klinische studies in multiple myeloom€¦ · a bortezomib-based induction regimen results in...
TRANSCRIPT
KLINISCHE STUDIES IN MULTIPLE MYELOOM
Sonja Zweegman
WAAR STAAN WE MOMENTEEL BIJ DE BEHANDELING VAN DEJONGERE PATIËNT MET MM, DIE EEN TX KAN ONDERGAAN?
DHC Zweegman| 2020
Gemiddelde overleving van Tx patiënten1995 4-5 jaarHeden ∼ 8 jaar
HOE ZIJN WE DAAR GEKOMEN?
1. INDUCTION2. STEM CELL TRANSPLANTATION3. CONSOLIDATION4. MAINTENANCE THERAPY
Door onderstaande te verbeteren
HOVON 65 en 131Bortezomib inductie
+ Daratumumab inductie
A bortezomib-based induction regimen results in superior response, PFS and OSmeta-analysis phase III RCT of IFM HOVON GIMEMA PETHEMAVd/PAD versus VAD or VTd versus Td
Vd: bortezomib-dexamethasone PAD: bortezomib-adriamycin-dexamethasone
VAD: vincristin-adriamycin-dexamethasone VTd; bortezomib-thallidomide –
dexamethasone Td thaldiomide-dexamethasone
Sonneveld JCO 2013 2013; 31(26):3279-87
PFS 35.9 vs 28.6 monthsHR 0.75, p<0.001
D-VTd, daratumumab/bortezomib/thalidomide/dexamethasone; VTd, bortezomib/thalidomide/dexamethasone; ECOG, Eastern Cooperative Oncology Group; IV, intravenous; QW, weekly; Q2W, every 2 weeks; SC, subcutaneous; PO, oral; PR, partial response; Q8W, every 8 weeks; PD, progressive disease; sCR, stringent complete response; PFS, progression-free survival; MRD, minimal residual disease; CR, complete response; OS, overall survival. aDexamethasone 40 mg on Days 1, 2, 8, 9, 15, 16, 22, 23 of Cycles 1-2 and Days 1 & 2 of Cycles 3-4; 20 mg on Days 8, 9, 15, 16 of Cycles 3-4; 20 mg on Days 1, 2, 8, 9, 15, 16 of Cycles 5-6.
Part 1 Part 2
Key eligibility criteria:
• Transplant-eligible NDMM
• 18-65 years• ECOG 0-2
Firs
t ran
dom
izat
ion
(1:1
)
Induction
D-VTdD: 16 mg/kg IV QW Cycles 1-2, Q2W
Cycles 3-4V: 1.3 mg/m2 SC Days 1, 4, 8, 11T: 100 mg/day POd: 20-40 mg IV/POa
VTdVTd administered as in the D-VTd arm
TRANSPLANT
Consolidation
D-VTdD: 16 mg/kg IV Q2WV: 1.3 mg/m2 SC Days 1, 4, 8, 11T: 100 mg/day POd: 20 mg IV/POa
VTdVTd administered as in the D-VTd arm
Maintenance
D monotherapyD 16 mg/kg IV Q8W untilPD (2 years maximum, then observation until
PD)
Observationuntil PD
(2 years maximum)
Patie
nts
with
≥PR
Seco
nd ra
ndom
izat
ion
(1:1
)
4 Cycles of 28 days 2 Cycles of 28 days
Follo
w-u
p
CASSIOPEIA Study Design • Phase 3 study of D-VTd versus VTd in transplant-eligible NDMM (N = 1,085)
6Philippe Moreau, MD
Efficacy: PFS From First Randomization• Median (range) follow-up: 18.8 (0.0-32.2) months
HR, hazard ratio; CI, confidence interval.aKaplan-Meier estimate.
% s
urvi
ving
with
out p
rogr
essi
on
0 3 6 9 12 15 18 21 33302724Months
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%
53% reduction in the risk of progression or death in the D-VTd arm
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
7Philippe Moreau, MD
Efficacy: OS• Median OS was not reached in either treatment arm
Data are immature after median follow-up of 18.8 months%
sur
vivi
ng
0 3 6 9 12 15 18 21 33302724Months
0
20
40
60
80
100
535539
542543
531535
528532
480485
371388
283292
206212
131137
7175
1717
00
VTdD-VTd
No. at risk
VTdD-VTd
D-VTd(n = 543)
VTd(n = 542)
Events, n (%) 14 (3) 32 (6)
HR (95% CI) 0.43 (0.23-0.80)
18-month OS rate, % (95% CI) 98 (96-99) 95 (92-97)
24-month OS rate, % (95% CI) 97 (95-98) 93 (90-95)
8Philippe Moreau, MD
64%
44%
0
10
20
30
40
50
60
70
MR
D-n
egat
ive
rate
, %
D-VTd(n = 543)
VTd(n = 542)
P <0.0001
Efficacy: MRD (Flow Cytometry; 10–5)a,b
aPost-consolidation.bAdditional MRD results will be presented during tomorrow’s Poster Discussion session: Avet-Loiseau H, et al. ASCO 2019. Abstract 8071.cBased on patients with available cytogenetics results.dBased on patients with available serum heavy chain disease type only.
9Philippe Moreau, MD
D-VTd superior across all subgroupsincluding high-risk cytogenetics and ISS stage III
Sex
Age
Site
1 10
VTd Better D-VTd Better
VTd D-VTd Odds Ratio (95% CI)
131 (41)105 (47)
38 (42)198 (44)
204 (45)32 (38)
103 (45)96 (41)37 (46)
38 (44)197 (43)
139 (44)97 (43)
216 (43)20 (48)
122 (39)59 (49)
112 (44)124 (44)
192 (61)154 (68)
56 (68)290 (63)
287 (64)59 (65)
137 (67)155 (61)54 (64)
49 (60)296 (64)
205 (62)141 (67)
310 (65)36 (57)
201 (61)61 (66)
172 (65)174 (63)
Subgroup Minimal residual disease negative, n (%)
2.22 (1.62–3.05)2.37 (1.62–3.48)
2.84 (1.53–5.28)2.19 (1.68–2.85)
2.16 (1.65–2.81)3.05 (1.65–5.65)
2.48 (1.68–3.67)2.21 (1.54–3.18)2.14 (1.15–4.00)
1.88 (1.02–3.46)2.35 (1.80–3.07)
2.07 (1.51–2.84)2.64 (1.79–3.89)
2.40 (1.85–3.10)1.47 (0.67–3.21)
2.43 (1.77–3.34)2.00 (1.15–3.50)
2.39 (1.68–3.41)2.17 (1.55–3.04)
ISS disease stage
Cytogenetic profile at trial entryc
Baseline creatinine clearance
Baseline hepatic function
Type of multiple myelomad
ECOG performance status
5
Male
IFM
IIIIll
lgG
0
Female
<50 years
HOVON
High riskStandard risk
>90 ml/min
NormalImpaired
Non-lgG
≥50 years
≤90 ml/min
≥1
1. INDUCTION2. STEM CELL TRANSPLANTATION3. CONSOLIDATION4. MAINTENANCE THERAPY
Consists of
HOVON 95
Transplanteren beter dan niet transplanteren
2x transplanteren bij hoog risico ziektet (4;14), t (14;16), del17p
PFS met transplanteren langer dan niet transplanteren
Cavo M et al. ASH 2016Attal M et al. N Engl J Med 2017 Apr 6;376(14):1311-1320
0.00
0.50
1.00
Pro
gres
sion
-free
sur
viva
l (%
)
497 400 298 142 27 1VMP695 596 449 192 39 2ASCT
Number at risk
0 12 24 36 48 60Time (months)
ASCT VMP
Tandem transplantatie superieur t.o.v. single transplantatie in hoog risico patiënten
HR: 0.79 (95% CI, 0.41-1.52), P=0.483
76.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.576.4%(69.2% ; 84.5
69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)69.2%(54.7% ; 87.5%)
0.00
0.25
0.50
0.75
1.00
0 12 24 36 48Months
PFS
pro
babi
lity
38 35 28 17 7
139 126 104 68 33--0 12 24 36 48
Months
Number at risk
Median PFS: ASCT-2: NR; ASCT-1: 26.7 mos HR: 0.42 (95% CI, 0.21-0.84), P=0.014
69.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 869.2%(54.7% ; 8
44.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.244.2%(31% ; 63.2
0.00
0.25
0.50
0.75
1.00
0 12 24 36 48Months
PFS
pro
babi
lity
43 33 22 15 3
38 35 28 17 7ASCT-2
ASCT-1
0 12 24 36 48Months
Number at risk
PFS 2 vs 1 auSCT PFS standard vs high risk with 2 auSCT
OS superior with tandem Tx in high risk disease
Cavo et al. ASH 2017
HR: 0.52 (95% CI, 0.28-0.98), P=0.042
84.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 984.9%(77.3% ; 9
72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)72.8%(63.6% ; 83.4%)
0.00
0.25
0.50
0.75
1.00
0 12 24 36 48Months
OS
pro
babi
lity
93 83 70 44 1390 83 72 49 24ASCT-2
ASCT-1
0 12 24 36 48Months
Number at risk
2
1
VRAGEN VOOR DE TOEKOMST
Onderhoudsbehadeling MRD - gestuurd?Staken in geval van bereiken MRD-negativiteit
Wat te doen in hoog risico ziekteMet daratumumab ook nog tandem transplantatie nodig?
al CAR-t cel therapie in eerste lijn?
EMN-HOVON PERSEUS TRIAL – MRD gestuurd
EMN Perseus trial
Hypothesis Dara-VRd superior over VRd,
increasing median PFS from 63 to 91 months, HR 0.69
MRD-based maintenance exploratory endpoint
WAAR STAAN WE MOMENTEEL BIJ DE BEHANDELING VAN DEOUDERE PATIËNT MET MM?
DHC Zweegman| 2020
Gemiddelde overleving van oudere patiënten1995 2-3 jaarTot voor kort 5-6 jaar
Hoe zijn we daar gekomen?
1. GEBRUIK VAN NIEUWE MIDDELEN2. CONTINUERING VAN DE THERAPIE TOT AAN PROGRESSIE3. IMPLEMENTEREN VAN HET CONCEPT FRAILTY EN AANPASSEN VAN DE THERAPIE
Door onderstaande te verbeteren
Nu is de verwachte PFS 3 jaar en is na 3 jaar nog ongeveer80% van de patienten in leven indien behandeld met Dara-MPV
Dara = daratumumab, M = melfalan, V = bortezomib, P = prednison
En een PFS van 4-5 jaar is de verwachting met Dara-Rd
Facon T et al. N Engl J Med 2019;380:2104-15
30 moa
% su
rviv
ing
with
out
prog
ress
ion
0
20
40
60
80
100
0 3 6 9 12 15 18 42Months
27
369368
332347
307335
280320
254309
236300
219290
00
149203
No. at riskRd
D-Rd
21 24 30
94146
1835
200271
RdMedian: 31.9 mo
D-RdMedian: not reached
33 36
311
5086
39
21
HR, 0.56;95% CI, 0.43-0.73; P <0.0001
71%
56%
aKaplan-Meier estimate; bP <0.001; P value was calculated with the use of the Cochran–Mantel–Haenszel chi-square test. CI, confidence interval; CR, complete response; D, daratumumab; HR, hazard ratio; PR, partial response; Rd, lenalidomide-dexamethasone; sCR, stringent complete response; VGPR, very good partial response.
DHC Zweegman| 2020
1. GEBRUIK VAN NIEUWE MIDDELEN2. CONTINUERING VAN DE THERAPIE TOT AAN PROGRESSIE3. IMPLEMENTEREN VAN HET CONCEPT FRAILTY IPV LEEFTIJD EN AANPASSEN VAN DE THERAPIE
Door onderstaande te verbeteren
LEEFTIJD IS VAN BELANG Overleving inferieur, tgv toxiciteit die leidt tot sterfte en tot een lagere kans op het krijgen van de
tweedlijnsbehandeling
MAAR ER IS EEN VERANDERING VAN LEEFTIJD NAAR ‘FRAILTY’
Bringhen S et al. Crit Rev Oncol Hematol 2018:130;27-35 and personal communicationVan der Holt B and Nasserinejad K. Subanalyses HOVON 87 and 123 study, Gavriatopoulou M et al. Leuk Lymphoma, 2019:1-10
No effect of ageALCYONE Study
Mateos MV et al. N Engl J Med 2018;378:518-28Usmani SZ, et al., ASCO 2019; abstract 8035, oral presentation
CI, confidence interval; D, daratumumab; HR, hazard ratio; PFS, progression-free survival; VMP, bortezomib-melphalan-prednisone.
Also in the MAIA study no impact of age was observed
Dus van oud naar frailty, maar wat is frailtyeigenlijk?
‘Biologisch syndroom gekarakteriseerd door verminderde biologischereserves, door dysregulaite van verschillende fysioloigsche systemin,
waardoor een individue meer kwetsbaar is ten tijde van minimale stress’
DHC Zweegman| 2020
Hoe meet je dat in MM?
Leeftijd
iADL ADL
Comorbiditeit
DHC Zweegman| 2020
IMWG Frailty score – de gouden standaard in MM
Palumbo A, et al. Blood 2015, 125: 2068-74
30% of patients
DHC Zweegman | 2020
HOVON 123Wat betekent de IMWG frailty index?
1. Vinden wij ook dat de prognose slechter is in frailpatiënten?
2. Toont de frailty score aan dat patiënten idd geriatrische tekortkomingen hebben?
HOVON 123 studie – in patienten ≥ 75 years
• 240 NDMM patienten - ‘Real life population’ • Ernstig hartfalen - NYHA classificatie IV • Enristige LF stoornis – kortademig in rust• Nierinsufficientie waar dialyse voor nodig is• Actieve maligniteit anders dan MM die behandeling behoeft
• Co-morbiditeiten and geriatrische assessments• Functioneel(ADL, iADL, selfreported physical functioning)• Cognitief (MMSE) and mentaal (GDS)• Nutritie (MNA)
• Biomarkers voor ‘aging’ • Spiermassa (CT scan) and functie (loopsnelheid en knijpkracht• Senescence markers
9 cycli, per 5 weeks
Melfalan 6 mg/m2
dag 1-4
Prednison 30 mg/m2
day 1-4
Bortezomib 1.3 mg/m2
day 1, 8, 15 and 22
OOK IN DE HOVON 123 STUDIE STAAKTEN MEER FRAILPATIËNTEN DE THERAPIE EN WAS HUN OVERLEVING SLECHTER
Treatment discontinuation Overall survival Progression free survival
Median follow-up 35.1 months (range 1.4-62.6)
TD ≤ 9 cycles unfit vs frail34 vs 50%
Median OS unfit vs frail43 vs 34 months
Median PFS unfit vs frail17 vs 17 months
Nieuwe methodenNederlandse HOVON 123 en 143 studie MPV in patienten ≥ 75 years
of ageFUNCTIONAL ASSESSMENTS
Zweegman EHA SWG Aging| October 2018
Nieuwe biomarkers om feasibility te voorspellenSarcopenie
DHC Zweegman | 2020 MET DANK AAN CLAUDIA STEGE EN KAREL KNECHTING
IMWG frailty index reflecteert biologische ‘frailty’ Het voorkomen van functionele, cognitieve, mentale and voedingstekortkomingen is hoger in frail dan in unfit
DHC Zweegman | 2020 Stege C et al, Blood, 2018, abstract
0
5
10
15
20
25
30
35
40
45
50
PRO physicalfunctioning <47
Low grip strength Slow walking speed Muscle mass <p10 Depression MMSE <24 MNA <7
UNFIT FRAIL*
*
*
*
*
*
* p-value < 0.05
PR-FUNCTIONAL PERFORMANCE SARCOPENIA MENTAL/COGNITIVE NUTRITIONAL
*
PROGNOSE BETER TE VOORSPELLEN DOOR BIOMARKERS VOOR VEROUDERING?P16 EXPRESSIE IN DE HUID
Zweegman ESH| April 2019
0
0,002
0,004
0,006
0,008
0,01
0,012
0,014
1 7 13 19 25 31 37 43 49 55 61 67 73 79 85 91 97 103
109
115
121
127
133
139
145
151
157
163
169
175
181
187
193
199
205
P16
expr
essio
n
rank number p16 expression
p16 expression per micrometer basal membrane
Kan het ook zonder de (i)ADL?
HOVON 87
Simplified frailty indexdefined in First trial, validated in the HOVON 87 trial
Facon T et al. Leukemia. 2020 Jan;34(1):224-233Stege C et al. Leukemia in press
1. GEBRUIK VAN NIEUWE MIDDELEN2. CONTINUERING VAN DE THERAPIE TOT AAN PROGRESSIE3. IMPLEMENTEREN VAN HET CONCEPT FRAILTY IPV LEEFTIJD EN AANPASSEN VAN DE THERAPIE
Door onderstaande te verbeteren
HOVON 123 - Bij patiënten ≥ 75 jaar
Slechtere uitkomst dan in studies met meer exclusiecriteriaVerschil tussen unfit en frail
Qua geriatrische assessment
Qua uitkomst
Vraag was – kunnen we de uitkomst van verbeteren?
1. Minder inductiekuren en dan langer door met onderhoud
2. Minder zware therapie
3. Andere vormen van therapie met een bijwerkingenprofiel wat ook bij ouderen kan
HOVON 123Minder inductiekuren bij unfit en frail – met zelfde response
Discontinuation ITT Unfit Frail
9 x MPV 42% 27% 46%
6 x MPV 30% 20% 31%
RESPONSE* ≥ PR ≥ VGPR ≥ CR
9 x MPV 73% 38% 11%
6 x MPV 69% 35% 2%
Zweegman S, et al. ASH 2016 (Abstract 3305)
VMP 9 cycli versus VMP 6 cycli plus bortezomib onderhoudClassic VISTA scheme versus 1-cycle twice weekly bortezomib plus 5-cycles of once weekly followed by bortezomib maintenance one cycle/3 months for 3 years
PFS OS
Mateos M-V et al. Ann Hematol 2016; 95:2033–2041DHC Zweegman| 2020
HOVON 143
Andere vorm van therapieDARATUMUMAB
IXAZOMIBLAGE DOSIS DEXAMETHASON
HOVON 143 studie66 UNFIT EN 66 FRAIL PATIENTENPLUS GERIATRIC ASSESSEMENTS EN BIOMARKER STUDIES
9 cycli, per 4 weken
Ixazomib 4 mgdag1, 8, 15
Dexamethasone20 mgdag1, 8, 15, 22, cyclus 1
Dexamethason 10 mgdag 1, 8, 15, 22, cycli 2–9
Daratumumab 16 mg/kgdag 1, 8, 15, 22, cycli 1–2
dag 1, 15, cycli 3–6dag 1, cycli 7–9
Maximum 2 jaar tot PDPer 8 weken
Ixazomib 4 mgDag 1, 8, 15, 29, 36, 43
Daratumumab 16 mg/kgdag 1
OnderhoudInductieRe
gist
rati
on
HOVON 143 - EudraCT 2016-002600-90
DEMOGRAPHICSOF THE FIRST 23 UNFIT AND 23 FRAIL PATIENTS WHO COMPLETED INDUCTION THERAPY
UNFIT (n=23) FRAIL (n=23)
Median age (range) 76 (75-80) 82 (76-92)
Age > 80 years n (%) - 16 (70)
WHO performance status (n)
0 9 (39) 4 (17)
1 9 (39) 11 (48)
2 4 (17) 6 (26)
≥3 - 2 (9)
unknown 1 (4) -Median creatinine clearance, ml/min [range] 60 [26-111] 60 [30-83]
< 30 ml/min (%) 1 (4) -< 60 ml/min (%) 4 (17) 6 (26)
EFFICACYRESPONSE DURING INDUCTION
OF THE FIRST 23 UNFIT AND 23 FRAIL PATIENTS
Response rate (%) UNFIT (n=23) FRAIL (n=23)ORR 74 78
CR - 4VGPR 35 26PR 39 48SD 27 13PD - -not evaluable 9
Median time to response (months) 2 2
EFFICACY - PROGRESSION FREE SURVIVALMEDIAN FOLLOW UP 18.9 MONTHS (RANGE 14-24) AND 17.9 MONTHS (RANGE 10.6-25.1)
9-months PFS 78% (95% CI 55-90) 9-months PFS 61% (95% CI 38-77)
Median PFS 12 monthsMedian PFS 23 months
MORTALITYn=132
MEDIAN FOLLOW UP UNFIT 11.1 MONTHS (3.2-24) AND FRAIL 13.5 MONTHS (0.4-25.1)
0
10
20
30
40
50
60
70
80
90
100
UNFIT n=65 FRAIL n=67
other
bleeding + persistent MM
cardiac
infections
sudden death
PD
% O
FPA
TIEN
TSW
HODI
ED
9%
21%
Early death rate (≤3 months of registration) - 7%
2% in unfit - 1/65
12% in frail - 8/67
1 before start of therapy 1 decompensated liver cirrhosis
2 sudden death 1 infection 1 bleeding 1 renal failure 1 “pneumonitis”
9%
EHA meeting Zweegman| June 2019
LET OOK OP SUPPORTIVE CARE – HOE GROOT IS DE KANS DATEEN PATIENT DIE MET DARA-VMP WORDT BEHANDELD EEN
PNEUMONIE ONTWIKKELD?
Dara-VD, daratumumab-bortezomib-dexamethasone.
EHA meeting Zweegman| June 2019
Toxiciteit bij DARA-VMP en DARA-RdGrade 3/4
ALCYONE MAIA
Dara-VMP VMP
HEMATOLOGISCH
Neutropenie 39.3 38.7
Thrombopenie 34.4 37.6
NON-HEMATOLOGISCH
Infecties 23.1 14.7
Pneumonie 11.3 4.0
Diarrhee 2.6 3.1
PNP 1.4 4.0
Dara-Rd Rd
HEMATOLOGISCH
Neutropenie 50.0 35.3
Anemie 11.8 19.7
NON-HEMATOLOGISCH
Infecties 32.1 23.3
Pneumonie 13.7 7.9
Diarrhee 6.6 4.1
Fatigue 8.0 3.8
Mateos MV et al. N Engl J Med 2018;378:518-28Facon T et al. N Engl J Med 2019;380:2104-15
Dara, daratumumab; Rd, lenalidomide-dexamethasone; VMP, bortezomib-melphalan-prednisone.
EHA meeting Zweegman| June 2019
Het belang van antibiotische prophylaxeTEAMM trial 977 patiëntenLevofloxacine versus placebo
Primary endpoint - febrile episodes/deaths 19 vs 27%
Reduction of infections caused by gram-negative microorganisms, similar incidence of gram-positive microorganisms
Also in patients using cotrimoxazole
HR=0.66 [95% CI=0.51-0.86]P=0.002
Courtesy of Drayson M et al. ASH 2017, abstract 903, oral presentation
CI, confidence interval; HR, hazard ratio.
BehandelingDoet langer leven
0%
25%
50%
75%
100%
0 1 2 3 40%
25%
50%
75%
100%
0 1 2 3 4
66-70 years71-74 years75-79 years80-84 years85+ years
Source: Dinmohammed A, et al. The Netherlands Cancer Registry
Years from diagnosis
Ove
rall
surv
ival
Overlevingsdata van de Nederlandse Kanker RegistratieData van 1.972 NDMM patienten van 2014-2016
ZONDER BEHANDELING MET BEHANDELING
ASCO meeting Zweegman| May 2019
Patients who participated in the studies
HOVON Myeloma Working groupAll Dutch and Belgian participating hematologists and sitesProf. dr. Pieter Sonneveld, MDProf. dr. Niels van de Donk, MD
The HOVON data centerDr. Kazem Nasserinejad and dr. Bronno van der Holt, statisticiansSonia Cunha and Heleen Visser, trialmanagers
Claudia Stege, MD and PhD student
dr. Larocca, dr. Bringhen and prof. Mateos for sharing their data
CAR-T TeamAfroditi KatsarouJort van der SchansAida ShahrabiRenee PoelsJannemiek van Arkel
MM clinical teamClaudia Stege, MDCorien Eeltink, NSPatty Bosman, NSDr. Inger Nijhof, MDDr. Niels van der Donk, MDSandy Kruiswijk, RNLouise Nieuwenhuis, RNYvonne den Hartog, RNJolijn Schellingerhout, RNEsther Brands, RN
MM preclinical teamLisa HolthofHilma van der HorstKris FrerichsChristy VerkleijWassilis Bruins Tamas CsikosJiaxian WangJyoti NaikRuud RuiterMarloes BroekmansJhon Marin Soto
Dr. Richard GroenProf. dr. Niels van de DonkDr. Inger NijhofProf. Dr. Tuna Mutis