A Randomized Phase III Trial of Thalidomide Plus
Dexamethasone Versus Dexamethasone in
Newly Diagnosed Multiple Myeloma (E1A00): A
Trial Coordinated by the Eastern Cooperative
Oncology Group
S. Vincent Rajkumar, Emily Blood, David H.
Vesole, Robert Shepard, Philip R. Greipp
Mayo Clinic, Rochester, MN; Dana Farber Cancer
Institute, Boston, MA; Medical College of
Wisconsin, Milwaukee, WI; University of Virginia,
Charlottesville, VA
Thalidomide in Relapsed Myeloma
No. of
Dose
Response
Study
patients
mg/day
rate (%)
Singhal et al
84
200-800
32
Weber et al
44
200-800
25
Durie and Stepan
33
50-400
24
Juliusson et al
19
200-800
47
Kneller, et al
17
200-800
65
Rajkumar et al
16
200-800
25
Shima et al
13
100-800
54
Neben et al
11
400
27
Sabir et al
10
200-800
70
Cheng et al
9
200
78
Schiller et al
8
200-800
50
Rajkumar & Witzig Cancer Treat Rev 26;351-62, 2000
Thal/Dex in Newly Dx MM
Rationale
Dexamethasone
45% RR in new MM
25% RR in relapsed disease
Synergy of Thal/Dex in preclinical studies
Thal/Dex effective in relapsed myeloma
Alexanian et al. Blood 80; 887-90, 1992
Weber et al. ASH 1999; Hideshima Blood 96:2943-2950, 2000
Thal/Dex in Newly Diagnosed MM
Mayo Clinic Study: 50 Patients
64% response rate
MDACC Study: 40 Patients
72% response rate
Rajkumar SV. J Clin Oncol 2002;20: 4319-4323; Weber JCO Jan 2003
Aim
A phase III trial comparing response and toxicity of
thalidomide plus dexamethasone (Thal/Dex)
versus dexamethasone alone (Dex) as first line
therapy in newly diagnosed multiple myeloma
Schema
E1A00: 207 patients
R
A
N
Off Rx @ 4
D
Thal + Dex
CR/PR/
months-
O
x4 cycles
Stable
for transplant*
M
I
Z
A
Dex
Prog
Off Rx
T
x 4 cycles
anytime
I
O
N
*Treatment beyond 4 cycles was permitted at physician discretion
Dose
Thalidomide
Dexamethasone
200 mg PO daily
40 mg day 1-4, 9-12,
17-20
All patients received pamidronate or zoledronic acid monthly
Response Definition
Intention to treat
50% reduction in serum and urine M protein as
measured by SPEP and UPEP
90% reduction in urine M protein as measured by
UPEP, if only urinary protein was evaluable for
response
Study Status as of November 18, 2004
Cases entered
207
Ineligible
7**
** No measurable disease at baseline (3), no baseline
UPEP (1), BM biopsy 7%, no biopsy of plasmacytoma (1),
BM biopsy dry tap, not repeated (1), No data sent (1)
Patient Characteristics
Characteristic
Thal/Dex (n=99)
Dex (n=101)
Age (median, range)
65 (38-83)
65 (38-82)
Gender (%Female)
49%
40%
S. M spike (median)
3.7 (n=95)
3.3 (n=96)
BMPC% (median)
28.0 (n=48)
30.5 (n=40)
B2M (median)
3.0 (n=65)
3.4 (n=55)
PCLI (median)
0.5 (n=46)
0.6 (n=38)
Results
Best Response within 4 Cycles using ECOG criteria
Thal/Dex: 62/99 pts (63%)
1-sided
Dex:
41/100 pts (41%)
p-value=0.002*
* The boundary for the p-value at 98% information is 0.038
* Response in 13 pts assessed using quantitative immunoglobulins
or urine light chain level
Results
Best Response* within 4 Cycles
Thal/Dex: 72/99 pts (73%)
Dex:
50/100 pts (50%)
*allowing for using serum M protein levels (or QI levels, in 2 pt) in patients in whom
measurable urine M protein was unavailable at follow-up
Results
Median time to response among responders
Thal/Dex:
1.1 (0.7-4.1) months
Dex:
1.1 (0.7-2.9) months
Results
Complete response (CR)
Thal/Dex:
4/99 patients (4%)
Dex:
0/100 patients (0%)
Results
Disease Progression within 4 cycles
Thal/Dex: 2%
Dex:
4%
Results
Status of harvest known on 80% of pts
37% have been harvested
Thal/Dex: 29/79 (37%)
Dex:
30/80 (38%)
Harvest successful
Thal/Dex: 26/29 (90%)
Dex:
27/30 (90%) [3/30 (10%) success unknown]
Monitored Toxicities Occurring Within 4
Cycles from Start of Treatment
Toxicity
Thal/Dex
Dex
(N=102)
(N=102)
DVT (Grade >=3)
17 (17%)
3 (3%)
Rash (Grade >=3)
4 (4%)
0 (0%)
Sinus bradycardia (Grade >=3)
1 (1%)
0 (0%)
Neuropathy (Grade >=3)
7 (7%)
4 (4%)
Toxicity of Any Type (Grade >=4)
35 (34%)
18 (18%)
Total **
46 (45%)
21 (21%)
** Rows do not add to total as patients could have more than one of
these toxicity types
Results
Grade 3 or higher non-hematologic toxicities within 4
cycles
Thal/Dex: 66%
Dex:
43%
Deaths within 4 cycles/4 months
Thal/Dex: 7%
Dex:
11%
Results
DVT (within 4 cycles) on Thal/Dex Arm
No significant association with age (<65,>=65)
(p=0.29) [<65 12%, >=65 22%]
No significant association with response (p=0.59)
42% of all occurrences were experienced in first 2
cycles of treatment
[9/23(39%) Thal/Dex, 2/3(67%) Dex]
Conclusions
Thal/Dex is an effective induction therapy in newly
diagnosed myeloma
Response rates are superior to Dex alone but
need to be balanced with the risk of added toxicity
Implications for use of VAD
Prophylaxis against DVT when using Thal/Dex
Future strategy: ECOG Phase III with CC-
5013+Dex (E4A03)
Document Outline