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