A Multicenter, Randomized, Double-Blind,
Placebo-Controlled Study Thalidomide Plus
Dexamethasone Versus Dexamethasone
Alone As Initial Therapy For Newly
Diagnosed Multiple Myeloma (MM 003)
S. Vincent Rajkumar, Mohamad Hussein, John Catalano,
Wieslaw Jedrzejczak, Svetlana Sirkovich, Marta Olesnyckyj,
Zhinuan Yu, Robert Knight, Jerry Zeldis, and Joan Blade
Mayo Clinic, Rochester, MN; Cleveland Clinic, Cleveland, Ohio; Frankston
Hospital, Frankston, Australia; Medical Academy of Warsaw, Warsaw,
Poland; Kiev Institution of Oncology of the UAMS, Kiev, Ukraine; Celgene
Corporation, Summit, NJ, and Hospital Clinic, Barcelona, Spain.
Thal/Dex in Newly Diagnosed MM
Mayo Clinic Study: 50 Patients
· 64% response rate
MDACC Study: 40 Patients
· 72% response rate
Cavo et al
· 76% response rate
Cavo et al (Case-control)
· VAD vs Thal/Dex: 52% vs 76%
Rajkumar SV. J Clin Oncol 2002;20: 4319-4323; Weber JCO Jan 2003; Cavo et al. Haematologica 2004:89:826-31;
Cavo M et al. Blood 2005;106:35-39
ECOG/CTSU Randomized Phase III
Trial (E1A00)
Best Response within 4 Cycles
198 of 202 eligible pts
· Thal/Dex: 63%
1-sided
·Dex:
41%
p-value=0.002
No data on TTP
S. V. Rajkumar et al. J Clin Oncol 2006;24:431-436
Study Objectives
· Primary: Compare the efficacy of
Thal/Dex vs Dex as initial therapy in MM
· Secondary: Compare the safety of
Thal/Dex vs Dex as initial therapy in MM
Trial Design
Thal 50 200 mg d 1-28
Dex 40 mg, d 1-4, 9-12, 17-20
TTP
OS
Same except
X 4 COURSES
Dex d 1-4
RR
Continue until PD Safety
Placebo d 1-28
Dex 40 mg, d 1-4, 9-12, 17-20
Eligibility Criteria
· Newly diagnosed, previously untreated,
symptomatic MM
·M protein in serum 1.0 g/dL or urine 200 mg/24h
·PS: 0-2
·Adherence to safety requirements
·Absolute Neutrophil Count (ANC) 1,000
·Platelet Count 50,000/mm3
·Serum Creatinine 3.0 mg/dL
·AST/ALT 3.0 x UNL; BR 2.0 mg/dL
Statistical Considerations and Analysis
· Planned sample size: 218 eligible pts per arm.
· One-sided log rank test with significance level of
0.025 to have 80% power to detect a 40%
improvement in TTP (16.8 mo in Arm A vs. 12 mo in
Arm B) would be achieved when 282 pts have
progressed.
· Pre-planned interim analysis of the primary endpoint
and safety was performed by an independent Data
Monitoring Committee (DMC).
· A P value < 0.0015 at this interim analysis would
indicate that Arm A is superior to Arm B
· The DMC recommended release of results.
Patient Characteristics
Thal/Dex
Dex
No. of Pts.
235
235
Male
118
120
Med. Age (yrs)
65
66
ECOG PS < 1
164
166
Patient Characteristics
Thal/Dex
Dex
DS Stage III n(%)
157
145
Lytic Lesions n(%)
184
188
Response Criteria
Partial Remission (PR)*
> 50% decrease in serum M-protein
> 90% decrease or decrease to <200mg/d in
urine M protein
Complete Remission (CR)*
No serum M-protein
By Immunofixation
No Bence Jones protein
< 5% marrow plasma cells
* Confirmed by consecutive measurements at least 6 weeks apart
Response Criteria
Progressive Disease (PD)
> 25% increase in nadir M-protein
(must be at least 0.5 g/dL increase in serum M-
protein or at least 200 mg/d for urine M protein
for PR; or reappearance for CR relapse)
New Lytic Bone Lesion/plasmacytoma
Hypercalcemia due to MM
Growth of soft tissue plasmacytoma
> 25% BM plasma cells
Response
PR+CR
80
PR (>50%)
(%)
CR (IF-)
48.5%*
60
* p<.01
Rate
40
35.3%*
20
43.8%
Response
4.7%
34.0% 1.3%
0
Thal/Dex
Dex
Blade Criteria
Time to Progression
Overall Survival
Hematological Toxicities
Thal/Dex (n=234)
Dex (n=232)
Gr 1-2
Gr 3-4
Anemia
Thrombocytopenia
Neutropenia
010
20
30
40
Percent
Common Non-Hematological Toxicities
Thal/Dex (n=234)
Dex (n=232)
Gr 1-2
Gr 3-4
Constipation
Edema
Insomnia
Weakness/
fatigue
Tremor
Neuropathy
0
1020
30
40
5060
70
Percent
Major Grade 3/4 Toxicities
Thal/Dex (n=234)
Dex (n=232)
DVT/PE
Pneumonia
Hyperglycemia
Atrial Fibrillation
Myocardial Ischemia
Cerebrovascular
Ischemia
Any Grade 4
010
20
30
40
50
Percent
Major Grade 3/4 Toxicities
Thal/Dex
Dex
N = 234
N =232
DVT/PE
42 (17.9%)
10 (4.3%)
Pneumonia
18 (7.7%)
14 (6.0%)
Hyperglycemia
14 (6%)
12 (5.1%)
Atrial Fibrillation
11 (4.7%)
8 (3.4%)
Myocardial ischemia
9 (3.8%)
5 (2.2%)
Cerebrovascular
7 (3%)
3 (1.3%)
ischemia
Any grade 4
71 (30.2%) 52(22.6%)
Reasons for Discontinuation
Thal/Dex
Dex
N = 235
N = 235
Discontinued (%)
172(73.2)
216(91.9)
PD/Lack of Effect
67(28.5)
143(60.8)
AE
56(23.8)
21(8.9)
Pt Declined
17(7.2)
16(6.8)
Lost to F/U
0 (0)
1(0.4)
Death
21(8.9)
23(9.8)
Other
11(4.7)
8(3.4)
Conclusions
· In newly diagnosed myeloma,
Thal/Dex is superior to Dex alone, with
a significantly longer time to progression
· As in ECOG E1A00, treatment with
Thal/Dex yields significantly higher
response rates
·Thrombotic events are frequent,
justifying need for routine prophylactic
anticoagulation