Höhepunkte ASH 2016 Stuttgart - Universitätsklinikum … · 2017-01-13 · Höhepunkte ASH 2016 ‐Stuttgart ... • Todd Zimmerman, Noopur S. Raje, Ravi Vij, Donna Reece, Jesus

Highlights ASH 2014Highlights ASH 2015Highlights ASH 2016

Höhepunkte ASH 2016 ‐ Stuttgart

San Diego 2.12.16 ‐ 6.12.16

Multiples MyelomKatja Weisel

Highlights ASH 2014Highlights ASH 2015

Multiples Myelom – NDMM Primärtherapie

Primärtherapie Patienten > 65/70 Jahre• Langzeitdaten zur Rd‐Therapie

ASH 2016


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

ASH 2016


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

ASH 2016


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)

ASH 2016


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)

ASH 2016


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%

ASH 2016


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



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


#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

ASH 2016


#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



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


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


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


Carfilzomib i.v.20/36 mg/m2

Days 1, 2, 8, 9, 15, 16

Lenalidomideoral 15/25 mg‡Days 1–21


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)

ASH 2016


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

ASH 2016


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

ASH 2016


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


Multiples Myelom – RRMM

Rezidiviertes Myelom• Update der Daratumumab‐Kombinationen

ASH 2016

Highlights ASH 2014Highlights ASH 2015ASH 2016







Patients with < 12 mo remission after last line benefit the most

ASH 2016







Rezidiviertes Myelom• Carfilzomib 1 x wöchentlich

ASH 2016


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


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


Days 1, 8, 15, 22

Carfilzomib dose expansion:

70 mg/m2 i.v. (30 min) Once-weekly


Days 1, 8, 15, 22

Phase 1 Phase 2 (N=104)

28-day cycles, up to ≥9 cycles

ASH 2016


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%

ASH 2016


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


Refraktäres MyelomPomalidomid‐Dreierkombinationen:• Pomalidomid‐Pembrolizumab‐Dexamethason• Pomalidomid‐Daratumumab‐Dexamethason• Pomalidomid‐Carfilzomib‐Dexamethason

• Pomalidomid bei Niereninsuffizienz

ASH 2016


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

ASH 2016


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)

ASH 2016


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

ASH 2016


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

ASH 2016


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

ASH 2016



Refraktäres Myelom• Daratumumab subcutan

ASH 2016








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

ASH 2016


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

ASH 2016

Documents

Höhepunkte ASH 2016 Stuttgart - Universitätsklinikum … · 2017-01-13 · Höhepunkte ASH 2016 ‐Stuttgart ... • Todd Zimmerman, Noopur S. Raje, Ravi Vij, Donna Reece, Jesus