multİpl mİyelomda hedefe yÖnelİk tedavİler ve …...lenalidomid+ deksvsdeks(mm-010) etkinlik...
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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