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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)