Prezentace aplikace PowerPoint€¦ · Současný stav poznatků o léčbě MM: co znamenají pro klinickou praxi? (Výstupy z klinických studií vs. klinická praxe) Roman Hajek

Současný stav poznatků o léčbě MM: co znamenají pro klinickou praxi? (Výstupy z klinických studií vs. klinická praxe)

Roman Hajek Department of Haematooncology, University Hospital Ostrava and Faculty of Medicine, University of Ostrava, Czech Republic

Mikulov 2014

© 2013 Millennium Pharmaceuticals, Inc.

Tato prezentace vznikla za finanční podpory společnosti Janssen-Cilag s.r.o.

Úvod

Department of Hematooncology, Ostrava University Hospital and Faculty of Medicine

Natural history of multiple myeloma

MGUS or smoldering myeloma

Asymptomatic Symptomatic

ACTIVE MYELOMA

M-p

rote

in (

g/L

)

20

50

100

1. RELAPSE

2. RELAPSE

REFRACTORY RELAPSE

First-line therapy

Plateau remission

Second-line Third-line

Clonal expansion

MGUS Late myeloma

Plasma cell leukemia

Early myeloma





ACTIVE MYELOMA

M-p

rote

in (

g/L

)

20

50

100

First-line therapy

Clonal expansion

MGUS Late myeloma


Early myeloma

DEATH IN COMPLETE REMISSION (>10 let)





ACTIVE MYELOMA

M-p

rote

in (

g/L

)

20

50

100

First-line therapy

Clonal expansion

MGUS Late myeloma


Early myeloma

DEATH IN COMPLETE REMISSION (>10 let)



MM: Oncology perspective

Symptomatic MM

Intervention

Clonal expansion

MGUS Late myeloma


Early myeloma

MILESTONES:

1. Molecular or Immunophenotypic

REMISSION

2. Sustained REMISSION

Cure Chronic disease

management

Agressive

clonal selection


Personalised medicine

&

„targeted“ treatment?


We need novel therapeutic strategies

Personalised medicine

&

„targeted“ treatment?


From diagnosis to treatment

ALL (TWO) novel drugs +

glucocorticoids and alkylating agents

upfront


NEW treatment paradigm for newly diagnosed patients

Novel agents

Induction Autograft

1 ± 2 Consolidation Maintenance

±

Multi Agent Sequential Therapy Targeting Different Clones


Recommendation in CMG guidelines for Czech Republic

Novel agents

Induction Autograft 1 ± 2

Consolidation Maintenance

±

Multi Agent Sequential Therapy Targeting Different Clones

VTD MEL 200 1 ± 2

V(T)D/CTD Len 10 mg


13

Klíčové účinné léky u MM

MM: Progress in Therapeutic Options

14

1950–1960s

MP

RTX

STEROID

1970–1980s

MP

RTX

STEROIDS

VAD

HDC

ASCT

1990s 2000s

MP

RTX

STEROIDS

BTZ = Bortezomib ASCT = Stem cell transplantation BISPH = Bisphosphonates HDC = High-dose chemotherapy PLD = Pegylated liposomal THAL = Thalidomide MP = Melphalan + Prednisone doxorubicin

ALLO

Mini-ALLO

BISPH

THAL

MP

RTX

STEROIDS

Mini-ALLO

BISPH

THAL

BTZ

Len

Palliation

Chronic illness Cure

Hsp90 KOS 953 Proteasome PR171, NPI0052 Aggresome Tubacin HDAC LBH, SAHA Akt elotuzumab XBP-1 XBP-1 peptide Muc-1 NM3 MEK AZD6244 NF-kB NPI1387 PKC Enzastaurin p38MAPK SCIO469 Telomerase GRN 163L Natural products EGCG ARRY 520 daratumumab

New Targets/Agents PLD

2013

• Develop effective combination with induction, and consolidation and maintenance strategy

• Genome-based selection • Prevent progression


VAD

HDC

ASCT

VAD

HDC

ASCT

15

MM:Progress in Therapeutic Options Key effective drugs

Alkylating agens

Glucocorticoids

IMIDs

Proteasome inhibitors


16


Alkylating agens

Glucocorticoids

IMIDs


melphalan cyclophosphamid

bendamustin

prednisolon dexamethason

thalidomide lenalidomide

pomalidomide i.v. : bortezomib, carfilzomib, MLN, marizomib s.c.: bortezomib p.o.: MLN (ixazomib), oprozomib, delanzomib


17

MM: Progress in Therapeutic Options Key effective drugs

Alkylating agens

Glucocorticoids

IMIDs



Přes obrovský vývoj nových molekul potenciálně účinných u MM patří a ještě delší dobu

budou patřit tyto 3 (USA) 4 (EU) klíčové skupiny

léků mezi „NEJ“ u MM

IMIDs and Proteasome inhibitors

• Multiple mechanisms of action

• Strong anti-myeloma effect

• Non targeted drugs

• No predictors of sensitivity/resistance

1. Kupperman E, et al. Cancer Res 2010; 70(5): 1970-80 2. Chauhan D, et al. Clin Cancer Res 2011;17(16):5311–21 3. Lee EC, et al. Clin Cancer Res 2011; 17(23): 7313-23 4. Chattopadhyay N et al. AACR 2011, Orlando, FL, USA (Abstract 2828)

18 Department of Hematooncology, Ostrava University Hospital and Faculty of Medicine

Možnosti stávající léčby

© 2013 Millennium Pharmaceuticals, Inc.

Department of Hematooncology, Ostrava University Hospital and Faculty of Medicine 19

20


Alkylating agens

Glucocorticoids

IMIDs


Department of Hematooncology, Ostrava University Hospital and Faculty of Medicine MODIFIED, Stewart AK, et al. Blood. 2009;114:5436-43.


Combinations in the upfront treatment of MM – near perspective

50-60% ORR

< 5% CR

? % i/mCR?


Combinations in the upfront treatment of MM – near perspective

50-60% ORR

< 5% CR

? % i/mCR?

100% ORR

70-80% CR

30-40% i/mCR?

MM

-

Kombinace IMIDs a PIs


23

Bortezomib Combinations as Induction Therapy for Elderly NDMM Patients (Phase 3 UPFRONT Trial): Final analysis

N = 502 Transplant-ineligible

NDMM patients

VD (n = 168)* BORT: 1.3 mg/m2, D 1, 4, 8, 11 DEX: 20 mg, D 1, 2, 4, 5, 9, 11, 12; Cycles 1–4; D 1-2, 4-5; Cycles 5–8 8 cycles

VTD (n = 167)* BORT as per VD THAL 100 mg, D 1–21 DEX as per VD 8 cycles

VMP (n = 167) BORT as per VD MEL: 9 mg/m2, D 1–4 every other cycle PRED: 60 mg/m2, D 1–4 every other cycle 8 cycles

Maintenance* BORT: 1.6 mg/m2, D1, 8, 15, 22 5 cycles

VD, bortezomib, dexamethasone; VMP, bortezomib, melphalan, prednisone; VTD, bortezomib, thalidomide, dexamethasone

Niesvizky R, et al. Blood. 2013;122:abstract 1966. Updated data presented at ASH 2013.

• Primary end-point: PFS, secondary end-points: ORR, OS, TTNT

*Jediným aktuálně schváleným režimem s bor v primoléčbě u netransplantabilních pacientů je režim VMP (dle SPC Velcade v01/2014).

Phase 3 UPFRONT Trial – VD vs VTD vs VMP: Response Rates

Niesvizky R, et al. Blood. 2013;122:abstract 1966. Updated data presented at ASH 2013.

I, induction; M, maintenance; VD, bortezomib, dexamethasone; VMP, bortezomib, melphalan, prednisone; VTD, bortezomib, thalidomide, dexamethasone

• ≥ VGPR rates were higher in VTD compared to VD (p = 0.0153)

Resp

on

se R

ate

, %

71% 73%

79% 80%

68% 70%

VD VTD VMP

Nestačí zvláště u fragilních

a starších nemocných

jen IMID nebo PI

s dexametazonem?


26

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

• Thierry Facon, Meletios A. Dimopoulos, Angela Dispenzieri, John V. Catalano, Andrew R. Belch, Cyrille Hulin, Michele Cavo, Antonello Pinto, Katja Weisel, Heinz Ludwig, Nizar J. Bahlis, Anne Banos, Mourad Tiab, Michel Delforge, James D. Cavenagh, Catarina Geraldes, Je-Jung Lee, Christine I. Chen, Albert Oriol, Javier De La Rubia, Lugui Qiu, Darrell J. White, Daniel Binder, Kenneth C. Anderson, Philippe Moreau, Michel Attal, Robert Knight, Guang Chen, Jason Van Oostendorp, Christian J. Jacques, Annette Ervin-Haynes, Lotfi Benboubker

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.

Abstract 2


RA

ND

OM

IZA

TIO

N 1

:1:1

Arm B Rd18

Arm C MPT

LEN + Lo-DEX: 18 Cycles (72 wks) LENALIDOMIDE 25mg D1-21/28 Lo-DEX 40mg D1,8,15 & 22/28

MEL + PRED + THAL 12 Cycles1 (72 wks) MELPHALAN 0.25mg/kg D1-4/42 PREDNISONE 2mg/kg D1-4/42 THALIDOMIDE 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 Phase Screening

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

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 Continuously LENALIDOMIDE 25mg D1-21/28 Lo-DEX 40mg D1,8,15 & 22/28

Arm A Continuous 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

Rd 535 400 319 265 218 168 105 55 19 2 0

Rd18 541 391 319 265 167 108 56 30 7 2 0

MPT 547 380 304 244 170 116 58 28 6 1 0

Hazard ratio Rd vs. MPT: 0.72; P = 0.00006 Rd vs. Rd18: 0.70; P = 0.00001 Rd18 vs. MPT: 1.03; P = 0.70349

Time (months)

Pa

tie

nts

(%

) 100

80

60

40

20

0

0 6 12 18 24 30 36 42 48 54 60

42% (Rd)

23% (Rd18) 23% (MPT)

FIRST Trial: Final Progression-free 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.


Nové přístupy


30

Sequential vs Alternating VMP and Rd in NDMM

Mateos MV, et al. Blood. 2013;122:abstract 403. Updated data presented at ASH.

a During the first cycle (6 weeks), bortezomib is given on D1, 4, 8, 11, 22, 25, 29, and 32.

Rd: Len: 25 mg/day, D1–21 Dex: 40 mg, D1, 8, 15, 22 Nine 4-week cycles

MPVRdMPV… for 18 cycles

MPV: Mel: 9 mg/m2, D1–4 Pred: 60 mg/m2, D–4 Bort: 1.3 mg/m2, D1, 8, 15, 22a One 6-week cyclea followed by eight 4-week cycles

Alternating therapy

N = 231 transplant- ineligible NDMM aged > 65 years

RdMPVRd… for 18 cycles

• Randomized phase 2 study to compare the efficacy and safety of two treatment schemes (MPV followed by Rd or MPV alternating with Rd)

• Primary end-points: TTP, safety; secondary end-points: RR, DOR, OS • Subanalysis in patients with high-risk cytogenetics


Sequential vs Alternating VMP and Rd: Response

• Median number of 13 cycles (1-18)

Subanalysis:

• CR rates were similar across different subgroups for both arms, including

– pts aged < vs ≥ 75 yrs

– ISS stage I/II vs III

– cytogenetic abnormalities

Mateos MV, et al. Blood. 2013;122:abstract 403. Updated data presented at ASH.

ORR 89% ORR 94%


Korde N, et al. Blood 2013;122: abstract 653. Updated data presented at ASH 2013.

CRd (Carfilzomib, Lenalidomide, Low-Dose Dex) Followed by Lenalidomide Extended Dosing (CRd-R)

CRd, carfilzomib, Lenalidomide, low-dose dexamethasone

N = 45 NDMM patients

(transplant & non-transplant)

CRd:

CFZ: 20/36 mg/m2, D1, 2, 8, 9, 15, 16 LEN: 25 mg, D1–21 DEX: 20/10 mg, D1, 2, 8, 9, 15, 16, 22, 23

Eight 28-day cycles

LEN: 10 mg, D1–21

2 years

Inductiona Maintenance

SD or better

a Patients < 75 years underwent stem cell collection after cycle 4, then continued therapy.

• 45 patients enrolled (median age 60 years, range 40–88)

• Median of 12 cycles of CRd-R received

• Primary objective was to determine the incidence of ≥ grade 3 neuropathy, secondary objectives included correlatives (GEP, biomarkers, proteasomes, flow cytometry, PCR, etc.) and ORR, PFS, OS, DoR


Efficacy

•ORR was 98%, with 88% ≥VGPR (n = 43)

•Median time to reach CR/sCR

was 5 months

•Response rates based on FISH/cytogenetics

or age (65 years cut-off) were non-differential

•PFS at 18 months was 91%; of 27 nCR/CR patients assessed

•by flow cytometry, all are MRD negative

CRd Followed by Lenalidomide Extended Dosing (CRd-R): Efficacy and Safety

ORR 98%

Korde N, et al. Blood 2013;122: abstract 653. Updated data presented at ASH 2013. CRd, carfilzomib, lenalidomide, low-dose dexamethasone; LFT, liver

function test


Závěr


35

36


Alkylating agens

Glucocorticoids

IMIDs


melphalan cyclophosphamid

bendamustin

prednisolon dexamethason

thalidomide lenalidomide

pomalidomide i.v. : bortezomib, carfilzomib, MLN, marizomib s.c.: bortezomib p.o.: MLN (ixazomib), oprozomib, delanzomib


37

MM: Future in Therapeutic Option IMIDs and PI combo regimens

100% - ORR; 1/3 of mCR/iCR

Alkylating agens

Glucocorticoids

IMIDs



38

MM: Futurein Therapeutic Option IMIDs and PI combo regimens for

several treatment lines

Glucocorticoids thalidomid bortezomib


VTD

39

MM: Future in Therapeutic Option IMIDs and PI combo regimens for



Glucocorticoids lenalidomide carfilzomib


VTD

CRD

40





Glucocorticoids pomalidomide ixazomib


VTD

CRD

IPD

41






pomalidomide oprozomib Glucocorticoids


VTD

CRD

IPD

OPD

42




pomalidomide oprozomib Glucocorticoids


VTD

CRD

IPD

OPD

Combinations of IMIDs and PIs with Glucocorticoids are the most

effective regimens There is not cross resistance thus rotation of different members from IMIDs and PIs is

possible in RRMM

Moreover some of regimens are

fully „per os“ regimen

43


Alkylating agens

Glucocorticoids

IMIDs



Despite many novel agens evaluation in the clinical

trials phase I/II

IMIDs and PIs

remain key players & backbone of myeloma

treatment on NDMM, as well as RRMM for this decade

Babak Myeloma Group Dept. of Pathological Physiology, Faculty of Medicine, MU

Grešliková Henrieta

Kryukov Fedor

Kubiczková Lenka

Kupská Renata

Mikulášová Aneta

Muthu Raja K.R.

Mužíková Jana

Němec Pavel

Perutka Tomáš

Piskacek Martin

Potáčová Anna

Sáblíková Barbora

Smejkalová Jana

Smetana Jan

Ševčíková Sabina

Šváchová Hana

Department of Clinical Hematology

University Hospital Brno

Penka Miroslav

Almáši Martina

Hanáková Božena

Kyjovská Drahomíra

Říhová Lucie

Suská Renata

Štouračová Marcela

Varmužová Tamara

Zarbochová Pavla

Department of Haematooncology

University Hospital Ostrava

Laura Adámková, Cecília Bodzásová,

Juraj Ďuráš, Jaromír Gumulec,

Zdeněk Kořístek, Tomáš Jelínek,

Michal Kaščák, Milan Matuška,

Milan Navrátil, Hana Plonková,

Zahradová Lenka, Jana Zuchnická,

Lenka Martinková , Eva Jarošová,

Eva Jakšíková, Petra Vrublová Laboratory of molecular

cytogenetic, Department of

Experimental Biology, Faculty of Science, MU

Kuglík Petr

Institute of Biostatistics and Analyses

Faculty of Medicine, MU

Jarkovský Jiři Budinská Eva

Ihnatová Ivana

Acknowledgement


Thank you for your attention.


45

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EC

H

GR

OU

P

M Y E L O M AM Y E L O M A

Documents

Prezentace aplikace PowerPoint€¦ · Současný stav poznatků o léčbě MM: co znamenají pro klinickou praxi? (Výstupy z klinických studií vs. klinická praxe) Roman Hajek