MULTİPL MİYELOMDA HEDEFE YÖNELİK TEDAVİLER ve

GÜNCEL TEDAVİDEKİ YERLERİ

Dr. Mert BAŞARANİ.Ü. ONKOLOJİ ENSTİTÜSÜ

Nüks hastalık• Tedaviye geçici yanıt• Sağkalım 1–2 yıl

Tanı• Sağ kalım 3–4 yıl

Nüks veya dirençli hastalık• Direnç gelişmesi• Ölümcül• Sağ kalım 6–9 ay

Yeni tedavi arayışları

Multipl Miyelom

MM kür imkanı yokKansere bağlı ölümlerin %2’si

A: normal böbrek fonksiyonları (serum kreatinin < 2 mg/dl)B: bozulmuş böbrek fonksiyonları

Serum β2 mikroglobulin ≥ 5.5 mg/LHerhangi biri olması halindeHb < 8.5 gr/dlCa++ >12 mg/dl> 3sayıda litik kemik lezyonuYüksek M proteiniÉIg G > 7 gr/dlÉIg A > 5 gr/dlÉBence Jones > 12 gr/gün

IIIEvre I ve II dışı kalan durumlarEvre I ve III dışı kalan durumlarII

Serum β2 mikroglobulin < 3.5 mg/LSerum albumin ≥ 3.5 gr/dl

Sayılan tüm kriterlerHb > 10 gr/dlCa++ ≤12 mg/dlKemik tarama normal veya tek lezyonDüşük M proteiniÉIg G < 5 gr/dlÉIg A < 3 gr/dlÉBence Jones < 4 gr/gün

I

ISS kriterleriGreipp P, San Miquel J, Durie B et al. JCO 23, 3412-20, 2005

Durie-SalmonDurie BGM, Salmon SE. Cancer 36, 842-854,1975

Evre

Multipl Miyelomda Kötü Prognostik Faktörler

Yaş >65 yaş:(tanı esnasında medyan yaş ~ 63)Öncesinde tedavi olmasıİlk tedaviye dirençli olmasıArtmış serum β2M düzeyiAzalmış serum albumin düzeyiSitogenetik anomalilerBöbrek fonksiyon bozukluğu

– MM tanılı hastaların % 50’ye yakınında vardır– Hastaların % 20–30’unda eşlik eden böbrek yetmezliği olur

Perez-Simon et al. Blood 1998;91:3366–71Kyle. Stem Cells 1995;13(Suppl 2):56–63

Bladé et al. Arch Intern Med 1998;158:1889–93Knudsen et al. Eur J Hematol 1994;53:207–12

Kyle et al. Mayo Clin Proc 2003;78:21–33Kumar et al. Mayo Clin Proc 2004;79:867–74Greipp et al. Blood 1993;81:3382–7Facon et al. Blood 2001;97:1566–71

Copyright © American Society of Clinical Oncology

Hideshima, T. et al. J Clin Oncol; 23:6345-6350 2005

Kemik iliği stromal hücreleri ve miyelom hücreleri arasında sinyal ileti kaskadı

MM’da tedavi seyri

MelMelfelanfelan19801980

MMiiyeloablayeloablasyonsyon+ ASCT+ ASCT

1998 1998 BortezomibBortezomib

19991999TalidomidTalidomid

19621962PredniPrednizzon + on +

MelMelfelanfelan

19901990Destek tedavisiDestek tedavisi

2004Bortezomib

2002 2002 LenalidomidLenalidomid

20002000Tandem Tandem

ASCTASCT

Başlangıç tedavisi: Eski Yaklaşım

İndüksiyon tedavisine yanıt– Transplant öncesi değerlendirilmiyor– TC, KC, veya stabil yanıt kabul edilebilir

İndüksiyonKemoterapi

Transplant KonvansiyonelAlkilleyici ajanlar

Kyle RA, et al. N Engl J Med. 2004;351:1860-1873.

Başlangıç tedavisi: Yeni Yaklaşım

Amaç: TC ve KC– Konvansiyonel tedaviye yanıtı artırmak– Tranplant öncesi minimal hastalık düzeyi sağlamak– Transplantı geciktirebilmek

İndüksiyonYeni Ajanlar

Transplant Konvansiyonel

Copyright ©2004 American Society of Hematology. Copyright restrictions may apply.

Munshi, N. C. et al. Blood 2004;103:1799-1806

MM patogenezinde muhtemel hedefler

Copyright ©2002 American Society of Hematology. Copyright restrictions may apply.

Zhan, F. et al. Blood 2002;99:1745-1757

M.M.’da down-regulasyonolan en önemli60 gen

Blood 99: 1745-1757, 2002

M.M.’da up-regulasyon olanen önemli 70 gen

Blood 99: 1745-1757, 2002

Yeni tanılı M.M.’daekspresyon artışı yapan genler

Blood 99: 1745-1757, 2002

Klinik Uygulamaya Çıkan Yeni Ajanlar

İmmunomodülatörler– Talidomid– Lenalidomid

Proteazom inhibitörü– Bortezomib

İmmunomodulasyon yapan ilaçlar

O

O O

O

HN

N

Talidomid

Lenalidomid

O

2

O OHN

N

NH

İMİD’ler miyelom hücre ve yakın çevre iletilerini etkiler

ECOG E1A00: Faz III, randomizeAmaç: yanıt oranı ve toksisite

Yeni tanı tedavisizsemptomatik MM

(N = 207)

Thal/Dex Talidomid 200 mg/day PO +Deksametazon 40 mg/gün

Günler 1-4, 9-12, 17-20

(n = 103)

Sadece DexDeksametazon 40 mg/gun

Günler 1-4, 9-12, 17-20

(n = 104)

4 ay süre ile her ay tekrarlanmasi

Stem cell transplant veya hekim kararına

göre tedavinin devamı

Stop tedavi

Prof’laktik antikoagulan kullanilmadi

CR/PR/SD

progresyon

Rajkumar V, et al. ASH 2004. Abstract 205.

İlk Tanıda Deksametazon veTalidomid + Deksametazon Karşılaştırması

CR

n = 104 n = 103

0102030405060708090

100

Deks Tal/Deks

PR

DVT grad ≥ 3– Deks 3% vs tal/deks 17%

Nöropati grad ≥ 3– Deks 4% vs tal/deks 7%

Ölüm– Deks 11% vs tal/deks 7%

Tüm grad ≥ 4 toksisite– Deks 18% vs tal/deks 34%

Rajkumar SV, et al. J Clin Oncol. 2006;24:431-436.

İlk Tanıda Deksametazon veTalidomid + Deksametazon Karşılaştırması

Rajkumar, S. V. et al. J Clin Oncol; 24:431-436 2006

4 siklus tedavi sonrası tedavi seçimi hekime bırakıldı

Genel Sağkalım

Nüks veya Refrakter Hastalıkta Talidomid Kombinasyonları

Kyriakou et al. Br J Haematol2005;129:763–70

17%79%52II+ siklofosfamid + deks

Offidani et al. Haematologica2006;91:133–6

32%76%50II+ pegile liposomal

doksorubisin

Palumbo et al. Haematologica2001;86:399–403

18%41%77

Dimopoulos et al. Ann Oncol 2001;12:991–5

–55%44II+ deksametazon

Yakoub-Agha et al. Hematol J 2002;3:185–9213%47%83

Barlogie et al. Blood 2001;98:492–414%30%169

IITek ajan talidomid

CR + nCRCR + PRnFaz

MP Standard MP, 12 siklus q 6-hafta

(n = 191)

MP-TMP + Tal MTD

≤ 400 mg/gün, MP bitimi ile sonlandırıldı(n = 124)

MEL100VAD x 2; Siklofosfamid 3 g/m2 +

G-CSF + PBSC harvest; (Melfalan100 mg/m2 + PBSC + G-CSF) x 2

(n = 121)

YeniYeni tantanıı MM MM yasyas 6565--7575(N = 436)(N = 436)

Primer Primer amaamaçç: : genelgenelsasağğkalkalıımm

Facon T, et al. ASH 2005. Abstract 780.

IFM 99-06: Yeni tanılı yaşlı hastalardaMP vs MP-T vs Mel100

0 12 24 36 48 60 720.0

0.2

0.4

0.6

0.8

1.0

12 24 36 48 60 720.0

0.2

0.4

0.6

0.8

1.0

0

Frac

tion

Frac

tion

ITT ay ITT ay

MP-TMPMEL100

PFS OS

Facon T, et al. ASH 2005. Abstract 780.

.0008.014

POS, ayPPFS, ay

38.6 ± 3.0

> 5630.3 ± 5.8

19.0 ± 1.3MEL100

29.5 ± 3.6MP-T

Tedavi

< .0001.0001

17.2 ± 1.5MP

IFM 99-06: Yeni tanılı yaşlı hastalarda MP vsMP-T vs Mel100

MPT vs MP

Yeni tanılı MM >65 yas¥

(n=255)Melfalan 4 mg/m2 D 1–7 +

Prednizon 40 mg/m2 D 1–7 q 4 hafta x 6

+ talidomid 100 mg/gun* süreklin=129

*Talidomid nüks veya progresyona kadar verildi§ Talidomide crossover nüks veya progression sonrası izin verildi

Melfalan 4 mg/m2 D 1–7 +Prednizon 40 mg/m2 D 1–7§

q 4 hafta x 6n=126

Palumbo et al. Lancet 2006;367:825–31

¥<65 yaş MPT 3%, MP 2%>80 yaş MPT 5%, MP 6%

MPT MP’ye göre daha etkilidir

Facon et al.Medyan takip: 32 ay

17215CR (%)

191729.5PFS (ay)

>56

81

MPTn=191

38.630.3OS (ay)

7240CR + PR (%)

ASCTn=121

MPn=124

Palumbo et al. Minimum takip: 6 ay

Facon et al. Blood 2005;106 (Abstract 780); Presented at ASH 2005Palumbo et al. Lancet 2006;367:825–31

4876CR + PR (%)

216CR

64803-yıl sağkalım (%)

27542-yıl EFS (%)

MPn=126

MPTn=129

MPT vs MP: toksisite

422İnfeksiyona bağlıÖlüm

6.5512DVT

No dataNo data30%Nöropati

1003241Nötropeni

391117Ağır infeksiyon

ASCT

n=121

MP

n=124

MPT

n=191

% insidens

Facon et al.Grada gore toksisite verlmedi

2548Tüm grad 3/4

08PE

Bilgi yok33Tedavi kesilmesi

Bilgi yok29Doz azaltılması 50%

212Tromboemboli

2522Hematolojik toksisite

210Infeksiyon

MP

n=126

MPT

n=129

% insidens

Palumbo et al.Grade 3–4

Facon et al. Blood 2005;106 (Abstract 780); Presented at ASH 2005Palumbo et al. Lancet 2006;367:825–31

VAD (vincristine, doxorubicin, and dexamethasone)

3-4 siklus; ve peşisıra

Melfalan140 mg/m2 + ASCT; peşisıra

Melfalan 200 mg/m2 + ASCT

Aidame yok(n = 200)

BPamidronat

90 mg/ay(n = 196)

CPamidronat 90 mg/ay

Talidomid100 mg/gun

(n = 201)

evre I, II veya III MM

< 65 yaşYeni tanılı

0-1 risk faktörü

(N = 780)

3. ay Progresyon olmazsa

randomizasyon(n = 593 / 6/05)

Attal M, et al. ASH 2005. Abstract 1148.

ASCT sonrası Talidomid İdame Tedavisi(IFM 99-02)

IFM 99-02: sonuçlar

*P=0.01 B vs C

Attal M, et al. ASH 2005. Abstract 1148.

NS182024Kemik hadiseleri %.0487*74*784-yıl OS, %

.0035035374-yıl EFS, %> 483838Medyan EFS, ay

.03

165068

154557

154555

0.04

P

36

CTal/Pam

BPam

A idamesiz

4748Hadise %

iyiPR veya CR, %VAD sonrasıRandomizasyondaRand sonrası

*P = .01 for Arm B vs Arm C

Total Tedavisi II ± Talidomid

668 hasta ≤ 75 yaş

Çok merkezli, randomize Faz III

Total Tedavisi II:

– İntensif indüksiyon + tandem ASCT + konsolidasyon + idame

– Randomizasyon talidomid olması veya olmaması

– Talidomid nüks veya komplikasyona kadar verildi

Medyan takip 42 ay

Barlogie et al. N Engl J Med 2006;354:1021–1030

Barlogie B et al. N Engl J Med 2006;354:1021-1030

Consolidated Standards of Reporting Trials Chart of the Trial

Barlogie B et al. N Engl J Med 2006;354:1021-1030

Treatment Protocol after Randomization

Barlogie B et al. N Engl J Med 2006;354:1021-1030

Percentages of Patients Who Entered Each Phase of Treatment (Panel A); Overall and Event-free Survival, Treatment-Related Mortality, and Percentage of Patients in the Thalidomide Group Who

Discontinued Thalidomide (Panel B); Survival after Relapse or Progression (Panel C); and Survival According to Age (Panel D)

Barlogie B et al. N Engl J Med 2006;354:1021-1030

Multivariate Analysis of Features Associated with the Clinical Outcome

Total Tedavisi II ± Talidomid

0.0012.71.1Nüks sonrası medyan sağkalım (yıl)

<0.0011730DVT ≥ grad 2 (%)17

654443

Kontrol grup

<0.00127PE ≥ grad 2 (%)

0.9655-yıl OS (%)0.01565-yıl EFS (%)

<0.00162CR (%)

P+ Talidomid

Barlogie et al. N Engl J Med 2006;354:1021–1030

Talidomid eklenmesi genel sağkalımı artırmadı

Talidomid eklenmesi yan etkileri artırdı

Talidomid sonrasi nüksler tedaviye daha dirençli görülüyor

Talidomidin Tedavideki Etkinliği

-√√≤ 75 yaş AST v AST + T

√√√Yaşlılarda AST versus Tal

??Genç hastalardaAST versus Tal

+ / -√√AST sonrasıidame

√√Kombinasyon

Yaşlı +Tüm hastalar -

√√İlk tanı

√Nüks Hastalık

OSEFSYanıt

Lenalidomid

Talidomid ile randomize direk karşılaştırması yok

Ancak yapılan çalışmalarda periferik nöropati belirginolarak daha az gözleniyor

DVT ve PE sıklığı daha az görülüyor

Etkinliği denk kabul edilmektedir

Nüks veya Dirençli MM Hastalarında Lenalidomid + Deks vs Deks (MM-010)

Lenalidomid 25 mg, d 1–21

Plasebo, d 22–28

Deks 40 mg, d 1–4, 9–12, 17–20

PlaPlasseboebo, d 1, d 1––2828

DeDeksks 40 mg, d 140 mg, d 1––4, 94, 9––12, 1712, 17––2020

× 4 siklus

TTP

RR

OS

Güvenlik

deks, D 1–4 Aynı sadece

PD olana kadarverilmesi

MM-010: (PI: M. Dimopoulos): 351 hasta, 51 merkez – Avrupa, Avustralya, İsrail

MM-009 (PI: D. Weber): 354 hasta, 48 merkez – ABD & Kanada

Sonlanım

Dimopoulos et al. Blood 2005;106 Abst 6ASH 2005

Nüks veya Dirençli MM Hastalarında Lenalidomid + Deks vs Deks (MM-010)Etkinlik “yanıt oranları”

3.4% CR15% CR*

42% PR*

20% PR

*P<0.001; Len/Deks vs Plasebo/Dex (PR ve CR)

2% nCR0.6% nCR

0

20

40

60

80

Len/Deks Plasebo/Deks

Yanı

t ora

nı(%

)

Dimopoulos et al. Blood 2005;106 Abst 6, ASH 2005

0

25

50

75

100%

pro

gres

yons

uz

Lenalidomid/deks Plasebo/deks

TTP (hafta)

P<0.001

9010 20 30 40 50 60 70 80

Medyan TTP (ay):

Len/deks Plasebo/deks

11.3 4.7

Nüks veya Dirençli MM Hastalarında Lenalidomid + Deks vs Deks (MM-010)Etkinlik “sağkalım”

Dimopoulos et al. Blood 2005;106 Abst 6, ASH 2005ASH 2006

Medyan OS nr vs 20.6 ay, p<0.001

Nüks veya Dirençli MM Hastalarında Lenalidomid + Deks vs Deks”Yan Etkiler”

Deksn=171

Lenalidomid + deksn=170

Deksn=175

Lenalidomid + deksn=176

2.9-

1010.610.63.5

24.1

?156402

-4PE2.95DVT

?

1061

27

MM-010 MM-009Grad 3/4 (%)

5.9Trombositopeni1.8Anemi

0.6Periferik nöropati

0Febril nötropeni3.5Nötropeni

Dimopoulos et al. Blood 2005;106 Abst 6 ASH 2005Weber et al. Haematologica 2005;90(Suppl 1):155 Abst738);

Poster at IMW, Sydney 2005

Nüks veya Refrakter MM’da Lenalidomid

Baz et al. Blood 2005;106 (Abstract 2559)

29%77%62II+ doxil+ vinkristin+ deks

Weber et al. IMW Sydney 200519.5%51.3%170

Dimopoulos et al. Blood2005;106 (Abstract 6)

17%59%176III

+ deks(MM-010)

(MM-009)

Richardson et al. Blood 2003;235a (Abstract 825)

6%24%101

Richardson et al. Blood 2005;106 (Abstract 1565)

27%222

IITek ajanlenalidomid

CR + nCRCR + PRnFaz

DVT ve PETalidomid

yüksek tromboemboli insidansı– 30% 1– 30% (talidomid indüksiyon,

konsolidasyon ve idame2

ağır trombotik hadiseler3

– DVT 20%– PE 7%

Profilaksi gerekiyor– DVT: 3% Enoxaparin ile vs 18.4%

profiksisiz4

– DVT (24%) heparin ile2

Lenalidomidyüksek tromboemboli insidansı

– Küçük çalışmalarda 75%’e çıkan oranlar5

– DVT 5–14 % 6,7

– PE 2–9 % 6,7

Faz III: Lenalidomid + deks 8,9

Aspirin profilaksisi 5

3.54.7MM-010 2.411.2MM-009 (US)

PE (%)DVT (%)

1. Evens et al. Blood 2005;106 (Abstract 2244)2. Barlogie et al. N Engl J Med 2006;354:1021-10303. Jacoub et al. Blood 2005;106 (Abstract 3501)4. Palumbo et al. Blood 2005;106 (Abstract 779)5. Zonder et al. Blood 2005;106 (Abstract 3455)

6. Niesvizky et al. Blood 2005;106 (Abstract 642)7. Baz et al. Blood 2005;106 (Abstract 2559)

8. Dimopoulos et al. Blood 2005;106 (Abstract 6)9. Weber et al. Poster at IMW, Sydney 2005

Lenalidomid Tedavideki Etkinliği

AST ± L

AST sonrasıidame

++Kombinasyon

+İlk Tan

+++Nüks Hastalk

OSEFSYanıt

Bortezomib

Proteazom

– Multikatalitik enzim kompleksi– Nukleus ve sitoplazmada eksprese edilir

– Hasar görmüş veya hatalı yapılmış proteinleriparçalar

– Hücre siklusu ve hücre yaşamında esansiyel– Substratlar: sinyal ileti molekülleri, tümör supresor,

hücre siklusu düzenleyici, transkripsiyon faktörleri, anti-apoptotik proteinler…

Rivett Arch Biochem Bioph 1989; Tanaka FEBS Lett 1988 ; Matthews PNAS 1989; Arrigo Nature 1989; Kisseley Chem Biol 2001

Proteazom inhibisyonunun hücre siklusu düzenleyici proteinler üzerine etkinliği gösterildi

- siklinler (B1)- siklin-bağımlı kinaz inhibitörleri (CDKIs) : p21, p27- tümör supresör proteinler: p53- transkripsiyon faktörü: NF-ΚB

Hideshima Cancer Res 2001; Adams Cancer Res 1999

Ubiquitin-proteasome pathwayWilkinson J Nutr 1999

19S

20S αβ

26S Proteazom- 19S ubiquitine olan proteinleri tanır

- 20S katalitik bölümü içerir

- Hücre içi protein döngüsünün % 80’ini

sağlar

Proteazom yapısı

Proteazomların fizyolojik substratları

NF-ĸB aktivasyonu

(MM hücrelerinde aktivite artar)IL-6TNFαsağkalım faktörleri IAPa, BCL 11ICAMVCAME-selektin

bortezomib(Microenvironment)

(Microenvironment)

X

XX

Bortezomib: Etkinlik ve Farmakokinetik

- 26S proteazom kompleksini geri dönüşümlü inhibe eder

- Proteolizisi önler

- Hücre içi sinyal ileti kaskadlarını etkiler

- Hücre ölümüne yol açar

APEX: Nüks Hastalarda Bortezomib vs DeksametazonRandomize, Faz III nüks hastalık

– 669 hasta (93 merkez)

Richardson et al. N Eng J Med 2005;352:2487–98

Tedavi planı

273 tredavi günü 280 tedavi günü

1.3 mg/m2 IV D 1, 4, 8, 11 q3w

8 siklus

1.3 mg/m2 IVD 1, 8, 15, 22 q5w

4 siklus

3 siklus 5 siklus

40 mg PO D 1–4, 9–12, 17–20 q5w

40 mg PO D 1–4 q4w

Randomizasyon

Bortezomib Deksametazoninduksiyon

İdame

APEX: Bortezomib vs Deksametazon

APEX primer analiz (NEJM 2005)– Bortezomib etkinliği daha fazla

APEX (güncel sonuçlar ASH)– Medyan 22 ay sonrası anlamlı farklar devam ediyor

662183.5

Deks

0.003801-year survival (%)<0.00113CR + nCR (%)<0.000138ORR (%)<0.00016.2TTP (months)

PBortezomib

1Richardson et al. N Engl J Med 2005;352:2487–982Richardson et al. Blood 2005;106 Abst 2547 ASH 2005

APEX “Yanıt oranları”ORR 38% vs 43%CR: M-proteinin tamamen kaybolması

<1% nCR 25% PR

16% PR7% nCR6% CR

Bortezomib Deks

Yanı

t%

38%

18%

P<0.0001

0

10

20

30

40

50

60

9% CR7% nCR

27% PR

43%

Bortezomib

Primer analizGüncellenen sonuç

<1% CR

Richardson et al. Blood 2005; 106 (Abstract 2547); Poster at ASH 2005

Uzayan Bortezomib Tedavisi ile Yanıt Oranları

504462420378336294252210168126844200.00.10.20.30.40.50.60.70.8

0.91.0

Has

ta y

üzde

si

Günler

12 hafta, 4 siklus

18 hafta, 6 siklus

24 hafta, 8 siklus

Yanıt veren hastalarda serum M-protein azalması

Richardson et al. Blood 2005; 106 (Abstract 2547); Poster at ASH 2005

APEXmedyan OS: Bortezomib vs Deks 29.8 vs 23.7 ay (P=0.0272)1-yıl OS: 80% vs 66% (P=0.0002)

Richardson et al. Blood 2005; 106 (Abstract 2547); Poster at ASH 2005

Bortezomib

Deksamethason

Has

ta y

üzde

si

Zaman gün

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1080990900810720630540450360270180900 1170

Genel Sağkalım

APEX: İlk Nükste Tedavi Edilen Hastalarda Daha Uzun TTP

Sonneveld et al. Haematologica 2005;90(Suppl 1):146 Abst 721

N = 60 ToksisiteGrad 4 – Sıvı yüklenmesi– Meningitis

Grad 3– Periferik nöropati

Yanı

t ora

nlar

ı(%

)

Richardson, et al. ASH 2005. Abstract 2548

Bortezomib ilk seçim, tek ajan

0102030405060708090

100

6 siklus

PRiyiPRCR

(siklus 2) (siklus 6)

N = 48

Yanı

t ora

nı(%

)

0102030405060708090

100

Bortezomib Bortezomib± Deks

PRnCRCR

İlk 2 siklusta sadece bortezomib;toplam 6 siklusta bortezomib ± deks

ORR: 90% (20% CR/nCR)

Periferik kök hücre toplama G-CSF in 23 hasta

– Medyan CD34+: 12.6 x 106/kg

Grad 3 nöropati: 12%

Erken ilaç kesilmesi: 26%

Jagannath S, et al. ASH 2005. Abstract 783.

Yeni Tanılı MM Hastalarında Bortezomib+ Deksametazon

Bortezomib, Doksorubisin ve Deks (PAD) İlk seçim

PAD: q3w x 4 siklus– Bortezomib 1.3 mg/m2 D 1, 4, 8, 11– Deks 40 mg D 1-4, 8-11, 15-18 (siklus 1); D 1-4

(siklus 2-4)– Doksorubisin 0, 4.5, or 9.0 mg/m2 D 1-4

HD melfalan (MEL200) ve PBSC tx

Oakervee HE, et al. Br J Haematol. 2005;129:755-762.

Bortezomib, Doksorubisin ve Deks (PAD) İlk seçim

Medyan gün– ANC > 500: 13– Plt > 20,000: 15

Grad 3 nöropati: 5%SAE: 57%; tedavi kesilmesi: 14%Yanıt, PAD ile: 95%– PAD + PBSCT: 95%

PBSC mobilizasyon 20/21– MEL200/PBSCT 18/20

N = 21

Yanı

t ora

nlar

ı(%

)

n = 21 n = 18

0102030405060708090

100

4 siklussonrası

Mel 200sonrası

PRnCRCR

Oakervee HE, et al. Br J Haematol. 2005;129:755-762.

Transplant olabilecek tedavisiz hastalarBTD q4w x 2 ve SCT– Bortezomib 1.3 to 1.7 mg/m2 D 1, 4,

8, 11– Talidomid 100-200 mg/d– Deksametazon 20 mg/m2 D 1-4,

9-12, 17-20ORR: 92% (35/38)– CR: 18%; PR: 74%

26 hasta transplant oldu ve ilave 6 CR

Bortezomib + Talidomid + Deks (BTD)

Wang, et al. ASH 2005. Abstract 784.

38toplam11.9*

Hasta(n)

91.7111.5

Doz(mg/m2)

171.3

Mateos MV, et al. ASH 2005. Abstract 786.

Bortezomib 1.0 or 1.3 mg/m2 D1, 4, 8, 11, ve 22, 25, 29, 32; 6-w siklus x 4; peşisıra:Bortezomib D 1, 8, 15, 22; 5-w siklus x 5MP: M 9 mg/m2 and P 60 mg/m2 x 4; D 1-4

Historikal kontrolMP x 6

41%38%3%NR

86%CR + PR

En iyi yanıt*(n = 56)

43%PR13%CR IF+

Yanıt

30%CR IF-

Yaşlı Hastalarda Bortezomib + MP Faz I/II

IF, immunofixation

*medyan 5 siklus

Subgrup analizi“etkinlik”

üBöbrek disfonksiyonu veya yetmezliği

üβ2M >2.5 mg/L

üdel(13q)

üYaşlı hastalar

Bortezomib

Nüks veya refrakter hastalıkta bortezomib

Abstracts in Blood 2005;106

+ pegileliposomal doksorubisin

+ steroid

+ oral siklofosfamid

+düşük doz iv melfalan

Tek ajan bortezomib (APEX)

CR + nCRCR + PRnFaz

Orlowski et al. Blood2005;105:3058–65

36%73%42I

Suvannasankha25626%60%30II

Kropff 254912%82%50II

Popat 25555%53%22I/II

Richardson 254716%43%331III

Bortezomib İMİD Kombinasyonları

I

I/II

II

II

Faz

Richardson 36510%52%24+ lenalidomid(Vel/Rev)

Zangari 255216%55%85+ tal, deks(VTD)

Palumbo 255327%69%29+ melfalan, pred,

tal(V-MPT)

Terpos 36342%58%36+ melfalan, deks,

tal(VMDT)

CR + nCRCR + PRn

Abstracts in Blood 2005;106

Bortezomibin Tedavideki Etkinliği

+AST sonrasiidame

+Kombinasyon

+İlk Tanı

+++Nüks Hastalık

OSEFSYanıt

Yan Etkiler

evetevet–DVT ve PE profilaksi ihtiyacı

evetevet-PE

evetevetevetNötropeni

evetevetevetGastrointestinal toksiste

?evetTeratojenik

evetdoz ayarlaması

nadirevet

doz ayarlamasıTrombositopeni

evetevetnadirDVT

nadirevet

geri dönüşümü az

evetçoğunda geri dönüşümlü

Peiferik Nöropati

LenalidomidTalidomidBortezomib

Etkinlik nüks hastalık

624–27Lenalidomid

Tek ajan

1643Bortezomib

13–1430–47Talidomid

CR + nCR (%)CR + PR (%)

10–4252–69Bortezomib + İMİD15–3645–82Bortezomib17–2951–77Lenalidomid17–3241–79Talidomid

CR + nCR (%)CR + PR (%)Kombinasyon

Proteasome inhibitor (bortezomib)I B kinase inhibitor (PS-1145, MLN120B)2-MethoxyestradiolLysophosphatidic acid acyltransferase-b inhibitorTriterpenoid 2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acidAzaspirane (atiprimod)Shingosine monophosphate 1 inhibitor (FTY720)R-etodolac (SDX-101)Targeting circuits mediating MM cell growth and survivalVEGF receptor tyrosine kinaseinhibitor (PTK787/ZK222584, GW654652)FGFR3 inhibitor (CHIR258)

Farnesyltransferase inhibitorHistone deacetylase inhibitor (LAQ824)Heat shock protein-90 inhibitor (17-AAG)Telomerase inhibitor (GRN163)Inosine monophosphatedehydrogenase (VX-944)RapamycinSmac mimeticsTargeting the bone marrow microenvironmentp38 MAPK inhibitor (SCIO-469)TFGß receptor inhibitor (SD-208)Targeting cell surface receptorsTNF-related apoptosis-inducing ligand (TRAIL)/Apo2 ligandIGF-1 receptor inhibitor (ADW)HMG-CoA reductase inhibitor (Statins)Anti-CD20 antibody (Rituximab)Anti-CD40(SGN40, CHIR12-12)Anti-CD56DM-1

Heat Shock Protein-90 İnhibitörü KOS-953

Faz I : KOS-953 nüks/refrakter MM[1]

– Minimal yanıt: 5% – Stabil hastalık: 58%– Hepatotoksisite 220 ve 340 mg/m2 (n = 2)

Doz çalışması: KOS-953 plus bortezomibnüks/refrakter miyelom[2]

1. Richardson PG, et al. ASH 2005. Abstract 361. 2. Chanan-Khan AA, et al. ASH 2005. Abstract 362.

KOS-95 Doz/Bortezomib Doz

11023 (25)PD02013 (19)SD31307 (44)Minimal yanıt00000 (0)PR02002 (13)nCR

150 mg/m2

1.3 mg/m2

(n = 4)

150 mg/m2

1.0 mg/m2

(n = 8)

100 mg/m2

1.0 mg/m2

(n = 3)

100 mg/m2

0.7 mg/m2

(n = 3)

Tüm Hastalar(N = 18)

Yanıt (%)

Sonuç

Günümüze kadar bilinen en iyi tedavi:– İndüksiyon + tandem transplant

Yeni ajanlar bu tedavinin neresinde olmalı– İndüksiyon– Konsolidasyon– İdame– Kombine şekilde

Transplantsız tedavi seçeneği olamaz mı?

Sonuç

2000’li yıllarda tedaviye yeni etkili ajanlar katıldı– Yanıt oranları arttı

• Post-transplant yanıt oranları da arttı • Ancak yanıt süreleri test edilmedi• Yanıt artışı sağkalımı artıracak mı?

– Yaşlı hastalarda transplantdan kaçınılabilir mi?

Yeni ajanlar kötü prognostik faktörler üzerine de etkili(del 13q, t4;14)Güncel yaklaşım: yanıt oranlarını artırarak sağkalımıetkilemek– Total II çalışmasında talidomid eklenmesi ile ek etkinlik yok

Sabrınız için teşekkür ederim.

Dr. Mert Başaran

Copyright © American Society of Clinical Oncology

Barlogie, B. et al. J Clin Oncol; 24:929-936 2006

Fig 1. Treatment schema and patient flow

Copyright © American Society of Clinical Oncology

Barlogie, B. et al. J Clin Oncol; 24:929-936 2006

Fig 2. Overall survival and progression-free survival for all 813 eligible patients from study enrollment

Copyright © American Society of Clinical Oncology

Barlogie, B. et al. J Clin Oncol; 24:929-936 2006

Fig 3. (A) Progression-free survival (PFS) and (B) overall survival (OS) from first random assignment

Copyright © American Society of Clinical Oncology

Barlogie, B. et al. J Clin Oncol; 24:929-936 2006

Fig 4. (A) Progression-free survival and (B) overall survival from second random assignment to observation or interferon (IFN) maintenance among 242 patients

achieving at least 75% myeloma protein reduction

The future role of transplantation in multiple myeloma

Current status: SCTIn patients <65 years old, ASCT considered standard of careRandomized trials have shown superiority over conventional chemotherapy

42m vs 58m+*16m vs 28m*6 vs 25*50–70194Italian MMSG(Blood 2004)

7-year estimate

38% vs 38%7-year estimate

14% vs 17%15 vs 1725–70813US Intergroup

(JCO 2006)

≤65

≤65

Age

401

200

n

42m vs 54m*19m vs 31m*8 vs 44*MRC7 (N Engl J Med 2003)

7-year OS 27% vs 43%*

7-year EFS 8% vs 16%*5 vs 22*IFM 90

(N Engl J Med 1996)

OS EFS CR (%)Author

Conventional chemotherapy versus ASCT

*Significant difference

ASCT: Recent improvements

Tandem ASCT can improve survival for patients who do not achieve a CR or VGPR after the first transplantation

– IFM 94 (7-year survival 42% vs 21%)– Current results of other randomized trials (Sonneveld,

Cavo, Fermand)Further intensification

– IFM 99-04 in poor risk patients (51% CR + VGPR, median EFS 30 months)

– Total therapy II: CR 66%, 4-year EFS 62%, 4-year survival 69%

Introducing novel agents in the ASCT paradigm

Attal et al. N Engl J Med 2003;3349:2495–502

Increasing treatment options for patients with newly diagnosed MM

Achievement of CR or VGPR significantly associated with superior survival Aim: improve outcomes of SCT with novel agentsStrategies to improve outcomes with novel agents

1. Induction to increase CR rate prior to transplantation

2. Preparative regimen prior to SCT3. Consolidation/maintenance therapy following

SCT

Harousseau Ann Oncol 2002;13(Suppl 4):49–54Attal et al. N Engl J Med 1996;335:91–97

Tedavide neredeyiz???

DVd, liposomal doxorubicin, vincristine, dexamethasone; VMCP/BVAP, vincristine, melphalan, cyclophosphamide, prednisone, carmustine, and doxorubicin.

NEJM1996Yes/No52%5%VMCP/

BVAP100IFM90

ASH 2005

Cancer2006

ASH 2005

JCO2006

Ref

No

Yes

Yes

Yes

Stem Cell Harvest

48%

43%

63%

50%

CR + PR

7%

3%

3%

0%

CR/ nCRRegimen

MP126Palumbo

N

DVd97Rifkin

VAD203Gold-schmidt

Study

Dex100Rajkumar

First-Line Therapy in MM:Traditional

Upfront Therapy in MM:Novel Agents + Dex

Blood2005Yes91%6%Len + dex34Rajkumar

ASH 2005

JCO2006

ASCO 2005

BrJH2005;ASH 2005

Ref

No

Yes

Yes

Yes

Stem Cell Harvest

86%

63%

67%

89%

CR + PR

36%

4%

21%

18%

CR/ nCRRegimen

Len + dex+ clarithro35Niesvizky

N

Thal + dex99Rajkumar

Bort + dex48Harousseau

Study

Bort ± dex48Jagannath

*CR/vgPR

Upfront Therapy in MM:Novel Agents + Combinations

ASH 2005No7010%Len + MP20Palumbo

ASH 2005No76%28%MPT129Palumbo

ASH 2005

ASH 2005

ASH 2005

BrJH2005

Ref

No

Yes

Yes

Yes

Stem Cell Harvest

85%

80%

92%

95%

CR + PR

43%

7%

19%

29%

CR/nCRRegimen

Bort + MP53Mateos

N

TAD203Gold-schmidt

Bort/TD36Wang

Study

PAD40Oakervee

Response After High-Dose Chemotherapy

88%50%Autograft x 2200

ASCO 200590%54%Bort/dex/

autograft x 142Harousseau

Blood199981%38%Autograft x 2231Total Therapy

I

BrJH 2005

NEJM2003

NEJM2003

NEJM1996

Ref

95%

84%

86%

81%

CR + PR

57%

42%

44%

38%

CR/nCRRegimen

PAD/autograft x 121Oakervee

N

Autograft x 1200IFM96

Autograft x 1200Child

Study

Autograft x 1100IFM90

Treatment of High-Risk MM

High-risk characteristics– Elevated beta-2 microglobulin– High plasma cell labeling index– Del(13)

• Independent adverse prognostic factor in MM1

• Predicts worse response to treatment1

1. Zojer N, et al. Blood. 2000;95:1925-1930.

Factors commonly associated with Factors commonly associated with poor prognosis in MMpoor prognosis in MM

Age >65 years: majority of patients with MM are elderly Age >65 years: majority of patients with MM are elderly (median age at diagnosis (median age at diagnosis ~~63 years)63 years)>1 prior treatment>1 prior treatmentRefractory to prior treatmentRefractory to prior treatmentIncreased βIncreased β22MMDecreased serum albuminDecreased serum albuminCytogeneticCytogenetic abnormalitiesabnormalitiesRenal dysfunctionRenal dysfunction

–– Up to 50% of patients with MM have renal dysfunctionUp to 50% of patients with MM have renal dysfunction–– Between 20Between 20––30% of patients have concomitant renal failure30% of patients have concomitant renal failure

Unmet need for new agents to treat these patients

Perez-Simon et al. Blood 1998;91:3366–71Kyle. Stem Cells 1995;13(Suppl 2):56–63

Bladé et al. Arch Intern Med 1998;158:1889–93Knudsen et al. Eur J Hematol 1994;53:207–12

Kyle et al. Mayo Clin Proc 2003;78:21–33Kumar et al. Mayo Clin Proc 2004;79:867–74Greipp et al. Blood 1993;81:3382–7Facon et al. Blood 2001;97:1566–71

BortezomibBortezomib dose modification is an dose modification is an efficient strategy to improve/resolve PNefficient strategy to improve/resolve PN

In APEX, 91 patients experienced grade ≥2 PNIn APEX, 91 patients experienced grade ≥2 PN–– 72 had dose modification or discontinuation as per 72 had dose modification or discontinuation as per

protocol protocol –– 19 had no dose modification (protocol violation)19 had no dose modification (protocol violation)

In the 72 patients who had In the 72 patients who had dose modificationdose modification as per as per protocolprotocol

–– 68% (49/72) had improvement or resolution68% (49/72) had improvement or resolution

In the 19 patients who did In the 19 patients who did not have dose modificationnot have dose modification–– 47% (9/19) had improvement or resolution47% (9/19) had improvement or resolution

San Miguel et al. Blood 2005;106 (Abstract 366); Presented at ASH 2005

Modification of dose and regimenModification of dose and regimenSeverity of PN signs/symptomsSeverity of PN signs/symptoms

Discontinue bortezomibDiscontinue bortezomibGrade 4 (permanent sensory Grade 4 (permanent sensory loss interfering with function)loss interfering with function)

Withhold bortezomib until toxicity Withhold bortezomib until toxicity resolves then reinitiate at resolves then reinitiate at 0.7 mg/m0.7 mg/m2 2 and administer once and administer once per weekper week

Grade 2 with pain or grade 3 Grade 2 with pain or grade 3 (interfering with ADL)(interfering with ADL)

Reduce bortezomib to 1.0 mg/mReduce bortezomib to 1.0 mg/m22Grade 1 with pain or grade 2 Grade 1 with pain or grade 2 (interfering with function but (interfering with function but not with ADL)not with ADL)

No actionNo actionGrade 1 (Grade 1 (paresthesiaparesthesia and/or and/or loss of reflexes without pain or loss of reflexes without pain or loss of function)loss of function)

Bortezomib dose modification Bortezomib dose modification for the management of PNfor the management of PN

SmPC Janssen-Cilag 2005www.emea.eu.int

Prophylaxis for thalidomideProphylaxis for thalidomide-- and and lenalidomidelenalidomide--associated DVTassociated DVT

Agents usedAgents used–– LowLow--dose heparin, aspirin, dose heparin, aspirin, coumarin/warfarincoumarin/warfarin

Possible complicationsPossible complications–– Bleeding of moderate to severe intensityBleeding of moderate to severe intensity

•• Unusual bleeding or bruising: nose or gum bleeds, blood in urineUnusual bleeding or bruising: nose or gum bleeds, blood in urine–– Bleeding inside the bodyBleeding inside the body

Guidance from the manufacturerGuidance from the manufacturer–– LenalidomideLenalidomide

•• Patients and physicians advised to be observant for signs and Patients and physicians advised to be observant for signs and symptoms of symptoms of thromboembolismthromboembolism

•• Decision to use prophylaxis should be done carefully after Decision to use prophylaxis should be done carefully after assessment of an individual patient’s risk factorsassessment of an individual patient’s risk factors

–– ThalidomideThalidomide•• No guidance from manufacturersNo guidance from manufacturers

http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202050.htmlwww.revlimid.comwww.thalidomide.com

Hematological adverse eventsHematological adverse eventsBortezomibBortezomib

ThrombocytopeniaThrombocytopenia–– Grade 1/2 5%Grade 1/2 5%–– Grade 3/4 30%Grade 3/4 30%

No No cytotoxiccytotoxic effect on effect on megakaryocytesmegakaryocytes

NeutropeniaNeutropenia–– Grade 1/2 5%Grade 1/2 5%–– Grade 3/4 14%Grade 3/4 14%–– Decreases in ANC Decreases in ANC

transient; rapid recovery transient; rapid recovery to baselineto baseline

Febrile Febrile neutropenianeutropenia: <1%: <1%

AnemiaAnemia–– Grade 1/2 16%Grade 1/2 16%–– Grade 3/4 10%Grade 3/4 10%

ThalidomideThalidomideThrombocytopeniaThrombocytopenia

–– UncommonUncommon

NeutropeniaNeutropenia–– Grade 1/2 10%Grade 1/2 10%–– Grade 3/4 14%Grade 3/4 14%

LenalidomideLenalidomideThrombocytopeniaThrombocytopenia

–– Grade 1/2 7%Grade 1/2 7%–– Grade 3/4 10%Grade 3/4 10%

CytotoxicCytotoxic effect on effect on bone marrowbone marrow

NeutropeniaNeutropenia–– Grade 1/2 9%Grade 1/2 9%–– Grade 3/4 27%Grade 3/4 27%

Febrile Febrile neutropenianeutropenia–– Grade 3/4 4%Grade 3/4 4%

AnemiaAnemia–– Grade 1/2 14%Grade 1/2 14%–– Grade 3/4 6%Grade 3/4 6%

Richardson et al. Blood 2005;106 (Abstract 1565)Dimopoulos et al. Blood 2005;106 (Abstract 6)Suppiah et al. Blood 2005;106 (Abstract 2570)

Richardson et al. N Engl J Med 2005;352:2487–98Palumbo et al. Blood 2005;106 (Abstract 779)

Characterization of thrombocytopenia Characterization of thrombocytopenia with bortezomib in APEXwith bortezomib in APEX

Platelet count followed a cyclical pattern, with recovery Platelet count followed a cyclical pattern, with recovery toward baseline during the rest period of each cycletoward baseline during the rest period of each cycleNadir ~40% of baselineNadir ~40% of baseline

Lonial et al. Blood 2005;106 (Abstract 3474); Poster at ASH 2005

Mean platelet countSc

reen

Day

1D

ay 4

Day

8D

ay 1

1D

ay 1

Day

4D

ay 8

Day

11

Day

1D

ay 4

Day

8D

ay 1

1D

ay 1

Day

4D

ay 8

Day

11

Day

1D

ay 4

Day

8D

ay 1

1D

ay 1

Day

4D

ay 8

Day

11

Day

1D

ay 4

Day

8D

ay 1

1D

ay 1

Day

4D

ay 8

Day

110

50

100

150

200

250

Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7 Cycle 8

Mea

n pl

atel

et c

ount

(x

109 /L

)

Bortezomib dose modification for Bortezomib dose modification for thrombocytopeniathrombocytopenia

Dose of bortezomib will be Dose of bortezomib will be reduced in the following cycles reduced in the following cycles by 25%*by 25%*

If 2 or more of the 4 doses were If 2 or more of the 4 doses were skipped due to hematologic skipped due to hematologic toxicitytoxicity

Skip bortezomib dose**Skip bortezomib dose**If <30,000/If <30,000/μμLL

During the cycleDuring the cycle

Withhold and once resolved Withhold and once resolved (grade 1 or better) (grade 1 or better) reinitiate at 25% reduced dose*reinitiate at 25% reduced dose*

If grade 4If grade 4

On the first day of a new cycleOn the first day of a new cycle

Grade 1: >75,000/mmGrade 1: >75,000/mm33

Grade 2: 50Grade 2: 50––75,000/mm75,000/mm33

Grade 3: 25Grade 3: 25––50,000/mm50,000/mm33

Grade 4: <25,000/mmGrade 4: <25,000/mm33

*Once dose of Bortezomib reduced, dose will not be increased** Bortezomib doses needing to be held WITHIN a cycle are skipped

SmPC Janssen-Cilag 2005www.emea.eu.int

ConclusionsConclusions

If necessary, adverse events of bortezomib can be If necessary, adverse events of bortezomib can be managed with dose reduction using wellmanaged with dose reduction using well--defined defined protocolsprotocols

–– PN, thrombocytopeniaPN, thrombocytopeniaPN reversible in the majority of patients within PN reversible in the majority of patients within 3 months and can be managed with dose modification3 months and can be managed with dose modificationThromboticThrombotic events are not a complication of events are not a complication of bortezomibbortezomib

Adverse events with bortezomib are predictable, manageable and reversible

MPT studies vs MPV study resultsMPT studies vs MPV study results

median 74median 74median 72median 726565––7575Age (years)Age (years)

Anticoagulants for DVTAnticoagulants for DVTPossible irreversible PNPossible irreversible PN

OralOralTreatment cyclesTreatment cycles

(Data for grade not provided)(Data for grade not provided)Severe infection 17%Severe infection 17%

NeutropeniaNeutropenia 41%41%DVT 12%DVT 12%

Neuropathy 30%Neuropathy 30%

81%81%15%15%

Median EFS 29 monthsMedian EFS 29 months

MPTMPT (n=124)(n=124)FaconFacon et alet al. .

IVIVTreatment cyclesTreatment cycles

OralOralContinuous Continuous thalthal

treatmenttreatmentAdministrationAdministration

PN reversible with dose PN reversible with dose adjustment adjustment

Thrombocytopenia reversibleThrombocytopenia reversible

Anticoagulants for DVTAnticoagulants for DVTPossible irreversible PNPossible irreversible PN

ManagementManagement

Grade 3/4Grade 3/4Infection 17%Infection 17%

Thrombocytopenia 52% Thrombocytopenia 52% Neutropenia 43% Neutropenia 43%

Diarrhea 17%Diarrhea 17%PN 18%PN 18%

Grade 3/4Grade 3/4Infection 10%Infection 10%

HematologicHematologic 22%22%ThromboembolismThromboembolism 12%12%

PN 8%PN 8%

ToxicityToxicity

86%86%30%30%

EFS 85% at 10.5 monthsEFS 85% at 10.5 months

76%76%16%16%

EFS 54% at 24 monthsEFS 54% at 24 months

Efficacy Efficacy CR + PRCR + PRCRCRSurvivalSurvival

MPVMPV (n=60)(n=60)MateosMateos et alet al..

MPTMPT (n=129)(n=129)Palumbo Palumbo et al.et al.

ConclusionsConclusions

Novel therapy combinations are challenging MP as Novel therapy combinations are challenging MP as the standard of care the standard of care Superior response rates, especially CR rates, of Superior response rates, especially CR rates, of bortezomibbortezomib and thalidomide combinations over MPand thalidomide combinations over MPBortezomibBortezomib

–– Highly effective in the elderly populationHighly effective in the elderly population–– Toxicities manageableToxicities manageable

Phase III VISTA trial will directly compare MPV with Phase III VISTA trial will directly compare MPV with MP MP

Summary of Summary of ImmunomodulatoryImmunomodulatory Drugs Drugs in Multiple in Multiple MyelomaMyeloma

Interim analysis: OS at 1 year ~ 70% for patients Interim analysis: OS at 1 year ~ 70% for patients receiving thalidomide for relapsed/refractory receiving thalidomide for relapsed/refractory myelomamyelomaAddition of thalidomide improves response rates Addition of thalidomide improves response rates over over melphalanmelphalan/prednisone in treatment/prednisone in treatment--naive naive patientspatients

–– Trend toward improved survivalTrend toward improved survivalImproved survival when thalidomide added to MP Improved survival when thalidomide added to MP in elderly patientsin elderly patients

–– Increased DVT ratesIncreased DVT ratesResponse rates with firstResponse rates with first--line thalidomide/ line thalidomide/ dexamethasonedexamethasone similar to MP in elderly patientssimilar to MP in elderly patients

–– Responses more rapidResponses more rapid

Summary of Summary of ImmunomodulatoryImmunomodulatory Drugs Drugs in Multiple in Multiple MyelomaMyeloma (cont’d)(cont’d)

Lenalidomide/dexamethasoneLenalidomide/dexamethasone vs vs dexamethasonedexamethasonein relapsed/refractory disease in relapsed/refractory disease

–– Improved response ratesImproved response rates–– Increased time to progressionIncreased time to progression

• Increased incidence of hematologicside effects

Addition of Addition of lenalidomidelenalidomide to to melphalanmelphalan/prednisone /prednisone produced high response rates in elderly produced high response rates in elderly Lenalidomide/dexamethasoneLenalidomide/dexamethasone effective in effective in treatmenttreatment--naive multiple naive multiple myelomamyeloma

BortezomibBortezomib Plus Plus LenalidomideLenalidomide for for Relapsed/Refractory Multiple Relapsed/Refractory Multiple MyelomaMyeloma

PPhase I study of hase I study of lenalidomidelenalidomide plus plus bortezomibbortezomib (N = (N = 24)24)2121--day cycles (maximum of 8) at 8 different dosing day cycles (maximum of 8) at 8 different dosing schedulesschedules–– BortezomibBortezomib 1.0 or 1.3 mg/m1.0 or 1.3 mg/m22, Days 1, 4, 8, 11, Days 1, 4, 8, 11–– LenalidomideLenalidomide 55--30 mg/day, Days 130 mg/day, Days 1--1414

2 reports of dose2 reports of dose--limiting toxicitylimiting toxicity–– No No thromboticthrombotic eventsevents

–– Little peripheral neuropathyLittle peripheral neuropathyTotal response rate: 67%Total response rate: 67%Richardson PG, et al. ASH 2005. Abstract 365.

CRnCRPRMR

SDPD

Response Rates (n = 21)

43%14%

29%5%5%5%

BortezomibBortezomib ±± DexamethasoneDexamethasone as Firstas First--line Multiple line Multiple MyelomaMyeloma TreatmentTreatment

Nonrandomized, prospective phase II trial (N = 50)Nonrandomized, prospective phase II trial (N = 50)Overall response rate with Overall response rate with bortezomibbortezomib + + dexamethasonedexamethasone: 90%: 90%Median PFS: 15 monthsMedian PFS: 15 months

Jagannath S, et al. ASH 2005. Abstract 783.

8% 2%10% 8%

71%

40%

8%

25%

2%25%

0

20

40

60

80

100

Bortezomib ±Dexamethasone

BortezomibAlone at Cycle 2

SD/PDMRPRnCRCR

Best Response

Perc

enta

ge o

f Pat

ient

s

22MyalgiaMyalgia66DiarrheaDiarrhea22ThrombocytopeniaThrombocytopenia1010NeutropeniaNeutropenia22Abdominal pain/crampsAbdominal pain/cramps22AnorexiaAnorexia44FatigueFatigue

1212Sensory neuropathy/ Sensory neuropathy/ neuropathicneuropathic painpain

Grade 3/4, %Grade 3/4, %Adverse EventAdverse Event

BortezomibBortezomib Plus Plus MelphalanMelphalan/ / Prednisone in Elderly MM PatientsPrednisone in Elderly MM Patients

Phase I/II trial (n = 60)Phase I/II trial (n = 60)–– TreatmentTreatment--naive patientsnaive patients –– Median age: 74 Median age: 74

yearsyears86% of patients responded after median of 5 cycles 86% of patients responded after median of 5 cycles

–– EventEvent--free survival rate: 85% (median followfree survival rate: 85% (median follow--up: 10.5 up: 10.5 mosmos))

Most common grade 3/4 toxicity Most common grade 3/4 toxicity –– Thrombocytopenia: 52%Thrombocytopenia: 52%–– NeutropeniaNeutropenia: 43%: 43%–– Infection: 17%Infection: 17%–– Diarrhea: 17%Diarrhea: 17%

Mateos M, et al. ASH 2005. Abstract 786.

Stable disease

30%

13%43%

13%

Partial response

Complete responseNear complete response

Response Rates

Summary of Summary of ProteasomeProteasome Inhibitors and Inhibitors and Other New Agents in MMOther New Agents in MM

High response rates with High response rates with bortezomib/lenalidomidebortezomib/lenalidomidein relapsed/refractory diseasein relapsed/refractory disease

–– No No thromboembolicthromboembolic events reportedevents reportedBortezomibBortezomib--based combination therapy effective based combination therapy effective as firstas first--line treatment in multiple line treatment in multiple myelomamyeloma

–– 90% overall response rate when combined with 90% overall response rate when combined with deexamethasonedeexamethasone

–– 86% overall response when added to 86% overall response when added to melphalanmelphalan/prednisone in elderly patients/prednisone in elderly patients

–– Improves response when added to thalidomide/ Improves response when added to thalidomide/ dexamethasonedexamethasone vs thalidomide alonevs thalidomide alone

HSPHSP--90 chaperone inhibitor KOS90 chaperone inhibitor KOS--953 showed 953 showed promise in early studiespromise in early studies

Bortezomib in patients with Bortezomib in patients with cytogeneticcytogenetic abnormalitiesabnormalities

TTF and OS shorter for patients with del(13q)TTF and OS shorter for patients with del(13q)

del(13q) plus gain of 1q21 or low serum albumin associated del(13q) plus gain of 1q21 or low serum albumin associated with shorter OSwith shorter OS

Drach et al. Blood 2005;106 (Abstract 509)

not reachednot reached6.76.7

13q normal13q normal

0.0470.047--PP

6.16.1median OS (months)median OS (months)2.62.6median TTF (months)median TTF (months)

del(13q)del(13q)

Bortezomib in patients with Bortezomib in patients with renal dysfunctionrenal dysfunction

Tolerability and efficacy of bortezomib Tolerability and efficacy of bortezomib in patients with renal impairmentin patients with renal impairmentSubanalysis of SUMMIT and CRESTSubanalysis of SUMMIT and CREST

Toxicity profile similar in patients with normal vs impaired Toxicity profile similar in patients with normal vs impaired renal functionrenal functionMean serum Mean serum creatininecreatinine appears unaffected by bortezomibappears unaffected by bortezomibProteasome activity in blood assay unaffected by renal functionProteasome activity in blood assay unaffected by renal functionComparable response rates in patients with compromised Comparable response rates in patients with compromised renal functionrenal function

Jagannath et al. Cancer 2005;103:1195–200

30301010<30<3025255252≤≤5050333399995151––80804545105105>80>80

ORR (%)ORR (%)nnCreatinineCreatinine clearanceclearance((mLmL/min)/min)

Bortezomib in patients with Bortezomib in patients with renal failure requiring dialysisrenal failure requiring dialysis

Retrospective analysis of 24 patients treated with Retrospective analysis of 24 patients treated with –– SingleSingle--agent bortezomibagent bortezomib–– Bortezomib combinations (+ Bortezomib combinations (+ dexdex + + thal/dexthal/dex + + thalthal/doxorubicin)/doxorubicin)

Number of therapies prior to bortezomib: median 2 (range 0Number of therapies prior to bortezomib: median 2 (range 0––6)6)

Chanan-Khan et al. Blood 2005;106 (Abstract 2550); Poster at ASH 2005

78%

28%

6%

44%

0 20 40 60 80

PR

nCR

CR

ORR

Best response (%)

Bortezomib in patients with renal Bortezomib in patients with renal failure requiring dialysisfailure requiring dialysis

High response ratesHigh response rates

Most adverse events were mild to moderate Most adverse events were mild to moderate and manageableand manageable

Incidence and severity of adverse events comparable Incidence and severity of adverse events comparable to those of patients with normal renal functionto those of patients with normal renal function

Comparable response rates and toxicity profile of bortezomib in patients requiring renal dialysis

Chanan-Khan et al. Blood 2005;106 (Abstract 2550); Poster at ASH 2005

Effect of bortezomib on bone Effect of bortezomib on bone metabolismmetabolism

Bone disease in MMBone disease in MM

Myeloma bone diseaseMyeloma bone disease–– Characterized by osteolytic destruction not Characterized by osteolytic destruction not

compensated by adequate new bone formation compensated by adequate new bone formation MM growth associated with suppressed MM growth associated with suppressed osteoblasticosteoblasticactivity possibly through inhibition of the WNT activity possibly through inhibition of the WNT signaling pathwaysignaling pathwayIncreased Increased osteoclasticosteoclastic activity and bone activity and bone resorptionresorption

Bataille et al. J Clin Invest 1991;88:62–6Tian et al. N Engl J Med 2003;349:2483–94

Effects of bortezomib on Effects of bortezomib on osteoblastosteoblast and and osteoclastosteoclast functionfunction

BortezomibBortezomib

Inhibits Inhibits osteoclasticosteoclastic bone resorption bone resorption

Increases Increases osteoblastosteoblast function (e.g. function (e.g. decreased DKKdecreased DKK--1 1 production)production)

Stimulates bone morphogenetic protein (BMP)Stimulates bone morphogenetic protein (BMP)--22--mediated mediated osteoblastosteoblast differentiationdifferentiation

Peles et al. Blood 2005;106 (Abstract 3548)Heider et al. Blood 2005;106 (Abstract 3457)

Results suggest that Bortezomib has a positive effect on bone metabolism in MM

Oyajobi et al. J Bone Miner Res 2004;19(Suppl1)S4Garrett et al. J Clin Invest 2003;111:1771–82

Bellido et al. J Biol Chem 2003;278:50259–72

Alkaline phosphatase levels during Alkaline phosphatase levels during bortezomib treatment in APEXbortezomib treatment in APEX

0%20%

40%

60%

80%

>25% ALP <25% ALP CR, P=0.1476

PR, P<0.0001CR/PR, P<0.0001

Alkaline phosphatase and response in 315 patients

A 25% increase in ALP from baseline to week 6 was strongly A 25% increase in ALP from baseline to week 6 was strongly associated with CR + PR and longer TTPassociated with CR + PR and longer TTP

Zangari et al. Blood 2005;106 (Abstract 510); Presented at ASH 2005

Markers of osteoblastic activation (such as ALP) during bortezomib treatment may predict response and response duration in patients with MM

Bortezomib in patients with Bortezomib in patients with cytogeneticcytogenetic abnormalitiesabnormalities

10

20

30

40

50

60

% p

atie

nts

resp

ondi

ng

del(13q) 13q normaln=22 n=22

18%

41%

54%

36%

Drach et al. Blood 2005;106 (Abstract 509)

Response to bortezomib: del(13q) vs 13q normal

Bortezomib is effective in patients with and without del(13q)

PR

CR + nCR

MR5%

18%

18%

DexamethasoneDexamethasone--treated patients: associated with treated patients: associated with poor survivalpoor survival–– HR: 9.31 (95% CI: 1.88HR: 9.31 (95% CI: 1.88--46.06)46.06)–– PP = .002= .002

BortezomibBortezomib--treated patients: no difference in treated patients: no difference in survivalsurvival–– HR: 1.61 (95% CI: 0.35HR: 1.61 (95% CI: 0.35--7.46)7.46)–– PP = NS= NS

Bortezomib may overcome adverse impact of Bortezomib may overcome adverse impact of Del(13q)Del(13q)

Richardson PG, et al. N Engl J Med. 2005;352:2487-2498.

APEX: Impact of Del(13) on Survival inAPEX: Impact of Del(13) on Survival inBortezomibBortezomib-- and Dexand Dex--Treated PatientsTreated Patients