520519

543542

501497

492475

442413

346319

261233

185163

122104

6150

1414

00

D-VTdVTd

No. at risk

VTd

D-VTd

18-month PFSa

93%

85%

Philippe Moreau, MD

Primary and final PFS

analysis of Part 1

*sCR definition: All required: SIFE and UIFE negative; <5% PC in BM; Four-color FCM; Normal FLC ratio; Disappearance of plasmacytomasReprinted from The Lancet, 394(10192), Moreau P, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple

myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study, 29–38. Copyright 2019, with permission from Elsevier.

No differences in AE

Primary endpoint: sCR by end of consolidation

42.4% vs. 32.0%; OR 1.57; p=0.068

10.1 10 100

RVd Better D-RVd Better

RVd D-RVd Odds Ratio (95% CI)

18/55 (32.7)

13/42 (31.0)

22/70 (31.4)

9/27 (33.3)

11/48 (22.9)

12/35 (34.3)

7/13 (53.8)

8/51 (15.7)

23/46 (50.0)

4/13 (30.8)

26/80 (32.5)

13/39 (33.3)

18/58 (31.0)

21/55 (38.2)

21/44 (47.7)

30/72 (41.7)

12/27 (44.4)

19/48 (39.6)

17/37 (45.9)

6/14 (42.9)

15/51 (29.4)

25/45 (55.6)

3/16 (18.8)

39/79 (49.4)

16/38 (42.1)

25/60 (41.7)

Subgroup, n/N (%)

Stringent Complete Response

1.27 (0.58–2.78)

2.04 (0.84–4.92)

1.56 (0.78–3.10)

1.60 (0.53–4.82)

2.20 (0.91–5.35)

1.63 (0.63–4.22)

0.64 (0.14–2.94)

2.24 (0.85–5.88)

1.25 (0.55–2.85)

0.52 (0.09–2.90)

2.03 (1.06–3.85)

1.45 (0.58–3.67)

1.59 (0.74–3.38)

Sex

Male

Female

Age

<65 years

≥65 years

ISS disease stage

I

II

Ill

Type of MMc

lgG

Non-lgG

Cytogenetic risk

High risk

Standard risk

ECOG performance status

0

1 or 2

– Infections G1/2 (82% vs. 55%), while G3/4 similar: 17%

– More patients used Perixaflor: 70% vs. 55%Voorhees PM, et al. Presented at IMW 2019; Abtract OAB-87. Reproduced with permission from Prof PM. Voorhees.

DARATUMUMAB-VRD VS. VRD IN TRANSPLANT-

ELIGIBLE NDMM: GRIFFIN STUDY

Induction x4 (3 w), ASCT, Consolidation x2, Maintenance x25 (DR vs. R) (4 w):

MRD –ve (10-5): 44.2% vs. 14.6%

≥VGPR:

73.2%

≥VGPR:

90.9%

≥CR:

51.5%

Pat

ient

s (%

)

≥CR:

42.3%

ORR = 99.0%

ORR = 91.8%

sCR: 1-sided

p=0.068b

ORR: 2-sided p=0.0160

Doctor, what about continuous optimised

treatment with novel agents, with the goal of

controlling the disease for as long as

possible, and to reserve ASCT for relapse?

Bz-Len-Dex x3

Bz-Len-Dex x5

Lenalid x12m

Stem Collection

Bz-Len-Dex x3

ASCT

Lenalid x12m

Stem Collection

Bz-Len-Dex x2

ASCT at relapse

“EARLY (UP-FRONT) VS. LATE (AT RELAPSE)

TRANSPLANT”

Attal M, et al. N Engl J Med 2017;376(14):1311–20

Early Late P

Pooled analysis of two trials

(n=529)1,2

4-year PFS 44% 26% p<0.001 (HR 0.53)

4-year OS 84% 70% p<0.001 (HR 0.51)

GIMEMA MM-RV-209… Rd-MPR vs. Rd-Mel200 (2nd rand: +/- maintenance)EMN MM-RV-441… Rd-CRD vs. Rd-Mel200 (2nd rand: R vs. RP Maint.)

IFM-DFCI 2009 trial34-year PFS 47% 35% p<0.001 (HR 0.69)

4-year OS 83% 81% p=NS

RVD x 8 + ASCT at relapse vs. RVD x 3 + ASCT (Mel200) + RVD x 2

EMN02/HO9543-year PFS 65% 57% p=0,001 (HR 0.73); High Risk 0.53

3-year OS 86.3% 84.6% p=NS

Induction VCD x 3-4 => VMP intensive vs ASCT => VRD conso vs. no conso => R maint

EARLY VS. LATE ASCT

1. Palumbo A, et al. N Engl J Med 2014;371:895–905; 2. Gay F, et al. Lancet Oncol 2015;16(16):1617–29; 3. Attal M, et al. Blood 2015;126: Abstract 391. Presented at ASH 2015;

4. Cavo M, el al. Blood 2016;128: Abstract 673. Presented at ASH 2016.

KRD (+/- ASCT) VS. KCD (FORTE TRIAL):

PRE-MAINTENANCE RESPONSE RATE AND MRD RATE

Induction x 4 + ASCT (or 4 KRD) + Consolidation x 4, ITT analysis.

MRD by Flow 10-5

KRd-ASCT-KRd and KRd12 significantly improved VGPR, sCR and MRD negativity compared with KCd-ASCT-KCd –

this was confirmed in most subgroups

^Patients whose samples were not available (~10%) were considered as positive; *Unconfirmed CR/sCR: patients missing immunofixation/sFLC analysis needed to confirm CR/sCR (6% in

KCd_ASCT_KCd; 8% in KRd_ASCT_KRd; 6% KRd_12); *Adjusted for ISS, Age, FISH, LDH.

KCd, carfilzomib, cyclophosphamide, dexamethasone; KRd, carfilzomib, lenalidomide, dexamethasone; ASCT, autologous stem cell transplant; sCR, stringent complete response;

CR, complete response; VGPR, very good partial response; ITT, intention-to-treat; OR, odds ratio.Gay F, et al. Blood 2018;132: Abstract 121. Presented at ASH 2018

DOUBLE VS. SINGLE ASCT

Double ASCT Single ASCT HR

PFS (months) 47 38 0.76

OS (10-year) 58% 47% 0.69

3 EU Phase 3 trials:

GIMEMA MMY-3006 (VTD/TD); PETHEMA/GEM (VTD/TD/VMCP);

HOVON65MM/GMMG-HD41 (PAD)/VAD)

Is there still room for

double ASCT?

In patients with ISS Stage II and III, high-risk cytogenetics and failure

to achieve best CR, tandem ASCT induced double PFS and a 56%

reduction in mortality

Cavo M, et al. Blood 2018;132: Abstract 124. Presented at ASH 2018

3-year → 64%

3-year → 73%

HR 0.7; p=0.04

PFS PFS in high-risk CAOS

ASCT-2 was superior to ASCT-1 in terms of prolonged PFS and OS in the overall population and

seems to be able to overcome the poor prognosis of patients with advanced R-ISS and HiR CA

In patients with 17p del receiving 2 ASCT, the 3-year PFS was 72% (73% in non-del17p); by contrast, if only 1 ASCT, the 3-year PFS was 43% vs 67%, respectively

MANAGEMENT OF MM IN THE TRANSPLANT

CANDIDATE ND PATIENT

What is the role of tandem ASCT?

Cavo M, et al. Blood 2017;130:40. Presented at ASH 2017. Reproduced with permission from Prof M. Cavo.

3-year → 89%

3-year → 81%

p=0.011

3-year → 76%

3-year → 69%

p=0.48

Consolidation

Improve response/deeper following therapy

◆ By administration of treatment for a limited period

Maintenance1

Maintain response achieved following therapy

◆ By administration of treatment for prolonged period

◆ VTD: Upgrade to CR by 30% (molecular and PFS)

Cavo M, et al. Blood 2012

◆ VRD: Upgrade CR (38% vs. 26%); PFS (HR: 0,78; p=0,04) no benefit

in high risk

Sonneveld P, et al. ASH 2016

What is the role of consolidation or

maintenance therapy?

◆ Thalidomide (6 trials) – PFS: + 6/6, OS: + 3/6

◆ Bortezomib (2 trials) – PFS: + 2/2, OS: + 1/2

◆ Lenalidomide (3 trials) – PFS: +3/3, OS: + 1/3

1. Morgan GJ, et al. Blood 2012;119(1):7-15; Kagoya Y, et al. Leuk Res 2012;36(8):1016–21; Attal M, et al. ASH 2013 (Abstract 406); McCarthy P. Presented at IMW 2013; Abstract S15-5; Gay F, et al. Blood

2013;122:Abstract 2089, Presented at ASH 2013; Sonneveld P, et al. Blood 2013;122: Abstract 404. Presented at ASH 2013; Rosiñol L, et al. Leukemia. 2017;31(9):1922–7.

PFS OS

VGPR: 50%, 47%, 44%

CONSOLIDATION VS. DOUBLE ASCT VS. MAINTENANCE

STAMINA TRIAL – PFS PER PROTOCOL ANALYSIS

BUT… 32% in the Tanden AUTO and 11% in the AUTO-RVD did not receive the planned treatment and 11.8%

in the consolidation arm

Stadtmauer EA, et al, J Clin Oncol 37(7), 2019: 589-597. Reprinted with permission. © 2019 American Society of Clinical Oncology. All rights reserved.

MAINTENANCE

p<10-7

Lena

Placebo

42 m

24 m

HR: 0.53

2nd malignancies: 7% vs 2.5%

OS: 75% vs. 75%. HR:0.91

Lena

Placebo

53 m

27 m HR: 0.38

IFM 2005-02: PFS1 CALGB 100104: PFS2

OS: 76 vs. NR, HR: 0,56 3-y OS: 88% vs. 79%. HR: 0,72

GIMEMA MM-RV-209: PFS3

56.9m

30.1m

UK Myeloma114

Lena

Placebo

42 m

22 m HR: 0.50 HR: 0.48

3-y OS: 87% vs. 80%. HR: 0,69

Lenalidomide improved OS irrespective of

cytogenetics. HR: 0.54,/0.51

LENALIDOMIDE VS. PLACEBO AFTER ASCT

PFS and OS from randomisation

1. Attal M, et al. N Engl J Med 2012;366:1782–91; 2. McCarthy PL, et al. N Engl J Med 2012;366:1770–81; 3. Palumbo A, et al. N Engl J Med 2014:371:895–905; 4. Jackson G,

et al. Lancet Oncology 2019;20(1):57–73. Available under the terms of the Creative Commons Attribution License (CC BY). Available at

https://creativecommons.org/licenses/by/4.0/. Accessed Aug 2019). Figures Adapted by Prof J. San Miguel

https://creativecommons.org/licenses/by/4.0/

aMedian 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. Attal M, et al. J Clin Oncol 2016;34(15_suppl):8001. Presented at ASCO 2016. Reproduced by permission of Dr M Attal

OVERALL SURVIVAL:

MEDIAN FOLLOW-UP OF 80 MONTHS

0.00 10 20 30 40 50 60 70 80 90 100 1 10 120

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 0

604 569 542 505 458 425 350 271 174 71 10 0

Overall Survival, mos

Sur

viva

l 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)

0.001

Follow-up 31 months

Ixazomib Placebo

PFS (months) 26.5 21.3

HR 0.72; 95% CI: 0.582-0.890

p=0.002

Landmark analysis

from ASCT (months)

30.7 24.9

HR 0.684; p<0.001

◆ There was a 28% reduction in Risk of progression or death

◆ PFS from ASCT: 30.7 vs. 24.9 months

◆ Upgraded the responses and conversions to MRD– (12 vs. 7%)

◆ Favourable safety profile with no risk of SPM and low rates of PN

◆ With only 14% of deaths reported, median OS not reached

PFS: Overall (Primary endpoint)

Patients at Risk, n

Ixazomib

Placebo395 363 340 311 279 255 238 213 187 135 93 56 35 9 3 0

261 238 210 195 174 153 130 117 100 69 46 32 15 3 0 0

30 42180

Ixazomib

Placebo

0.6

03 6 9 12 15 21 24 27 33 36

1.0

0.8

0.4

0.2

HR: 0.72 (95% CI: 0.582, 0.890;

p=0.002)

Median PFS, Mos

26.5

21.3

Pro

babi

lity

of P

FS

Months from randomisation

39 45

IXAZOMIB MAINTENANCE POST-ASCT VS. PLACEBO:

TOURMALINE-MM3 PHASE 3 TRIAL

Dimopoulos M, et al. Blood 2018;132; Abstract 301. Presented at ASH 2018. Reproduced by permission of Dr M Dimopoulos

Induction (VT/RD or KRD)+(Dara)

ASCT(Mel 200) (Bu-MEL) (Tandem)

CR

Maintenance (Len +/- Ixz )

Consolidation (VRD)

No CR

KRD+Dar

KRD+Dar

KRD+Dar

. . . . .

Late ASCT

TRANSPLANT CANDIDATE PATIENT:

STANDARD TREATMENT

AUTO/ALLO-RIC VS. TANDEM AUTO

4 studies (IFM1, HOVON2, PETHEMA3, BMTCTN4)… No benefit

2 studies (GIMEMA5, EBMT6)… Significant benefit (EFS, OS)

The role of Allo should be revisited in the era of novel drugs: “integrated programmes”

... Early relapses (after optimised induction and ASCT) + high risk cytogenetics

1. Garban F, Blood 2006;107:3474-3480; and Moreau P, et al. Blood 2008 112:3914–5; 2. Lokhorst H, et al. Blood 2008 112: Abstract 461. Presented at ASH 2008;

3. Rosiñol L, et al. Blood 2008;112: Abstract 654. Presented at ASH 2008; 4. Krishnan A, et al. Blood 2010;116: Abstract 41. Presented at ASH 2010; 5. Bruno, N Engl J Med. 2007;356(11):1110–20. (updated EBMT

2009); 5. Gahrton G, et al. Blood 2009;114: Abstract 52. Presented at ASH 2009; 6. Knop S, et al. Blood 2009;114: Abstract 51. Presented at ASH 2009.

MYELOMA TREATMENT

Newly diagnosed



Relapsed patients

MRD negativity is associated with 60% and 70% reduction in risk of

relapse and death, respectively

OSPFS

IMPACT OF MRD ACROSS MM SUBGROUPS

FISH, fluorescence in situ hybridisation; ISS, International Staging System

Lahuerta JJ, et al. J Clin Oncol 35(25), 2017: 2900–10. Reprinted with permission. © 2017 American Society of Clinical Oncology. All rights reserved.

6

22

0

5

10

15

20

25

VMP (n = 356) D-VMP (n = 350)

MR

D-n

egat

ive

rate

(%

)

p<0.0001

3.6X

>3-fold higher MRD-negativity rate with D-VMP;

Lower risk of progression or death in all MRD-negative patients

22

78

334

272

22

78

281

244

22

78

254

234

22

77

239

221

21

75

210

210

14

58

113

121

8

31

53

62

0

0

0

0

0

2

2

8

No. at risk

VMP MRD negative

D-VMP MRD negative

VMP MRD positive

D-VMP MRD positive

4

14

14

21

% s

urv

ivin

g w

ith

ou

t p

rog

ress

ion

0

20

40

60

80

100

0 3 6 9 12 15 18 27Months

21 24

VMP MRD negative

VMP MRD positive

D-VMP MRD negative

D-VMP MRD positive

From N Engl J Med, Mateos MV, et al. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma, 378(6), 518–28. Copyright © 2018 Massachusetts Medical Society. Reprinted with permission

from Massachusetts Medical Society.

MRD ASSESSMENT BY NGS IN ALCYONE

Impact of persistent MRD after induction in elderly MM

MP

VMP

Alkylators-based regimens1,2 Alkylators-free regimens3

Len-dex

IMiDs

One randomised trial:

Benefit in PFS: 8 months

OS: 13 months


Benefit in PFS and OS vs MPT

CURRENT STANDARDS OF CARE FOR ELDERLY

MM PATIENTS

1. San Miguel J, et al. N Engl J Med 2008;359:906–17; 2. San Miguel J, et al. J Clin Oncol. 2013; 31:448–55; 3. Benboubker L, et al. N Engl J Med 2014;371:906–17.

BORTEZOMIB + MP (VMP) VS. MP (682 PATIENTS)

RR (CR) (%): 71 (30) vs. 35 (4)

OS: 13.3 months benefit2

*Weekly and/or subcutaneous administration reduced peripheral neuropathy (grade 3) from 14% to 5% – 3%. RR, response rate1. From N Engl J Med, San Miguel J, et al. Bortezomib plus Melphalan and Prednisone for Initial Treatment of Multiple Myeloma, 359(9):906–17 , Copyright © 2008 Massachusetts Medical Society.

Reprinted with permission from Massachusetts Medical Society;. 2. San Miguel JF, et al. J Clin Oncol 31(4), 2013: 448–55. Reprinted with permission. © 2013. American Society of Clinical Oncology. All rights reserved.

Mateos MV, et al. Lancet Oncol 2010;11(10):934–41.

Time to Progression1

0 3 6 9 12

Time (months)

15 18 21 24 27

0

20

40

60

80

100

VMP

MP

Pat

ient

s w

ithou

t eve

nt (

%)

VMP: 24.0 months

MP: 16.6 months; p<0.000001

Median follow-up 60.1 months

CARFILZOMIB + MP (KMP) BORTEZOMIB + MP (VMP)

In elderly newly diagnosed MM patients: CLARION Trial

KMP

(n=478)

VMP

(n=477)

Disease progression or death, n (%) 207 (43.3) 214 (44.9)

Median PFS, months 22.3 22.1

HR for KMP vs. VMP (95% CI) 0.91 (0.75–1.10)

1-sided p-value 0.16

Pro

port

ion

even

t-fr

ee

0Months

12 18 24 366 30

1.0

0.8

0.6

0.4

0.2

0

478

477

327

309

217

202

85

77

0

0

384

367

15

9

Number at risk:

KMP

VMP

KMPVMP TTP: 27.5 vs. 23.5

No differences in OS

AEs in KMP arm were consistent with known safety profile of CFZ

◆ Incidence of Grade ≥3 AEs: 74.7% KMP arm, 76.2% VMP arm

◆ Fatal treatment-emergent AEs: 6.5% KMP patients, 4.3% VMP patients. Cardiac G3 (8.2 vs. 2.8%); Hypertension (10 vs. 3.6%)

◆ Incidence of Grade ≥f2 PN (secondary endpoint): 2.5% KMP arm, 35.1% VMP

Median follow-up time: 22.2 months

KMP, carfilzomib, melphalan, prednisone; VMP, bortezomib, melphalan, prednisoneFacon T, et al. Abstract OP-044. Presented at IMW 2017. Adapted by Prof J. San Miguel

• Rd continuous significantly improved PFS compared with MPT (HR 0.69; 95% CI: 0.59, 0.79; p<0.00001)

• Rd continuous significantly extended OS compared with MPT (HR 0.78; 95% CI: 0.67, 0.92; p=0.0023)

RR (CR) (%): 62 (9) vs. 73 (14) vs. 75 (15)

RD CONTINUOUS:

FINAL ANALYSIS OF THE FIRST TRIAL

Benboubker L, et al. N Engl J Med. 2014;371(10):906–17. Facon T, el al. Blood. 2016;128: Abstract 241.

ResponseRd continuous

(n=535)

Rd18

(n=541)

MPT

(n=547)

PFS, median (m) 26.0 21.0 21.9

4-year PFS, % 32.6 14.3 13.6

OS, median (m) 59.1 62.3 49.1

4-year OS, % 59.0 58.0 51.7

DOSE/SCHEDULE-ADJUSTED RD-R VS. CONTINUOUS RD

IN ELDERLY AND INTERMEDIATE-FIT NDMM PATIENTS

Phase III RV-MM-PI-0752 study

Event-free survival*

Median follow-up:

25 months

Early drop-out rate

(9%) primarily due

to toxicity

PFS

Comparable efficacy for Rd-R vs. Rd

*Definition of event: hematologic grade 4 AEs; Non-hematologic grade 3–4 AEs including SPM; Discontinuation of lenalidomide therapy; Disease progression; Death for any causeLarocca A, et al. Blood 2018;132: Abstract 305. Presented at ASH 2018. By permission of Prof A. Larocca.

Improved tolerability for Rd-R vs. Rd

Rd-R: 9 cycles Rd (len 25 mg/day D1-21 + dex 20 mg QW) induction + R (10 mg/day D1–21) maintenance vs. Rd: Continuous Rd

199 intermediate-fit* patients (>65 years and 80 years unfit and unsuitable for standard treatments)

Median age: 75–76 years; 13% (Rd-R) and 16% (Rd) of patients had high-risk cytogenetics

MP

VMP

Alkylators-based regimens1,2 Alkylators-free regimens3

Len-dex

IMiD’s


Benefit in PFS: 8 months

OS: 13 months


Benefit in PFS and OS vs. MPT

NEW STANDARDS OF CARE FOR ELDERLY PATIENTS

WITH MM

1. San Miguel J, et al. N Engl J Med 2008;359:906–17; 2. San Miguel J, et al. J Clin Oncol 2013; 31: 448–55; 3. Benboubker L, et al. N Engl J Med 2014;371:906–17.

Is it possible to combine bortezomib and lenalidomide in elderly?

Median follow-up: 51 months (29–64)

VISTA: 21 months (TTP); FIRST: 26 months (cont Rd)

SWOG: 43 months (VRD)*

VISTA: 56 months for VMP; FIRST: 59 months (cont Rd)

SWOG: 75 months (VRD)*

Median PFS: 32 months

Median OS: 64 months

PFS OS

ORR (CR) (%): 81(41) and MRD-positive in 22%

VMP x 9 cycles Len-dex x 9 cycles

GEM2010 TRIAL: VMP-RD X 18 CYCLES IN

ALTERNATING/SEQUENTIAL APPROACH

Mateos MV, et al. Haematologica 2017;102(s2): Abstract S409.. By permission of Prof MV Mateos.

1.0

0.8

0.6

0.4

0.2

0.0

1.0

0.8

0.6

0.4

0.2

0.0

*For all analyses, both SWOG and IRC assessments have been conducted using the fully updated datasets with current data lock in May 2018.Durie BGM, et al. Blood 2018;132: Abstract 1992. Presented at ASH 2018. Reproduced with permission from Dr BGM. Durie.


(VRD) VS. (RD) LENALIDOMIDE AND DEX

In patients with NDMM without an intent for immediate ASCT: SWOG S0777

Age (years) VRd Rd

<65 48 34

≥65 34 24

>75 34 17

Impact of age on outcomes*

Months from registration

48 m

Median PFS (months) OS by age

Using Forest plot technique, other correlates of improved

outcomes (PFS and OS) with VRd are Sβ2M (<4); BMPC

(60%); hemoglobin (>10 GMS/dL); serum creatinine

(<2 mg/dL), ie, predominantly good risk (early disease)

risk features

Can monoclonal antibodies be used in elderly patients?

NEW STANDARDS OF CARE FOR ELDERLY PATIENTS

WITH MM

PHASE III RANDOMISED STUDYOf daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) vs. bortezomib, melphalan,

and prednisone (VMP) in NDMM patients ineligible for transplant (ALCYONE)

Key eligibility criteria:

•Transplant- ineligible

NDMM

•ECOG 0-2

•Creatinine clearance

≥40 mL/min

•No grade ≥2 peripheral

neuropathy or grade ≥2

neuropathic pain

Stratification factors

ISS (I vs. II vs. III)

Region (EU vs. other)

Age (<75 vs. ≥75 years)

1:1

Ran

dom

isat

ion

(N =

706

)

D-VMP × 9 cycles (n=350)

Daratumumab: 16 mg/kg IV

Cycle 1: once weekly

Cycles 2-9: every 3

weeks

+

Same VMP schedule

Follow-up

for PD and

survival

Primary endpoint:

◆PFS

Secondary endpoints:

◆ORR

◆≥VGPR rate

◆≥CR rate

◆MRD (NGS; 10–5)

◆OS

◆Safety

VMP × 9 cycles (n=356)

Bortezomib: 1.3 mg/m2 SC

Cycle 1: twice weekly

Cycles 2-9: once weekly

Melphalan: 9 mg/m2 PO on Days 1-4

Prednisone: 60 mg/m2 PO on Days 1-4

D

Cycles 10+

16 mg/kg IV

Every 4 weeks:

until PD

Statistical analyses

360 PFS events: 85% power

for 8-month PFS improvementa

Cycles 1-9:

6-week cycles

Cycles 10+:

4-week cycles

ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; EU, European Union; SC, subcutaneously; PO, orally; IV, intravenously; D, daratumumab;

PD, progressive disease; ORR, overall response rate; VGPR, very good partial response; CR, complete response; MRD, minimal residual disease; NGS, next-generation

sequencing. a8-month PFS improvement over 21-month median PFS of VMP.Dimopoulos MA, et al. Blood 2018;132: Abstract 156. Presented at ASH 2018

DARATUMUMAB + VMP VS. VMP: PHASE III ALCYONE

STUDY 1-YEAR UPDATE

PFS Median follow-up: 27.8 (0-39.2) months ORR

MRD (NGS 10–5) ◆ 57% reduction in the risk of progression or death in patients receiving

D-VMP vs. VMP

◆ Significantly higher ORR, ≥VGPR rate, and ≥CR rate with D-VMP;

>2-fold increase in sCR rate with D-VMP

◆ Deepening MRD-negative rate with longer follow-up for D-VMP (>3-fold)

◆ No new safety signals were observed except for higher infection

events that resolved

Dimopoulos MA, et al. Blood 2018;132: Abstract 156. Presented at ASH 2018; Mateos MV, et al; ALCYONE Trial Investigators. N Engl J Med 2018;378(6):518–28 . By permission of Prof MV Mateos.

DARATUMUMAB + RD VS. RD IN TRANSPLANT-

INELIGIBLE NDMM: MAIA STUDY

Phase III study of D-Rd vs. Rd (N=737)

aOn days when daratumumab was administered, dexamethasone was administered to patients in the D-Rd arm and served as the treatment dose of steroid for that day, as well as the

required pre-infusion medication. bFor patients older than 75 years of age or with BMI <18.5, dexamethasone was administered at a dose of 20 mg weekly. cEfficacy endpoints were

sequentially tested in the order shown.

ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; NA, North America; IV, intravenously; QW, once weekly; Q2W, every 2 weeks; Q4W, every 4 weeks; PD,

progressive disease; PO, orally; CR, complete response; VGPR, very good partial response; MRD, minimal residual disease; NGS, next-generation sequencing; ORR, overall response rateFacon T, et al. Blood 2018;132: Abstract LB-2. Presented at ASH 2018

Key eligibility criteria:

•Transplant- ineligible

NDMM

•ECOG 0-2

•Creatinine clearance

≥30 mL/min

Stratification factors

ISS (I vs. II vs. III)

Region (NA vs. other)

Age (<75 vs. ≥75 years)1:

1 R

ando

mis

atio

n

Rd (n=369)

R: 25 mg PO daily on Days 1-21 until PD

d: 40 mgb PO or IV weekly until PD

Primary endpoint:

◆PFS

Secondary endpointsc:

◆≥CR rate

◆≥VGPR rate

◆MRD-negative rate

(NGS; 10–5)

◆ORR

◆OS

◆Safety

D-Rd (n=368)

Daratumumab (16 mg/kg IV)a

Cycles 1-2: QW

Cycles 3-6: Q2W

Cycles 7+: Q4W until PD

R: 25 mg PO daily on Days 1-21 until PD

d: 40 mgb PO or IV weekly until PD

Cycle: 28 days

DARATUMUMAB + RD VS. RD IN TRANSPLANT-

INELIGIBLE NDMM: MAIA STUDY

1428

32

28

17

12

30 12

0

10

20

30

40

50

60

70

80

90

100

D-Rd(n = 368)

Rd(n = 369)

OR

R,

%

PR VGPR CR sCR

P <0.0001

ORR = 81%

ORR = 93%

≥CR:

48%c

≥VGPR:

79%c

≥CR:

25%

≥VGPR:

53%

24%

7%

0

5

10

15

20

25

30

D-Rd(n = 368)

Rd(n = 369)

MR

D-n

eg

ative

rate

, %

P <0.0001

PFSMedian follow-up: 28 months (0–41.4)

ORR

MRD (NGS 10–5) ◆ 44% reduction in the risk of progression or death in

patients receiving D-Rd vs. Rd

◆ Significantly higher ORR, ≥CR rate, ≥VGPR rate, and

MRD-negative rate with D-Rd than Rd

◆ Safety profile is consistent with findings from POLLUX for

D-Rd and the population evaluated in ALCYONE

Facon T, et al. Blood 2018;132: Abstract LBA-2. Presented at ASH 2018. Reproduced with permission from Prof T. Facon.

ONGOING TRIALS

Ixazomib-Dex +/- Dara

CyBorD +/- Dara

VRD +/- Isatuximab

RD based:

Ixazomib-RD vs. RD: Tourmaline 1

Elo-RD vs. RD: Eloquent 2

MoAb based:

Is there an age

limit for ASCT?

PAD MEL100-ASCT

LP

Consolidation L Maintenance

CR or VGPR 55% 76% 80% 82%

CR 12% 33% 48% 53%

VGPR 43% 43% 32% 29%

PR 33% 17% 14% 13%

Median follow-up: 66 months

◆ PFS: 48 months, 5-year PFS 43%

◆ OS not reached, 5-year OS 63%

Death related to AEs (8/102) higher in patients >70 years (19% vs. 5%, p=0.024) (5/26 vs. 3/76)

ASCT in the Elderly (65 years to 75 years) (n=102) Bortezomib, reduced-intensity ASCT (Tandem MEL100), lenalidomide consolidation and maintenance

This sequential approach may represent a valid alternative for selective patients with MM <70 years old

Gay F, et al. Blood 2013;122(8):1376–83.

VRD

VMP + Rd

Dara + VMP

Dara + RdIRD/KRD

Dara + VRD

VMP or Rd

Light VRd / IRd

+ mAb?

Light VCyP or Rd

CyP

MP

Bz Weekly

Thal <100 mg

Len 25 mg in Ld and 15 mg in RVD

Cy 300 mg/m2 days 1, 8, 15

Melph 6-7 mg/m2

Dex 20 mg weekly

Bt Weekly

Thal <50 mg

Len 10-15 mg

Cy 50 mg daily

Melph 5-6 mg

Predni instead of dex

Fit <80 years

Karnofsky ≥80%/Charlson index = 0

Fit >80 years Unfit

Karnofsky 60% to 80%Charlson index ≤2

Karnofsky <60%Charlson index >2

- Comorbidities

- Cognitive condition

- Physical condition

- Social condition

INDIVIDUALISED TREATMENT FOR ELDERLY

PATIENTS: FRAILTY*

MYELOMA TREATMENT

Newly diagnosed



Relapsed patients

Efficacy

POLLUX (n=569)

DaraRd vs. Rd1-4

ASPIRE (n=792)

KRd vs. Rd5,6

ELOQUENT-2 (n=646)

ERd vs. Rd7,8

TOURMALINE-MM1

(n=722)

IRd vs. Rd9

PFS HR (▲m)0.44 (▲27)

44.5 vs. 17.5 m

0.67(▲8.7 m)

26.3 vs. 17.6 m

0.71 (▲4.5 m)

19.4 vs. 14.9 m

0.74(▲5.9 m)

20.6 vs. 14.7 m

ORR, % 93 87 79 78

≥CR, % 51 32 5 14

OS HR (95% CI) 0.630.79 (▲8 m)

48 vs. 40 m

0.78 (▲4.1 m)

43.7 vs. 39.6 mNE

High Risk: m (HR) 22.6 (0.64) 23 (0.70) 19 (0.60) 21 (0.54)

This table is provided for ease of viewing information from multiple trials with different patient populations. Direct comparison across trials is not intended and should not be inferred.

DOR, duration of response; NE, not evaluated.

FIRST RELAPSE AFTER BORTEZOMIB-BASED

INDUCTION: FIXED DURATION TT

VMP, VCD, VTD without Len Maintenance or IMID-naive patients Len-based

regimens: efficacy (Ld vs. triplets with Ld backbone)

1. Bahlis NJ, et al. ASH 2018; abstract 1996; 2. Dimopoulos M, et al. Poster presented at EHA 2017; abstract P334; 3. Usmani SZ, et al. Oral presentation at ASH 2016; abstract 1151; 4. Dimopoulos MA, et al. N Engl J

Med 2016;375:1319-31; 5. Siegel DS, et al. Poster presented at EHA 2017; abstract P333; 6. Stewart AK, et al. N Engl J Med 2015;372:142-52;

7. Lonial S, et al. N Engl J Med 2015,373:621-31; Oral presentation at ASCO 2017; abstract 8028; 8. Dimopoulos MA, et al. Br J Haematol 2017;178:896-905.

9. Moreau P, et al. N Engl J Med. 2016;374:1621-34; 9.

EfficacyENDEAVOR (n=929)

Kd vs. Vd1

CASTOR (n=499)

DaraVd vs. Vd2,3

OPTIMISMM (n=559)

PVd vs. Vd4

PANORAMA-1 (n=768)

PanoVd vs. Vd5

PFS HR

Median

0.53 (▲9.3 m)

18.7 vs. 9.4 m

0.32 (▲9.6 m)

16.7 vs. 7.1 m

0.61 (▲4.1 m) *

11.2 vs. 7.1 m

0.63 (▲4 m)

12 vs. 8 m

ORR, % 77 85 82.2 60.7

≥CR, % 13 30 15.7 27.6

Len Refract 24% (8.6 m) 18% (9.3 m) 71% (9.5 m) <10%

*

PROTEASOME INHIBITORS-BASED REGIMENS:

EFFICACY

1st relapse following continuous lenalidomide-dex, Len maintenance,

VRD-Rd... will be considered Len-Refrac

1. Dimopoulos MA, et al. Lancet Oncology 2016; 2. Palumbo A, et al. N Engl J Med 2016; 3. Spencer A, et al. ASH 2017. Poster presentation. Abstract 3145; 4. Richardson P, et al. Lancet Oncol. 2019;20(6):781-794. ; 5. San Miguel J, et al. Lancet Oncology 2014,15(11):1178-9

ENDEAVOR/Kd CASTOR/DVd OPTIMISMM/PVd PANORAMA/PANO-Vd

Percent patients

Poma – Dexa1 (backbone)

ORR: 31%; PFS 4 m; OS: 13.1 m

Daratumumab5

ORR: 31%; PFS 4 m; OS 20.1 m

PCyDex (ORR 65%; PFS 9.5 m )2

EloPom Dex (ORR:53%, PFS 10.2 m)3

DaraCfzDex *

DaraPomDex (ORR 60%, PFS 8.8 m)

IxaPomDex (ORR 55%)4

*DaraCfzDex n=85 (60% Len Ref)6

• ORR: 86% (81%)

• PFS: 71% at 12 m (14.1 m )

CfzPomDex n=(60) EMN0117

• ORR: 87% (31% CR)

• PFS: 18 m

TREATMENT AT 3RD/SUBSEQUENT RELAPSES

1. San-Miguel J, et al. Lancet Oncology 2013;14(11):1055-66; 2. Baz R, et al. Blood 2016;127(21):2561–8; 3. Dimopoulos M, et al. N Engl J Med 2018;379:1811–22;

4. Voorhees PM, et al. ASH 2015. Abstract 375; 5. Usmani S, et al. Blood 2016;128(1):37–44; 6. Lonial S, ASH 2017. Abstract 1869; 7. Sonneveld P, et al. ASH 2018,. Abstract 801

XPO1-INHIBITOR SELINEXOR IN RRMM –

SUMMARY OF PHASE I DATA

First-in-class, oral Selective Inhibitor of Nuclear

Export (SINE) that inhibits XPO1 and produces

nuclear accumulation and activation of tumour

suppressor proteins and inhibition of NF-kB, and

suppression of several oncoprotein mRNAs

(eg, c-myc, cyclin D)

◆ Cancer cells (and MM) overexpress XPO1, causing

increased export of tumour suppressors and growth

regulatory proteins from the nucleus

◆ Selinexor inhibit XPO1 mediated nuclear-cytoplasmic

transport by transiently binding to XPO1 cargo binding site

◆ Accumulation of tumour suppressors in the nucleus

amplifies the natural apoptotic function in cancer cells with

damaged DNA

PHASE I OF SELINEXOR PLUS/MINUS DEX IN RRMM →

Single agent (oral: 3–45 mg twice weekly): 17% MR (Chen, et al. ASH 2014)

◆ Main AEs: Anorexia, nausea/vomiting, fatigue, thrombocytopenia

+ Dex (n=122) (STORM-2): 26% ORR (Pent a-Refrct) PFS: 3.7 m (Vogl, et al. JCO 2018; Chari, et al. NEJM 2019 381: 727

AEs: nausea 73%, vomiting 49%, anorexia 49%, thrombocytopenia 73% (59% Grade 3-4)

+ Bortz/dex (n=42): 63% ORR (43% in Btz Rfct); PFS: 9 m (6.1 m in Btz Rfct) (Bahlis NJ, et al. Blood 2018; Phase III BOSTON trial ongoing)

◆ AEs: anorexia 33%, nausea 67%, thrombocytopenia 17%

+ Pom/dex (n=24): 65% ORR in Pom Naive/Len R (29% in Pom/Len Rft) (Chen, et al. ASH 2017. Abstract 3136)

+ Dara/dex (n=25): 74% in double Rft (Gasparetto, et al. ASH 2018. Abstract 599)

Tai YT, et al. Leukemia 2014.

1. Roberts AW, et al. NEJM 2015;

2. Punnoose E, et al. Mol Cancer Ther 2016

VENETOCLAX (BCL-2 INHIBITOR) IN RRMM –

SUMMARY OF PHASE 1 DATA

Monotherapy (n=66)1: ORR 21% (40% in t(11;14)

◆ (median 5 prior lines) G 3-4 AEs: thrombocytopenia (26%) and

neutropenia (21%)

+Dex in t(11;14) (n=20)3: ORR 65% (ORR 82% in Btz-R and 71% in Len-R)

◆ G3-4 AEs lymphopenia (>10%), tumour lysis Sd (10%)

+Btz/Dex (n=66)2: ORR 67% (90% in BTz sensitive and 94% in BCL2 high)

◆ (median 3 prior lines) G3-4 AEs: thrombocytopenia (29%), anaemia

(15%), neutropenia (14%)

+Kdex (n=42)4: ORR 79% (≥CR 38%) (1–3 prior lines)

◆ non-t(11;14) (n=34): CR 32% (in t(11;14), n=8; CR 38%)

Venetoclax is a selective, orally available small molecule BCL-2 inhibitor1,

induces cell death in multiple myeloma (MM) cell lines and primary samples,

particularly those positive for the translocation t(11;14), which correlates with

higher ratios of BCL2 to MCL1 and BCL2 to BCL2L1 (BCL-XL) mRNA1

1. Kumar S, et al. Presented at ASH 2016 (Abstract 977); 2. Moreau P, et al. ASH 2016 (Abstract 975); 3. Kaufman JL, et al. Abstract 3131, ASH 2017; 4.Costa LJ, et al. ASH 2018, abstract 303.

Source: AbbVie

BORTEZOMIB/DEX +/- VENETOCLAX (291 PATIENTS,

2:1 RANDOM) BELLINI STUDY

Venetoclax: 800 mg qd; BtzDex: C1–8 /21 d....C9/35 d.... until progression

No. at Risk 194

97

58

15

82

25

98

38

112

57

159

82

134

67

20

3

5

2

0

0

Pro

gres

sion

-Fre

e S

urvi

val

0

0.0

0.2

0.4

0.6

0.8

1.0

3 6 9 12 15 18 21 24 27

Ven+Bd

Pbo+Bd

Time (Months)

In patients with t (11;14) or BCL2high (qPCR) the HR for PFS was 0.11 and 0.34, respectively

PFS Ven+Bd Pbo+Bd

Median, mo 22.4 11.5

HR (95% CI) 0.630 (0.443, 0.897)

Kumar S, et al. Presented at IMW 2019; Abstract OAB-045. Reproduced with permission from Dr S. Kumar.

Ove

rall

Sur

viva

l

0

0.0

0.2

0.4

0.6

0.8

1.0

3 6 9 12 15 18 21 24 27

No. at Risk 194

97

136

76

149

85

158

87

165

88

186

95

174

91

111

57

44

24

11

6

Ven+Bd

Pbo+Bd

30

0

1

33

0

Time (Months)

OS Ven+Bd Pbo+Bd

Events, n (%) 51 (26) 19 (20)

Median, mo Not reached Not reached

HR (95% CI) 1.474 (0.870, 2.498)

PFS OS

p=0.01

◆ Melflufen is a highly lipophilic alkylating peptide, belonging to the novel class of

Peptidase Enhanced Compounds

◆ Intracellular amino-peptidases that are overexpressed in most malignant cells, will

rapidly cleave melflufen, releasing the hydrophilic, active alkylating metabolite

◆ In vitro, treatment of tumour cells with melflufen results in 50-fold higher intracellular

concentration of alkylating metabolite than those treated with equimolar melphalan alone.

In vivo, human xenograft mouse models treated with melflufen showed prolonged survival

RRMM patients ≥2 lines and refr. to last line.

n=45. Median 4 (2-14) lines; 64% double refr.; 53% Alkylator refr.

ORR 31%... 5 VGPR and 9 PR patientsPFS: 5.7 m… DOR 8.4 m; OS: 20.7 m

G3/4 AEs: thromboc. (58%), neutrop. (51%), anaemia: 42%

Phase II O-12-M1 trial1 Phase II Horizon trial2

RRMM patients ≥2 lines and 86% double Ref

n=83. Median 5 (2-13) lines; Alkylator refr. 55%; Pom and Dara Refr: 60%

ORR 33%... 1 sCR, 9 VGPR and 17 PR patientsPFS: 4.0 m

G3/4 rel. TEAEs: thromboc. (59%), neutropenia (61%), anaemia: 25%

Melflufen 40 mg IV every 28 days + Dex 40 mg weekly

MANAGEMENT OF PATIENTS >3 LINE –

NOVEL DRUGS UNDER DEVELOPMENT

Novel alkylators: Melflufen

1. Richardson P, et al. Blood 2017;130: Abstract 3150. Presented at ASH 2017; 2. Richardson P, et al. Blood 2018;132: Abstract 600. Presented at ASH 2018.

Image reproduced by permission of Dr P Richardson.

Bispecific T cell engagers:

BCMA–CD3 Phase I trials

Conjugated mAb:

GSK2857916: BCMA – MMAF*

AMG 224: BCMA – DM1

STRO-001: CD74-DBCO

MONOCLONAL ANTIBODIES:

FUTURES PERSPECTIVES

AMG 420: 35 patients: (Topp MS, et al. ASH 2018;1010)

28% ORR (6CR). 83% ORR at MTD (including MRD-)

SAE: 49% (infections ); CRS (3 cases).

Toxin, chemotherapeutic agent

or radioisotope

*35 patients (Trudel S, et al. Blood 2017;130:741)

ORR: 60% (43% previous data) PFS: 7,9m

63% corneal events most G1-2

To overcome the limitations of an

immunosuppressive tumour microenvironment

by linking CTLs with the tumour cell.

MMAF, monomethyl auristatin F; DM1, maytasanoid N(2’)- deacetyl-N(2’)-(3-mercapto-1-oxopropyl)-maytansine.Reprinted by permission from Springer Nature, Nat Rev Clin Oncol, Immune-based therapies for childhood cancer, Mackall CL, et al. 11(12):693-703.Copyright 2014

ADOPTIVE CELL THERAPY: GENETICALLY-MODIFIED

T CELL THERAPY

TCR engineered T cells CAR T cells

HLA - restricted Antigen recognition is independent of MHC molecule

Potential recognition of intracellular antigens Only extracellular proteins can be recognised

(like mAb)

TCR-mediated activation Possibility to insert other genes

Targeting element

single-chain variable

fragments (scFvs)

Spacer

Transmembrane domain

Costimulatory domains

(eg, CD28 or 4-1BB)

CD3𝛇Essential signalling domain

Viral vector

with CAR

DNA CAR-

engineered

T cell

This construct is then transfected or transduced

into patients’ autologous T cells 1. Peptide vaccine

2. Apheresis

6. Expansion

3. Selection of

anti-tumour

T cells &

expansion

7. Transfusion

into recipient

5. Genetic modification:

TCR transgenic4. TCR

sequencing

HLA, human leukocyte antigen; mAb, monoclonal antibody; MHC, major histocompatibility complex; TCR, T cell receptor., Chimeric antigen receptor (CAR) T cells Reprinted from Cell, 168(4), Lim WA & June CH, The Principles of Engineering Immune Cells to Treat Cancer, 724-740, Copyright (2017), with permission from Elsevier

Abstracts ASH 2018: 488, 955-7, 959, 960, 1009, 1011-14

This slide is provided for ease of viewing information from multiple trials. Direct comparison between trials is not intended and should not be inferred.

BCMA, B-cell maturation antigen; CRS, cytokine release syndrome; MM, multiple myeloma; CR, complete response; ORR, overall response rate; PR, partial response; sCR, stringent

complete response, VGPR, very good partial response, PR, partial response 1. Ali A, et al. Presented at ASH 2015. Abstract LBA 1; 2. Raje NS, et al. N Engl J Med. 2019 ;380(18):1726-1737; 3. Cohen AD, et al. Blood 2017;130:505;

4. Zhang W, et al. Presented at EHA 2017. Abstract S103.

BCMA CAR T-CELL THERAPIES FOR MM

Anti-BCMA CAR1 NCT02215967Bb21212

NCT02658929

CART-BCMA3

NCT02546167

LCAR-B38M4

NCT03090659

Group/company NIH Bluebird/Celgene University of Pennsylvania/ Novartis Nanjing Legend Biotech

Patients 16 patients at 9x106/kg dose level 22 (>150 x 106 cells)

21 (3 cohorts):

9 (10-500 x 106, No Cyt)

5 (10–50 x 106 , Cyt)

7 (5 (100–500 x 106 , Cyt)

57

BCMA expression required? Yes Yes; ≥ 50% BCMA expression No Yes

Median prior lines of therapy 7 7 7 (3–11) 3

Reported efficacy

ORR 14/16 (81%)

11/14 (79%) MRD-

EFS: 7.2 months

86.4% ≥VGPR

(50% sCR/CR)

PFS: 11.8 months

#1: 67% (1 sCR, 1VGPR)

#2: (40%) 1 PR, 1 MR both PD

#3: (83%) 1 CR, 3 PR, 1 MR

ORR: 88%

CR: 74%

MRD-: 93% of CR

PFS: 15 months

Safety data CRS all grades: 100%, 37%G3-4

CRS all grades: 63%

2 events of CRS grade ≥3 resolved

within 24 hours

CRS: 17 pts (grade 3: 32%)

Neurotoxicity: 3 (2 grade 4)

1 death – PD candidaemia

Transient CRS (5,7% G3)

No neurotoxicity

Progress in MM Cell Biology

Prognostic factors

and

Myeloma subtypes*

Discovery of New Drugs

Singular mechanism of action

Individualised and tailored treatment

MULTIPLE MYELOMA

A model for scientific and clinical progress from biology to therapeutics

*MM should not be considered a single entity.

THANK YOU!

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