Myélome Multiple: Prise en charge thérapeutique

d'aujourd'hui et de demain

N. Meuleman

Charleroi

3 Octobre 2017

Questions à se poser:

1. Est-ce qu’il y a une indication de traitement?

2. Caractéristiques du patient?

3. Caractéristiques de la maladie?

4. Le patient est-il candidat pour une étude?

5. Le patient est-il candidat pour une autogreffe?

6. Quel est le traitement supportif adéquat?

Indication de traitement

CRAB:

• Calcium levels • serum calcium > 0.25 mmol/l above upper limit of normal or

> 2.75 mmol/l

• Renal insufficiency• creatinine > 170 mmol/l

• Anaemia• haemoglobin 2.0 g/dl below lower limit of normal or < 10 g/dl

• Bone lesions• lytic lesions or osteoporosis with compression fractures

(MRI or CT may clarify)

• Other• symptomatic hyperviscosity, amyloidosis, recurrent infections (>

2 episodes in 12 months)

CRAB (calcium, renal insufficiency, anaemia, or bone lesions)

International Myeloma Working Group. Br J Haematol. 2003;121:749-57.

Pourquoi changer?

Sarah Newburry (1844)Kyle. Br J Haematol, 2001

Myélome indolent: Comment mieux identifier les patients à risque d’évolution rapide vers une maladie symptomatique?

Probability of Progression to Active Multiple Myeloma or Primary Amyloidosis in Patients with Smoldering Multiple Myeloma or Monoclonal Gammopathy of Undetermined Significance (MGUS).

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

10%/an

3%/an1%/an

Ch. lourdes

Ch. légères

Quel est le meilleurs traitement pour mon patient?

Choix du traitement

MobilitéAge

Présentation agressive

Profession

PScytogénétique

Volonté du patient

comorbidités

MYELOME

Fonction rénale

But

Coût?

Remboursement

Choix du traitement

MobilitéAge

Présentation agressive

Profession

PScytogénétique

Volonté du patient

comorbidités

MYELOME

Fonction rénale

But

Coût?

Remboursement

International Staging System

JCO 2005; 23 : 3412-3420

Classification pronostic ISS

Stade I Béta2-M< 3,5

albumine ≥ 3,5

Stade II Ni I, ni II

Stade III béta2-M > 5,5

International Staging System

Cytogenetic

R-ISS

LDH

Antonio Palumbo et al. JCO 2015;33:2863-2869

©2015 by American Society of Clinical Oncology

revised International Staging System (R-ISS)

(A) Overall survival (OS) in patients with multiple myeloma stratified by revised International

Staging System (R-ISS) algorithm.

Antonio Palumbo et al. JCO 2015;33:2863-2869

©2015 by American Society of Clinical Oncology

Traitement en 2017

Mon patient est-il éligible pour une autogreffe?

Patient candidat à l’autogreffeBut: atteindre la meilleure réponse → certaine toxicité

Achievement of CR after initial treatment is associated with improvedPFS and OS

Summary of frontline therapy.

Philippe Moreau et al. Blood 2015;125:3076-3084

©2015 by American Society of Hematology

(A) Kaplan-Meier distribution curve (intent-to-treat analysis) for the key efficacy end point of

progression-free survival.

Pieter Sonneveld et al. JCO 2013;31:3279-3287

PFS benefit: median 36 months vs 26.8, p < 0.001 OS benefit: 3-year OS, 79.7 vs 74.7%, p = 0.04

Philippe Moreau et al. Blood 2016;127:2569-2574

©2016 by American Society of Hematology

Philippe Moreau et al. Blood 2016;127:2569-2574

P. Moreau et al ; Annals of Oncology, 2017

Consolidation?Double autogreffe?

Maintenance?

Overall Survival According to Whether Patients Had at Least a Very Good Partial Response after One Transplantation (Panel A) or Had No Such Response (Panel B)

Attal, M. et al. 2003

IFM94:

Single vs Double

autologous SCT

OS according to response

after

the 1st ASCT

SECOND TRANSPLANTATION

Front-line therapy, tandem-ASCT Patients in CR/VGPR after one ASCT do not benefit from a

second ASCT

Patients with HR cytogenetics, t(4;14) or del(17p).

Slide 10

Slide 11

Slide 12

EMN02 Study: Tandem-ASCT/ Consolidation

Sonneveld ASH 2016

EMN02: Impact de la Consolidation

• Results for consolidation:• PFS increase, ony for low risk cytogenetics

• No impact on OS

Soneveld ASH 2016

EMN02 : rôle de la double ASCT

Soneveld ASH 2016

StaMINA Study: rôle de la Consolidation par RVD vs ASCT

Stadtmauer, ASH 2016, LBA1

n = 758

StaMINA: PFS

Pas de différence en OS, PFSPas d’intéret consolidation ou double autogreffe à l’époque du Len en maintenance???Rôle de la durée de l’induction?

Maintenance

Lenalidomide Maintenance After High-Dose Melphalan and ASCT in MM: A Meta- Analysis of Overall Survival

M Attal ASCO 2016

00 10 20 30 40 50 60 70 80 90 100 110 120

0.2

0.4

0.6

0.8

1.0

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 (months)

Su

rviv

al

pro

ba

bilit

y

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

N = 1,209

Lenalidomide en maintenance:Meta Analyse IFM2005-02/ CALGB/GIMEMA

Attal, McCarthy, EHA 2016Median FU :80 months

Estimation de augmentation de survie de 2,5 ans

Maintenance: Myeloma XI

Jackson, ASH 2016 #1143Med Follow up: 27 mo

Maintenance: Myeloma XI

Jackson, ASH 2016 #1143

Transplant eligible Non Transplant eligible

Patient non éligible à la greffe

San Miguel JF et al. N Engl J Med 2008;359:906-917

Bortezomib plus Melphalan and Prednisone

for Initial Treatment of Multiple Myeloma

Jesús F. San Miguel, M.D.

24vs 16.6 months

RA

ND

OM

IZA

TIO

N 1

:1:1

Arm BRd18

Arm CMPT

LEN + Lo-DEX: 18 Cycles (72 wks) LENALIDOMIDE 25mg D1-21/28Lo-DEX 40mg D1,8,15 & 22/28

MEL + PRED + THAL 12 Cycles1 (72 wks)MELPHALAN 0.25mg/kg D1-4/42PREDNISONE 2mg/kg D1-4/42THALIDOMIDE 200mg D1-42/42

PD

, OS

and

Sub

seq

ue

nt

anti

-MM

Tx

PD

or

Un

acce

pta

ble

To

xici

ty

Active Treatment + PFS Follow-up PhaseScreening LT Follow-Up

Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL2 (100 mg D1-42/42); MEL2 0.2 mg/kg D1–4

44

• Stratification: age, country and ISS stage

1Facon T, et al. Lancet 2007;370:1209-18; 2Hulin C, et al. JCO. 2009;27:3664-70.

FIRST Trial: Study Design

LEN + Lo-DEX ContinuouslyLENALIDOMIDE 25mg D1-21/28Lo-DEX 40mg D1,8,15 & 22/28

Arm AContinuous Rd

ISS, International Staging System; LT, long-term; PD, progressive disease; OS, overall survival

Facon T, et al. Continuous Lenalidomide and Low-dose Dexamethasone Demonstrates a Significant PFS and OS Advantage in Transplant Ineligible NDMM Patients – The FIRST Trial: MM-020/IFM 0701. Plenary presentation at: American Society of Hematology. 2013; December 7-10; New Orleans, LA.

Median PFS

Rd (n=535) 25.5 mos

Rd18 (n=541) 20.7 mos

MPT (n=547) 21.2 mos

Ld 535 400 319 265 218 168 105 55 19 2 0

Ld18 541 391 319 265 167 108 56 30 7 2 0

MPT 547 380 304 244 170 116 58 28 6 1 0

Hazard ratioRd vs. MPT: 0.72 (CI: 0.61-0.85); P < 0.001Rd vs. Rd18: 0.70 (CI: 0.60-0.82) ; P < 0.001 Rd18 vs. MPT: 1.03 (CI: 0.89-1.20); P = 0.70

Time (months)

Pat

ien

ts (

%)

100

80

60

40

20

00 6 12 18 24 30 36 42 48 54 60

45

FIRST Trial - Final Progression-free Survival

23% (Rd18) 23% (MPT)

42% (Rd)

CI, confidence interval; mos, months; FIRST, Frontline Investigation of Revlimid and Dexamethasone versus Standard Thalidomide; MPT, melphalan, prednisolone, thalidomide; mos, months; PFS, progression-free survival; Rd, lenalidomide plus low-dose dexamethasone; Rd18, lenalidomide plus low-dose dexamethasone for 18 cycles; wks, weeks

Facon T, et al. EHA 2014: Abstract S643; Benboubker L, et al. NEJM. 2014;371:906-17.

Median follow-up of 37 months as of 24 May, 2013

72

wks

FIRST Trial - Overall Survival

Facon T, et al. FIRST Study: Updated Overall Survival in Stem Cell Transplant-ineligible Newly Diagnosed Multiple Myeloma Patients Treated With Continuous Lenalidomide Plus Low-dose Dexamethasone vsMelphalan, Prednisone, and Thalidomide. ASCO 2015, abstract #8524.

4-year OS Median OS

Rd (n=535) 60% 58.9 mos

Rd18 (n=541) 57% 56.7 mos

MPT (n=547) 51% 48.5 mos

Rd 535 488 457 433 403 366 337 246 156 74 13 0Rd18 541 505 465 425 394 362 329 238 146 72 18 0MPT 547 484 448 418 375 347 310 230 130 58 10 0

Number at risk

697 deaths (43% of ITT)

Median follow-up of 45.5 months as of 03 March, 2014

100

80

60

40

20

00 6 18 24 30 36 42 48 54 6012 66 72

Overall Survival (months)

Pat

ien

ts, %

60%

57%

51%

Hazard ratioRd vs. MPT: 0.75; P = 0.002Rd vs. Rd18: 0.91; P = 0.305Rd18 vs. MPT: 0.83; P = 0.034

Is it more always better?CLARION study: KMP versus VMP

T Facon, IMWG NewDelhi 2017

Traitement à la rechute

Choosing becomes more and more complicated , especially for relapsed pts…

• Which drugs?• How much drug?• How to give them?

Individualisation du traitement à la rechute

Patient

Maladie

But

Traitement antérieur

Inhibiteurs du protéasome de deuxième génération

More specific and ireverssiblelink

Marizomib

IxazomibOral

57

ENDEAVOR / Vel-dex versus KDProgression-Free Survival*

All patients

mPFS Kd = 18.7 monthsmPFS Vd = 9.4 months

Dimopoulos et al. Lancet Oncology 2016; 17: 27-38

Bortezomib-naive patients

mPFS Kd = NEmPFS Vd = 11.2 months

Update of the study: OS advantage

New Dehli February 2017

60

ASPIRE phase 3 trial: KRd vs Rd

N=792

1–3 prior therapies

Stratification: • β2-microglobulin• Prior bortezomib• Prior lenalidomide

KRd (n=396)

• Carfilzomib: 27 mg/m2 IV (10 min) - days 1, 2, 8, 9, 15, 16 (20 mg/m2 days 1, 2, cycle 1 only)

• Lenalidomide: 25 mg - days 1–21 • Dexamethasone: 40 mg - days 1, 8, 15, 22

Rd (n=396)

• Lenalidomide: 25 mg - days 1–21• Dexamethasone: 40 mg - days 1, 8, 15, 22

After cycle 12, carfilzomib given on days 1, 2, 15, 16 After cycle 18, carfilzomib discontinued

28-day cycles

Stewart et al. NEJM 2015;372:142–52

61

ASPIRE Progression-Free Survival

Stewart et al. NEJM 2015;372:142–52

mPFS KRd = 26.3 monthsmPFS Rd = 17.6 months

P Moreau et al 2016

Anticorps monclonaux

mAb-based therapies for multiple myeloma (MM). mAbs used therapeutically in MM can trigger

antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC);

block signaling pathways mediating MM cell growth and survival and drug r...

Kenneth C. Anderson Clin Cancer Res 2016;22:5419-5427

©2016 by American Association for Cancer Research

CS1 is expressed on the surface of MM tumor cells, where it contributes to

cell-cell adhesion between MM cells and bone marrow stromal cells

Don M. Benson Jr, and John C. Byrd JCO 2012;30:2013-2015

Elotuzumab mechanisms of action:(A) Direct activation of CS1-bearing NK cells(B) Antibody-dependent cellular cytotoxicity,(C) Disruption of CS1-mediated interaction between MM cells and BMSCs.

• Member of the signalinglymphocytic activation molecule (SLAM F7) family

Lonial S et al. N Engl J Med 2015;373:621-631.

Rev-dex vesrsus elotuzumab-RD : Progression-free Survival.

Niels W. C. J. van de Donk, Immunological review 2016

Daratumumab

ADCP:Antibody dependent cellular phagocytosisADCC: antibody-dependent cell-mediated cytotoxicity Promote T cell expansion

Daratumumab: Single-agent activity

• Daratumumab as a single agent

• Approved by FDA and by EMA in relapsed/refractory multiple myeloma1,2

• Patients received a median of 5 prior lines of therapy

• 86.5% of patients were double refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD)3

• Combined overall response rate (ORR): 31%3

• Median overall survival (OS): 20.1 months3

• 2-year OS was ~75% in responders

• Median OS was 18.5 months MR/SD patients

Lokhorst HM, et al. N Engl J Med. 2015;373:1207-19; 2. Lonial S, et al. Lancet.

Responders

MR/SD

PD/NE

100

75

50

25

0

Responder

s

MR/SD

PD/NE

Median

OS=NE(95% CI, NE-NE)

Median OS=18.5 months (95% CI, 15.1-22.4)

Median OS=3.7 months (95% CI, 1.7-7.6)

Pa

tie

nts

Aliv

e (

%)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

MonthsNo. at risk

46

77

25

46

74

16

46

67

12

45

63

11

44

57

7

43

53

7

43

48

5

41

45

4

40

38

4

39

34

4

28

20

3

12

8

2

12

4

1

2

1

0

0

0

0

CASTOR: Progression-free survival : velcade dex versus daratumumab-velcade-dexa

0 3 6 9 12 15

0

0.2

0.4

0.6

0.8

1.0

Months

Pro

po

rtio

n s

urv

ivin

g w

ith

ou

t p

rogr

essi

on

No. at riskVd

DVd247251

182215

106146

2556

511

00

Median : 7.2 months

Median : not reached

DVd

Vd

HR: 0.39 (95% CI, 0.28-0.53); P<0.0001

1-year PFS*

26.9%

60.7%

61% reduction in the risk of disease progression or death for DVd vs Vd

Palumbo et al. Presented at ASCO 2016 (Abstract LBA4), oral presentation

*KM estimate; HR, hazard ratio.

POLLUX: Progression-free survivalRevlimid-dexa vs daratumumab-revlimid-dexa

63% reduction in the risk of disease progression or death for DRd vs

RdDimopoulos et al. Presented at EHA 2016 (Abstract LB2238), oral presentation

Pro

port

ion

surv

ivin

g w

ith

ou

t pro

gre

ssio

n

0

0.2

0.4

0.6

0.8

1.0

0 3 6 9 12 15 18 21

283

286

249

266

206

248

179

232

139

189

36

55

5

8

0

0

Rd

DRd

No. at riskMonths

Rd

DRd

12-month PFS*

83%

60%

18-month PFS*

78%

52%

HR: 0.37 (95% CI, 0.27-0.52; P <0.0001)

Median PFS: 18.4 months

*KM estimate; HR, hazard ratio.

ASH 2016 - D’après Avet-Loiseau H et al., abstr. 246, actualisé

10-4 10-5 10-6 10-4 10-5 10-6

18

10

442 1

0

9

18

26

35

MR

D n

ég

ati

ve

, %

Seuil de sensibilité

DVd Vd

*** p < 0,0001

** p < 0,005

* p < 0,05

***

3,6X

***

4,2X

***

4,0X***

4,5X

**

5,0X

*

4,0X32

25

129

63

0

5

10

15

20

25

30

35

MR

D n

ég

ati

ve

, %

Seuil de sensibilité

DRd Rd

CASTORPOLLUX

Pollux-Castor: Proportion de patients MRD-négatives

➜ Le daratumumab en combinaison avec le standard de traitement améliore significativement la MRD négative à tous les niveaux

Comment choisir? : Guidelines 2017

• Moreau P, Ann Onco 2017

• D. Dingli et al, Mayo Clin Proc. 2017

Comment choisir?

IRd

KRd

DRd

ERd

Inhibiteur des PToxicité cardiaque, lyse tumorale, IR, Hemato IV (KRd)Hemato, Po (IRd)

Réaction infusion , BPCO

Infusion

Mauvaisecytogénétique

POLLUX DRd vs Rd

ASPIREKRd vs Rd

ELOQUENT-2ERd vs Rd (4-14)

TOURMALINEIRd vs Rd

mPFS 22.6 vs10.2

23.1 vs13.3

15.8 vs5.5

21.4 vs9.7

PFS HR (95% CI)

0.53(0.25-1.13)

0.7(00.42-1.16)

0.53(0.29-0.95)

0.54

Conditions de remboursement

IRd

• KD• KRD• Elotuzumab-RD• Ixazomib (1 octobre)

2018• D-len-dex• D-Vel-D• Len Maintenance

NATURAL HISTORY of MM

Progression-free survival

Pomalidomide plus low-dose dexamethasone versus high-dose

dexamethasone alone for patients with relapsed and refractory

multiple myeloma (MM-003): a randomised, open-label, phase 3 trial

The Lancet Oncology, Volume 14, Issue 11, 2013, 1055 - 1066

PFS 4vs 1.9 mos

OS 18.7 vs 9.4 mos

Pomalidomide, Cyclophosphamide, and Dexamethasone Is Superior to Pomalidomide and Dexamethasone in Relapsed and Refractory Myeloma: Results of a Multicenter Randomized Phase II Study

Abstract 303, Rachid Baz et al.

CBR, clinical benefit rate; Cyclo, cyclophosamide; LoDEX, low-dose dexamethasone; MR, minimal response; ORR, overall response rate; POM, pomalidomide; PR, partial response; VGPR, very good partial response.

Baz R, et al. Pomalidomide, Cyclophosphamide, and Dexamethasone Is Superior to Pomalidomide and Dexamethasone in Relapsed and Refractory Myeloma: Results of a Multicenter Randomized Phase II Study. ASH 2014, abstract #303

POM-LoDEX ± Cyclo: Response Rates

- N= 70

- LEN-refractory pts

• Median prior tt n=4

• > 70% Brt refractory

• > 1/3 CFZ refractory

Demain?

Response rate in patients treated with daratumumab plus pom-dex.

Ajai Chari et al. Blood 2017;130:974-981

©2017 by American Society of Hematology

Venetoclax: selective BCL2 inhibitor

RR according to cytogenetic

Selinexor Mechanism of Action

• XPO1 is the nuclear exporter for the majority of TSPs, the GR, and eIF4E-bound oncoprotein mRNAs

• Selinexor is a first-in-class XPO1 inhibitor that induces nuclear retention and activation of TSPs and the GR in the presence of steroids and suppresses oncoprotein expression

Slide credit: clinicaloptions.comVogl DT, et al. ASH 2016. Abstract 491. Reproduced with permission.

Selinexor Mechanism of Action

§ XPO1 is the nuclear exporter for the majority of TSPs, the GR, and eIF4E-bound oncoprotein mRNAs

§ Selinexor is a first-in-class XPO1 inhibitor that induces nuclear retention and activation of TSPs and the GR in the presence of steroids and suppresses oncoprotein expression

Slide credit: clinicaloptions.com

CYTOSOL

NUCLEUS

Nuclear pore

complex

Nuclear

envelope Tumor

suppressors

SINE

XPO1

Tumor

suppressors

p53

Par-4

PP2A

pRB

p21

IkB

BRACA1

p27

eIF4E

XPO1

Tumor

suppressors

Vogl DT, et al. ASH 2016. Abstract 491. Reproduced with permission.

STORM: OS and PFS

• Median OS for all pts: 9.3 mos; ≥ MR: not reached

• Median PFS for all pts: 2.3 mos; ≥ MR: 5.5 mosSlide credit: clinicaloptions.com

OS and PFS: All Pts

OS (all)

PFS (all)

N = 78

Su

rviv

al (%

)

100

50

0200 5 10 15

Mos Following Initiation of

Selinexor Treatment

OS and PFS: Pts with ≥ MR

OS ( ≥ MR)

PFS ( ≥

MR)N = 26

Su

rviv

al (%

)

100

50

0200 5 10 15

Mos Following Initiation of

Selinexor Treatment

Vogl DT, et al. ASH 2016. Abstract 491. Reproduced with permission.

Checkpoint inhibitors

• Pembrolizumab-Pom-DXM• 48 RRMM, med age 64y

• 3 med prior lines, 73% dble refractory

• ORR: 65% (68% DR, 56% HR) • ≥ VGPR 29% (24% DR, 15%HR)

• Deep and durable responses

• Quick relapse after suspending

• High AEs (12% pneumonitis)