Multiple Myeloma: Novel Agents Robert A. Kyle, M.D. Germany June ...
Multiple Myeloma: Novel Agents Robert A. Kyle, M.D. Germany June ...
Multiple Myeloma: Novel Agents Robert A. Kyle, M.D. Germany June ...
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<strong>Multiple</strong> <strong>Myeloma</strong>: <strong>Novel</strong> <strong>Agents</strong><br />
<strong>Robert</strong> A. <strong>Kyle</strong>, M.D.<br />
<strong>Germany</strong><br />
<strong>June</strong> 28, 2008<br />
Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida
<strong>Multiple</strong> <strong>Myeloma</strong> Untreated<br />
Initial Therapy<br />
Transplant eligible
<strong>Multiple</strong> <strong>Myeloma</strong> Untreated<br />
N = 470<br />
Resp TTP DVT<br />
CR/PR mos %<br />
% (med)<br />
Thal 50-200 mg/day +<br />
Dex 40mg(day 1-4, 1<br />
9-12, 9<br />
17-20)<br />
63 22.6 12<br />
Placebo +<br />
vs.<br />
Dex 40mg (day 1-4, 1<br />
9-12, 9<br />
17-20)<br />
46 6.5 2<br />
Rajkumar et al., JCO 26:2171, 2008
Survival Rate<br />
N<br />
Survival Probability<br />
One-Year<br />
Two-Year<br />
% %<br />
Lenalidomide 25 mg d 1-211<br />
+ 223 88 78<br />
Dexamethasone 40 mg<br />
d 1-4, 1<br />
9-12, 9<br />
17-20<br />
vs.<br />
Lenalidomide 25 mg d 1-211<br />
+<br />
Dexamethasone 40 mg<br />
d 1, 8, 15, 22 222 96 88<br />
Rajkumar, et al., ASCO 2008
Overall Survival (months)<br />
Rd<br />
RD<br />
Rajkumar, et al., JCO 25:18S, 2007 (ASCO)
<strong>Multiple</strong> <strong>Myeloma</strong><br />
Untreated<br />
N = 48<br />
Response<br />
Bortezomib 1.3 mg/M2 %<br />
2/wk x 2 q3 wks CR/NCR 19<br />
+<br />
Dexamethasone 40 mg<br />
Day of and day after Bortezomib PR 71<br />
if no response<br />
Total 90<br />
Jagannath, et al., Blood 108: 238a, 2006
<strong>Multiple</strong> <strong>Myeloma</strong> Untreated<br />
Initial therapy<br />
Transplant ineligible<br />
CP1123175-32
<strong>Multiple</strong> <strong>Myeloma</strong><br />
Untreated – age 65-75 years<br />
IFM 99-06<br />
N= 447<br />
PFS<br />
med mos<br />
OS<br />
med mos<br />
MPT (400 mg) x 12 28 52<br />
MP x 12 18 33<br />
VAD/Mel 100x2 19 38<br />
Facon, et al., Lancet, 2007 370:1209
<strong>Multiple</strong> <strong>Myeloma</strong><br />
Untreated – age > 75 years<br />
IFM 01/01<br />
N= 229<br />
PFS<br />
med mos<br />
OS<br />
med mos<br />
MPT (100 mg)<br />
d 1-4, 1<br />
q. 6 weeks x 12 24.2 45.3<br />
M 0.2 mg/kg + P 2 mg/kg 19 27.7<br />
d 1-41<br />
4 q. 6 weeks x 12<br />
Hulin, et al., Blood 2007, 110:31a
San Miguel, et al, ASH 2007<br />
<strong>Multiple</strong> <strong>Myeloma</strong><br />
Non-Transplant Candidates<br />
Cycles 1-4<br />
Bortezomib 1.3 mg/m2 IV d 1,4,8,11,22,25,29,32<br />
+<br />
Melphalan 9 mg/m2 and prednisone 60 mg/m2 d 1-4<br />
Cycles 5-9<br />
Bortezomib 1.3 mg/m2 IV d 1,8,22,29<br />
+<br />
Melphalan 9 mg/m2 and prednisone 60 mg/m2 d 1-4<br />
vs.<br />
Melphalan 9 mg/m2 and prednisone 60 mg/m2 d 1-4<br />
Nine 6-week cycles of both arms
<strong>Multiple</strong> <strong>Myeloma</strong><br />
Response to Treatment<br />
MPV<br />
MP<br />
N=336 N=331<br />
p-value<br />
M-protein*<br />
M-protein* M<br />
CR (IF-) 35% 5% (<br />
90% ÄM-protein) 10% 5%<br />
PR 46% 45%<br />
*measured in serum or urine by centralized laboratory<br />
San Miguel, et al., ASH 2007
<strong>Multiple</strong> <strong>Myeloma</strong><br />
Grade 3/4 adverse events (%)<br />
VMP (n=340)<br />
MP (n=337)<br />
Gr 3 Gr 4 Gr 3 Gr 4<br />
Neutropenia 30 10 23 15<br />
Thrombocytopenia 20 17 16 14<br />
Anemia 16 3 20 8<br />
GI 19 1 5
<strong>Multiple</strong> <strong>Myeloma</strong><br />
Treatment<br />
Relapsed, Refractory
Refractory <strong>Multiple</strong> <strong>Myeloma</strong><br />
Therapy<br />
• Vcr Adria Dex (VAD)<br />
• High-dose corticosteroids<br />
Dexamethasone 40 mg<br />
d 1 – 4, 9 – 12, 17 – 20 q mo<br />
• Thalidomide<br />
• Bortezomib (Velcade)<br />
• Lenalidomide (Revlimid)
Single-Agent Thalidomide in<br />
Recurrent/Refractory <strong>Multiple</strong> <strong>Myeloma</strong><br />
Dose<br />
Pt<br />
RR<br />
Study<br />
(mg/d)<br />
(no.) (%)<br />
Singhal, et al. 200-800<br />
84 32*<br />
Barlogie, et al. 200-800<br />
169 30**<br />
Grosbois 200-400<br />
121 41<br />
(incl minor<br />
response)<br />
* >25% Ä in paraprotein<br />
** 2-yr event-free survival and overall survival rates of 20% and 48%, respectively<br />
CP1123175-35
Refractory <strong>Multiple</strong> <strong>Myeloma</strong><br />
Treatment<br />
Bortezomib (VELCADE TM ) (PS-341)<br />
n = 193<br />
Response (CR/PR) 35%<br />
Duration response<br />
12 mo<br />
Richardson et al: NEJM 2003, 348:26.
<strong>Multiple</strong> <strong>Myeloma</strong><br />
Relapsed<br />
Bortezomib, 1.3 mg/M 2<br />
d 1, 4, 8, 11 q 3wks<br />
vs.<br />
N = 669<br />
Dexamethasone, 40 mg<br />
d 1-4; 1<br />
9-12; 9<br />
17-20<br />
TTP<br />
mos<br />
Survival<br />
med<br />
mos<br />
6.2 29.8<br />
3.5 23.7<br />
Richardson, et al., Blood, 2007, 110:3557
<strong>Multiple</strong> <strong>Myeloma</strong><br />
Relapsed/Refractory<br />
Bortezomib, 1.3 mg/m 2 IV<br />
d 1, 4, 8, 11<br />
vs.<br />
N = 646<br />
Bortezomib, 1.3 mg/m 2 IV<br />
d 1, 4, 8, 11<br />
+<br />
Doxil 30 mg/m 2 IV<br />
d 4<br />
Orlowski et al., JCO, 2007, 25:3892<br />
TTP<br />
Survival<br />
mos<br />
at 15 mos<br />
med %<br />
6.5 65<br />
9.3 76
Lenalidomide<br />
25 mg d1-21 +<br />
Dexamethasone<br />
40 mg d 1-4, 1<br />
9-12, 9<br />
17-20<br />
vs.<br />
Placebo d. 1-211<br />
+<br />
Dexamethasone<br />
40 mg d 1-4, 1<br />
9-12, 9<br />
17-20<br />
<strong>Multiple</strong> <strong>Myeloma</strong><br />
Relapsed/Refractory<br />
009,010<br />
N = 704<br />
Response CR/PR<br />
TTP<br />
% Mos<br />
(Med)<br />
60.5 11.2<br />
22 4.7<br />
Weber, et al., NEJM, 2007, 357:2133; Dimopoulos, et al., NEJM, 2007, 2<br />
357:2123
1.0<br />
<strong>Multiple</strong> <strong>Myeloma</strong> 1971-1996<br />
1996<br />
n=2,981<br />
Proportion surviving<br />
0.8<br />
0.6<br />
0.4<br />
0.2<br />
0.0<br />
Survival, med<br />
29.9 mo<br />
0 20 40 60 80 100 120 140<br />
Kumar et al: Blood 111:2516, 2008<br />
Survival, med<br />
44.8 mo<br />
Diagnosis during/<br />
before 1996<br />
Diagnosis after 1996<br />
Time from diagnosis (months)<br />
P
Proportion surviving<br />
Relapse After Autologous Transplant<br />
for <strong>Multiple</strong> <strong>Myeloma</strong><br />
1.0<br />
0.8<br />
0.6<br />
0.4<br />
0.2<br />
0.0<br />
n=161<br />
Survival, med<br />
30.9 mo<br />
0 20 40 60 80 100<br />
Kumar et al: Blood 111:2516, 2008<br />
Exposed to new drugs<br />
n=226<br />
Survival, med<br />
14.8 mo<br />
No exposure to new drugs<br />
n=387<br />
P
<strong>Multiple</strong> <strong>Myeloma</strong><br />
<strong>Novel</strong> <strong>Agents</strong><br />
Histone deacetylase inhibitor<br />
SAHA<br />
Heat Shock protein- 90 inhibitor<br />
KOS-953<br />
Tanespimycin<br />
VEGF Inhibitors<br />
Farnesyl transferase inhibitor<br />
Arsenic Trioxide<br />
Proteosome inhibitor (oral)<br />
FGFR3 inhibitor<br />
P 38 MAPK inhibitor<br />
PTK787/2K222584<br />
SCH-66336<br />
Trisenox<br />
NPI-005<br />
Chir-258<br />
Scio-469
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