KLINISCHE STUDIES IN MULTIPLE MYELOOM€¦ · A bortezomib-based induction regimen results in...

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


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)


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.


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


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


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


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.


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.


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

KLINISCHE STUDIES IN MULTIPLE MYELOOM€¦ · A bortezomib-based induction regimen results in...

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