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Höhepunkte ASH 2016 ‐ Stuttgart
San Diego 2.12.16 ‐ 6.12.16
Multiples MyelomKatja Weisel
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Multiples Myelom – NDMM Primärtherapie
Primärtherapie Patienten > 65/70 Jahre• Langzeitdaten zur Rd‐Therapie
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Abstract 241
Final Analysis of Overall Survival From the FIRST Trial
Thierry Facon, Meletios Dimopoulos,Angela Dispenzieri, John V. Catalano, Andrew Belch, Michele Cavo, Antonello Pinto, Katja Weisel, Heinz Ludwig,
Nizar J. Bahlis, Anne Banos, Mourad Tiab, Michel Delforge, Jamie D. Cavenagh, Catarina Geraldes, Je‐Jung Lee, Christine Chen, Albert Oriol, Javier De La Rubia, Darrell White, Daniel Binder, Jin Lu,
Kenneth C. Anderson, Philippe Moreau, Michel Attal, Jean‐Paul Fermand, Hervé Avet‐Loiseau, Annette Ervin‐Haynes, Guang Chen, Vanessa Houck,
Cyrille Hulin, and Lofti Benboubker
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FIRST (MM‐020): Final Survival AnalysisObjective
• To evaluate the effect of treatment with Rd continuous vs MPT on OS at the prespecified final OS analysis
RANDOMIZAT
ION 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, O
S an
d
Subseq
uent anti‐M
M Tx
PD or U
naccep
table To
xicity
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
• Stratification: age, country and ISS stage
LEN + Lo-DEX ContinuouslyLENALIDOMIDE 25mg D1-21/28Lo-DEX 40mg D1,8,15 & 22/28
Arm AContinuous Rd
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FIRST (MM‐020): Final Survival AnalysisPatient Disposition at Final Overall Survival Analysis
• Median follow‐up for surviving patients: 67 months (range, 0‐86.8 months)
• Disease progression was the most common reason for study discontinuation
Rd Continuousn = 535
Rd18n = 541
MPTn = 547
Median duration of Tx, mosa 18.4 16.6 15.4
Still on Tx, n (%) 52 (9.7) 0 0
Discontinued study, n (%)
Disease progression 271 (50.7) 362 (66.9) 337 (61.6)
Adverse event 64 (12.0) 71 (13.1) 76 (13.9)
Death 60 (11.2) 28 (5.2) 37 (6.8)
Other 68 (12.7) 54 (10.0) 73 (13.3)
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FIRST (MM‐020): Final Survival AnalysisProgression‐Free Survival by Response
• Median PFS was prolonged in patients who responded to Rd continuous vs MPT, particularly in those who achieved a deeper response (CR/VGPR)
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FIRST (MM‐020): Final Survival AnalysisOverall Survival
• The pre‐specified final OS analysis for the primary comparison showed that Rd continuous significantly extended OS vs MPT
Median OS, mos
4-yr OS, %
Rd continuous 59.1 59.0
Rd18 62.3 58.0
MPT 49.1 51.7
HR (95% CI)Rd continuous vs MPT: 0.78 (0.67-0.92), P = .0023
1.0
0.8
0.6
0.4
0.2
0.00 6 12 18 24 30 36 42 48 54 6660 7872 9084
Overall Survival (Months)
Sur
viva
l Pro
babi
lity
4-year OS
59.0%58.0%
51.7%
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FIRST (MM‐020): Final Survival AnalysisAuthors’ Conclusions1
• Rd continuous significantly prolonged PFS compared with MPT in transplant‐ineligible patients with NDMM, consistent with previously published analyses2,3
• In this final analysis of OS, Rd continuous significantly improved OS compared with MPT
• No new safety signals were observed with long‐term follow‐up of Rd continuous
• The final analysis of this trial reaffirms Rd continuous as a standard of care for transplant‐ineligible patients with NDMM
ASH 2016
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Multiples Myelom – NDMM Primärtherapie
Primärtherapie Patienten bis 70 Jahre
Cavo et al.: Bleibt HD‐Therapie Standard?
Zimmerman et al.: KRd vor/nach Hochdosis als effektivste Kombination
Sonneveld et al.: Was bringt die Konsolidierung?
ASH 2016
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#673 Cavo et al: Intensification Therapy with ASCT versus VMP in NDMM: EMN‐02/HO95 MM trial
VCD4 cycles
SC collection
VMP4 cycles
HDM 1/2a
INTENSIFICATION
MAINTENANCE
No consolidation
CONSOLIDATION
R1 R2
INDUCTION
NDMMN = 1510
• Enrollment: February 14, 2011 to April 15, 2014• Data cutoff: July 1, 2016• Primary endpoints: PFS from R1 and R2• Secondary endpoints: CR, ORR, MRD, OS, molecular prognostic factors
LEN LEN 10 mg PO
Treatment until PD or toxicity
RVdBORT 1.3 mg/m2 IV
D1, 4, 8, 11
LEN 25 mg PO D1–21DEX 20 mg PO
D1, 2, 4, 5, 8, 9, 11, 12
2 28‐day cycles
Study Design
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#673 Cavo et al: Intensification Therapy with ASCT versus VMP in NDMM: EMN‐02/HO95 MM trial
ASCT
VMP
Progressionsfreies Überleben• Die primäre Hochdosistherapie hat zu einem signifikanten Vorteil im PFS geführt im Vergleich zu VMP
• Der Vorteil blieb über alle analysierten Subgruppen erhalten
• Hochdosistherapie blieb unabhängige Variable in der Multivariatanalyse
• Auch in der Ära der neuen Substanzen bleibt die Hochdosistherapie Standardtherapie für alle geeigneten Patienten
High‐risk patients ASCT VMP
PFS median, mos 42.3 20.3
PFS at 3 yrs, % 52.4 29.5
ASH 2016
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Multiples Myelom – NDMM Primärtherapie
Primärtherapie Patienten bis 70 Jahre
Cavo et al.: Bleibt HD‐Therapie Standard?
Zimmerman et al.: KRd vor/nach Hochdosis als effektivste Kombination
Sonneveld et al.: Was bringt die Konsolidierung?
ASH 2016
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675. Final Results of a Phase 2 Trial of Extended Treatment (tx) with Carfilzomib (CFZ), Lenalidomide (LEN), and Dexamethasone (KRd) Plus Autologous Stem Cell
Transplantation (ASCT) in Newly Diagnosed Multiple Myeloma (NDMM)
• Todd Zimmerman, Noopur S. Raje, Ravi Vij, Donna Reece, Jesus G. Berdeja, Leonor A Stephens, Kathryn McDonnell, Cara A. Rosenbaum, Jagoda Jasielec, Paul G Richardson, Sandeep Gurbuxani, Jennifer Nam, Erica Severson, Brittany D. Wolfe, Shaun Rosebeck, Andrew Stefka, Dominik Dytfeld, Kent Griffith, and Andrzej Jakubowiak
ASH 2016
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Phase 2 clinical study of KRd with ASCTin NDMM
• Primary endpoint: Rate of sCR at the end of cycle 8• An sCR rate of 50% or better for KRd plus ASCT would indicate superior outcome
compared with a historical sCR rate of 30% for KRd w/o ASCT
Transplant‐eligible NDMM
(tx required according to IMWG criteria;
no age limitation)
N=76
Carfilzomib i.v.20/36 mg/m2†
Days 1, 2, 8, 9, 15, 16
Lenalidomideoral 25 mgDays 1–21
Dexamethasone oral 40 mg/week
Carfilzomib i.v.20/36 mg/m2†
Days 1, 2, 8, 9, 15, 16
Lenalidomideoral 25 mgDays 1–21
Dexamethasone oral 40 mg/week
Carfilzomib i.v.20/36 mg/m2
Days 1, 2, 8, 9, 15, 16
Lenalidomideoral 15/25 mg‡Days 1–21
Dexamethasone oral 20 mg/week
Induction (cycles 1–4)
Consolidation(cycles 5–8)
28‐day cyclesSingle‐agent lenalidomide was recommended off‐study after cycle 18.
Stem
cell collection*
& ASCT
KRd as in cycle 8
(carfilzomib only days 1, 2, 15, 16)
Maintenance(cycles 9–18)
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KRd plus ASCT: ResponseRate of sCR over time
20
6982
0
20
40
60
80
100
post‐ASCT After 8 cycles After 18cycles
Patie
nts (%)
MRD rates
82 90 90 100
66 71 6380
0
50
100
MRD rate at cycle 8 MRD rate at cycle 18 MRD rate at cycle 8 MRD rate at cycle 18
Patie
nts (%)
MFC
NGS
All evaluable patients High-risk patients
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KRd plus ASCT: Survival and safety
EfficacyAll patients (N=76)
MRD‐negative patients*
MRD‐positive*/unknown patients
High‐risk disease patients (n=27)
2‐year PFS, % 97 100 93 96
2‐year OS, % 99 100 98 Not stated
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Author’s conclusions
• Extended KRd tx with incorporated ASCT results in high rates of sCR and MRD‐negative disease in both standard and high risk disease, which correspond to high rates of PFS and OS
• These results compare favourably with data from the KRdwithout ASCT study, based on pre‐specified improvement of sCR rate at the end of 8 cycles and beyond, and with historical studies in NDMM
• These results will require validation in ongoing and planned randomised trials
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Patient ND MM
FISH‐Analysis
I‐KRd x 6
I‐KR Maintenance
I‐KRd x 4I‐KRd x 4
I‐KR Maintenance
High‐risk disease*
Transplant‐eligible Transplant‐ineligible
Cy + G-CSF + leukapheresis
HDM + TPL
2. HDM + TPL (if no nCR/CR)
GMMGstandardintensification
I‐KRdx 6
I‐KRd x 2
N = 117 N = 36
*del 17p, t(4;14), +1q21 (more than 3 copies) + ISS2/3
NDMM Patient with 1 cycle (4 weeks) of MM
treatment
NDMM Patient with 1 cycle (4 weeks) of MM
treatment
GMMG‐CONCEPT‐Trial
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Multiples Myelom – RRMM
Rezidiviertes Myelom• Update der Daratumumab‐Kombinationen
ASH 2016
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Patients with < 12 mo remission after last line benefit the most
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Multiples Myelom – RRMM
Rezidiviertes Myelom• Carfilzomib 1 x wöchentlich
ASH 2016
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2129. Once‐Weekly Carfilzomib With Dexamethasone Demonstrated Promising Safety and Efficacy in Patients With Relapsed or Refractory Multiple
Myeloma Regardless of Age and Prior BortezomibExposure
CHAMPION‐1, NCT01677858
• Jesus G. Berdeja, Robert M. Rifkin, Roger M. Lyons, Hui Yang, Anita Zahlten‐Kumeli, Sanjay Aggarwal, Karim Iskander, James R. Berenson
ASH 2016
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Phase 1/2 CHAMPION‐1 secondary analysis: Once‐weekly carfilzomib with dexamethasone
• Primary objectives: MTD and overall response rate of Kd • The efficacy and safety of once‐weekly carfilzomib at 70 mg/m2 were evaluated
by prior bortezomib (BTZ) exposure and age1
* 20 mg/m2 on day 1, cycle 1 only, then stepping up to assigned dose level. For cycles 1−8; dexamethasone was omitted on day 22 for cycles ≥9. i.v., intravenous; Kd, carfilzomib+dexamethasone; MM, multiple myeloma: MTD, maximum tolerated dose.1. Berenson et al. Blood 2016;127:3360−3368
Relapsed or refractory MM
(1-3 prior therapies)
Carfilzomib dose determination:
45, 56, 70, or 80 mg/m2
i.v. (30 min)Days 1*, 8, 15
Dexamethasone 40mg oral or i.v.
Days 1, 8, 15, 22
Carfilzomib dose determination:
45, 56, 70, or 80 mg/m2
i.v. (30 min)Days 1*, 8, 15
Dexamethasone 40mg oral or i.v.
Days 1, 8, 15, 22
Carfilzomib dose expansion:
70 mg/m2 i.v. (30 min) Once-weekly
Dexamethasone 40mg oral or i.v.
Days 1, 8, 15, 22
Phase 1 Phase 2 (N=104)
28-day cycles, up to ≥9 cycles
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17,624,6
37,0
41,2
45,5 17,4
23,515,2
7,4
11,8 6,1
1,9
0
20
40
60
80
100
No priorexposure (n=17)
Exposed but notrefractory (n=33)
Refractory (n=54)
Parital response Very good partial responseComplete response Stringent complete response
Lower response rates to once‐weekly carfilzomib in patients refractory to bortezomib
• As expected, median PFS in the BTZ‐naïve or ‐sensitive patients was longer relative to that in the BTZ‐refractory patients
Med
ian
PFS
(mon
ths)
Response by prior BTZ (N=104)
21,019,4
5,3
0,0
5,0
10,0
15,0
20,0
25,0
No priorexposure(n=17)
Exposedbut not
refractory(n=33)
Refractory(n=54)
Pat
ient
s (%
)PFS by prior BTZ (N=104)
ORR=94.1% ORR=91.4%
ORR=63.7%
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Higher incidences of adverse events in older patients
Pat
ient
s (%
)Most common grade ≥3 AEs (N=104)
• Rate of treatment‐emergent discontinuation was 3%, 17%, and 21% for the age groups <65, 65‐74, and >75 years respectively
• Higher incidences of grade ≥3 AEs in older patients compared to younger patients
3 2
7
0
10
14
3
10
7
3
0
3
0 0
3
0
5
10
15
20
<65 years (n=34) 65‐74 years (n=41) >75 years (n=29)
DyspnoeaHypertensionAcute kidney injuryCardiac failurePeripheral sensory neuropathy
ASH 2016
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Refraktäres MyelomPomalidomid‐Dreierkombinationen:• Pomalidomid‐Pembrolizumab‐Dexamethason• Pomalidomid‐Daratumumab‐Dexamethason• Pomalidomid‐Carfilzomib‐Dexamethason
• Pomalidomid bei Niereninsuffizienz
ASH 2016
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Abstract 492
Clinical Efficacy of Daratumumab, Pomalidomide, and Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients: Utility of Retreatment With
Daratumumab Among Refractory Patients
Ajay K. Nooka,1 Nisha Joseph,2 Larry H. Boise,3 Charise Gleason,3
Jonathan L. Kaufman,1 and Sagar Lonial1
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DARA + POM/DEX in RRMMResponse
Response Category, n (%)
Cohort 1DARA and POM
Naive(n = 19)
Cohort 2DARA or POM Refractory(n = 22)
Cohort 3DARA and POM
Refractory(n = 12)
ORRsCRCRVGPRPRMR/SDPD
17 (89)7 (37)1 (5)3 (16)8 (42)1 (5)1 (5)
9 (41)
1 (5)8 (36)9 (41)4 (18)
4 (33)
1 (8)3 (25)6 (50)2 (17)
Number of cycles, median (range) 15 (1‐23) 3 (1‐8) 3 (1‐8)
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DARA + POM/DEX in RRMMAuthors’ Conclusions
• DARA + POM/DEX was a well tolerable regimen yielding deep responses and long PFS even among pts refractory to PIs and IMiD agents
• Median PFS was comparable to results from the STRATUS trial investigating POM + LoDEX vs high‐dose DEX, despite these pts being POM and DARA refractory and being more heavily pretreated
• From our data, 80% of these heavily pretreated pts who were penta‐refractory were alive at the 8‐mo follow‐up
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Abstract 3311
Safety Results of a Phase 2, Multicenter, Open‐Label Study of Pomalidomide Plus Low‐Dose
Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma and Renal
Impairment
Katja Weisel,1 Meletios Dimopoulos,2 Niels van de Donk,3 Karthik Ramasamy,4Barbara Gamberi,5 Matthew Streetly,6 Massimo Offidani,7 Frank Bridoux,8
Javier de la Rubia,9 Elisabeth Kueenburg,10 Frederik Lersch,10 Barbara Rosettani,10Pamela Bacon,10 Pieter Sonneveld11
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MM‐013: Safety of POM + LoDEX in RRMMStudy Design
• Enrollment for this study has been completed• Data cut‐off date was November 15, 2016
POM: 4 mg D1-21LoDEX: 40 mg (≤ 75 yrs) or
20 mg (> 75 yrs) D1, 8, 15, 22
28-day cycles until PD, unacceptable AE, or
discontinuation
Pts with RRMM and RI
N = 81
Cohort B (n = 34)Severe RI eGFR ≤ 30
mL/min/1.73 m2
without dialysis
Cohort C (n = 14)Severe RI eGFR ≤ 30
mL/min/1.73 m2
requiring dialysis
Cohort A (n = 33) Moderate RI
eGFR > 30 to < 45 mL/min/1.73 m2
Follow-up for up to 5 years
for SPM, survival, and subsequent
Tx
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Multiples Myelom – RRMM
Refraktäres Myelom• Daratumumab subcutan
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Myelomzentrum Tübingen
Manola ZagoWolfgang Bethge
Hartmut GoldschmidtUta BertschDirk HoseKatharina LisenkoStefanie HuhnMichael Hundemer
Bärbel SchurichJohanna‐Marie LehmlerThomas KrämerBernhard RaboldSteffen LuntzJada Hajek
Axel BennerChristina KunzNatalia Becker
Britta BesemerBarbara HermesLoreen DegenNina StarzmannAndrea KortenkampAnnette HailfingerHelga KateMonika SchäferMonika Ums
Cecile GouttefangeasHans‐Georg Rammensee
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Rezidiv
„Mye
lom
last
“
Zeit
Symptomatisches MMMGUS
nicht
behandlungsbedürftig
Stadium I
behandlungsbedürftig
Erstbehandlung Refraktär
KEYNOTE-185-StudiePembroLenDex vs. Len/dex
CA-125:Pom-Elo-Dex vs. Pom-Dex
GMMG-HD6:VRD-Elo + HD-MEL, VRD-Elo Kons + R-EloMaint.
Medimmun-MM001:Durva-Pom
MOR202C101:MOR202 in rrMM
Medimmun-MM003Durva-Dara
GMMG-DANTEDaraVd in RI
MM-007Vel/Dex versus Pom/Vel/Dex
Anti-SLAMF7 Konj.
Medimmun MM-002-StudieDurvaLenDexNTNDMM + Erhaltung HRMM
GMMG-CONCEPT:KRd-Isa+ HD-MEL, KRd-Isa Kons + KR-Isa Maint.
GMMG-BIRMABRAF+MEK-Inh
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