Is Thalidomide Frontline
Therapy for MM???
Donna Weber, MD
The University of Texas, MD Anderson Cancer Center
Houston, Texas, USA
Smoldering (Asymptomatic) MM
Observation
Clinical Trial
Untreated Multiple Myeloma
Low or Intermediate Tumor Mass
80
60
40
Response%
20
0
Dexa
M+D
VAD
(140)
(170)
(128)
Autologous SCT
Alexanian et al
(n=81)
PR
CR
36%
Primary
PR
49%
69%
Refractory
CR
19%
Thalidomide-Dexamethasone for Untreated Myeloma
MDACC
MDACC
Mayo
Low or Int
All
Total No. Patients
70
130
50
No. Pts. Remission
8CR 43PR
11 CR 79 PR
32PR
(73%)
(69%)
(64%)
Time to remission
1.1
1.1
(median mos.)
Remission Duration
12+
Not
(median mos.)
reached
Toxicity
Thalidomide
Thal/Dex
(% Pts.)
(% Pts.)
Constipation
63
55
Neurologic
68
50
Fatigue
39
55
Pruritic rash/dry skin
61
55
Edema
25
35
Deep vein thrombosis/PE
4
24/15
ECOG: Thal-Dex vs Dex for Untreated Myeloma
TD
D
Total No. Patients
103
107
Response (%)
58 (69)
42 (51)
Progressed @ 4 mos (%)
35
> Gr 3 Toxicity (%)
68
43
DVT
18
3
Neuropathy
7
4
Rajkumar et al, ASH 2004, Abst #205
Thalidomide/Dexamethasone vs Dexamethasone: Drug-
Related Adverse Events
Thal/Dex, %
Dex, n %
Drug-Related Adverse Event
(n=102)
(n=102)
DVT grade 3
18
3
Rash grade 3
4
0
Sinus bradycardia grade 3
1
0
Neuropathy grade 3
7
4
Any toxicity grade 4
34
17
Total*
46
20
Deaths within 4 cycles: Thal/Dex, 7%; Dex, 11%
*Rows do not add to total as patients could have more than one of these adverse events
Rajkumar SV et al. Blood. 2004;104(part 1):63a [abstract 205]
BLT-D for Untreated MM/WM (n=50)
Clarithromycin 500 mg po bid
Thalidomide 50-200 mg/d po
Dexamethasone 40 mg po q wk
Response
n
%
Total
50
CR
5
10
74%
PR
34
64
Grade 3/4 Neurotoxicity 18%, CV toxicity 16%, Death 6%,
GI 4%, Endocrine 4%
(DVT/PE 8% - then ASA 81mg prophylaxis)
Coleman et al, Leukemia and Lymphoma, 2002
MPT vs. MP
Melphalan 4 mg/m2/d po x 7d
MP
Prednisone 40 mg/m2/d po x 7d
MPT
Thalidomide 100 mg/d po
Total No. Pt.
MPT n=193
MP n=100
CR
26
4
80
48
PR
54
44
EFS @ 26 mo.
68
32
OS
NR
NR
G1-2 Neurotoxicity
36
6
G3-4 Heme
23
28
DVT
19
2
Infection
13
2
Palumbo et al, ASH 2004, Abst #207
Thromboembolism in MPT-Treated Elderly
Patients Reduced With Prophylaxis
· More DVT with MPT than with MP (P=0.003)
· DVT prophylaxis: enoxaparin, 0.4 mL/day for 4 months
Incidence, %
No Prophylaxis With Prophylaxis
Adverse Event
(n=61)
(n=28)
DVT
21.3
7.1
Pulmonary
4.9
0.0
thromboembolism
Arterial occlusion
1.6
0.0
Palumbo A et al. Blood. 2004;104(part 1):63a [abstract 207]
IFM 99-06 MP vs MP-Thal and MP vs Mel100 in
Newly Diagnosed Myeloma Pts Aged 65­75 Years
Standard MP x 12 courses q6wk
3
Untreated
MP + Thal at MTD or 400
1o Endpoint:
MM
Overall
mg/day, stopped at end of
(65­75 yrs)
2
survival
MP
(N=500)
VADx2
cyclophosphamide 3 g/m2
2
Melphalan 100 mg/m2
All patients received clodronate
Facon T et al. Blood. 2004;104(part 1):63a [abstract 206]
MP vs MP-Thal and MP vs Mel100 in Newly
Diagnosed Myeloma Patients Aged 65­75 Years
IFM 99-06 Trial Response to Treatment*
% of Patients at 12 mo
MP
MP-Thal
MEL100**
Response
(n=153)
(n=95)
(n=92)
3
14
18
Complete response, (%)
90% (%)
8
51
39
50% (%)
34
84
71
*2nd planned interim analysis; Median follow-up time = 24 months
** Only 65% got second transplant
Facon T et al. Blood. 2004;104(part 1):63a [abstract 206]
IFM 99-06 Trial: Adverse Events Overview
Patients with history of DVT were excluded from trial
Incidence of DVT*, n (% of Patients)
MP (n=153)
MP-Thal (n=99) MEL100 (n=92)
8 (5%)
12 (12%)
6 (6.5%)
· No toxic deaths related to DVT
· 36% of patients in MP-Thal arm had peripheral neuropathy
· Hematologic/other adverse events as expected in each arm
*2nd planned interim analysis; Median follow-up time = 24 months
Facon T et al. Blood. 2004;104(part 1):63a [abstract 206]
Intermittent MDT Regimen in Elderly Patients
With Previously Untreated Multiple Myeloma
Melphalan 8 mg/m2 Days 1­4
Dexamethasone 12 mg/m2 D1­4, 14­18
X 3, q5wk
Thalidomide 300 mg Days 1-4, 14-18
PR--61.4%
CR--6.8%
79.2%
Median time to response--2 months
(range 0.5­14 months)
Apparent lower incidence of DVT, neuropathy
Dimopoulos MA et al. Blood. 2004;104(part 1):414a
[#1482] Updated data from oral presentation.
DVd-T for Untreated Myeloma
Pegylated Doxorubicin 40 mg/m2 IV day 1
Vincristine 2 mg IV day 1
Q4wk x 6*
dexamethasone 40 mg po qd × 4
Thalidomide 50­400 mg/day
CR/NCR
46%
Time to best response
4.2 mo
Stable disease
84%
*Prophylactic amoxicillin, acyclovir, ASA, G-CSF; SWOG criteria used to assess response,
NCR=decrease in M protein by >90%
Agrawal NR et al. Blood. 2003;102:237a [abstract 831]
TVED for Untreated MM (n=31)
Vincristine 1.5 mg d1 IV
Epirubicin 30 mg/m2/d d1, 2 IV
q 3wk until
plateau, then
Dexamethasone 20 mg/m2/d d1-5 IV
T alone
Thalidomide 200-400 mg/d PO
Response
n
%
Total
31
CR
6
19
80%
PR
19
61
PD
1
3
Stem cell Collection 20/20, Death 2, Neutropenic fever 33%, DVT 26%,
Neuropathy 16%, Bradycardia 32%, Cytopenia 35%
Schutt et al, Eur J Haematol, 2005
Retrospective Thal-Dex Vs VAD
Dex 40 mg/d po x 4d on d1,9,17 (odd cyc), d1 (even cyc)
AND EITHER
Thal 200 mg/d po* OR Vincristine 0.4 mg/d by CI x 4d
Doxorubicin 9 mg/m2/d by CI x 4d
Total No. Pt.
TD n=100
VAD n=100
CR
10
8
76
52
p.0004
PR
66
44
nCR
3
5
9
6
VGPR
6
1
> PR @ 2 mos
71
59
(% among responsive)
*Thal 100 mg/d x 14d then 200 mg/d
Cavo et al, Blood E Prepub. 3/10/05
Toxicity Retrospective Thal-Dex Vs VAD
Grade 3-4 Toxicity
TD n=100
VAD n=100
DVT
15
2
Granulocytopenia
0
12
Constipation
9
3
Infections
4
5
Death During
6
6
Treatment
Cavo et al, Blood E Prepub. 3/10/05
Stem Cell Collection Retro TD Vs VAD
TD n=100
VAD n=100
No Mobilized
91
91
Med. Days to HD Cy
138
142
Med. CD34+ x 106/kg
7.85
10.5
p.4
Successful collection(%)
83
88
p.3
Med. No. Aphereses
2
2
Cavo et al, Blood E Prepub. 3/10/05
BTD for Untreated MM
T/D
B/T/D
No. patients
130
30
No. response
88 (68%)
24 (80%)
p.18
Thalidomide 200 mg/hs
Dexamethasone 20 mg/m2 p.o. days 1-4, 9-12, 17-20
Bortezomib (mg/m2)
1.1
0/2
64%
1.3
9/12
p.04
1.5
10/10
1.7
4/5
94%
1.9
1/1
Alexanian et al, ASH 2004, 210
Bortezomib-Thalidomide-Dexamethasone
Platelets
Granulocytes
6
200
(K/UL)
(K/UL)
4
count
count
100
Nadir
Nadir 2
1.1 1.3 1.5 1.7 1.9
1.1 1.3 1.5 1.7 1.9
Bortezomib dose (mg/m2)
Thalidomide Combinations for Untreated MM
100
80
OVERALL
60
Response%
DVT
40
NEUROPATHY
SURVIVAL
20
0
TD
MPT
TD
MDT BLT-D TVED
BD PAD LenD B>1.5/TD
Dexa
MP
VAD
Mel 100
D Weber, MD
D Weber, MD
Survival in Myeloma
100
1965-1974
1975-1984
1985-1998
g
1999-2004
inivLt
p<.01
50
nerceP
0
510
15
Years of Treatment
MDs
Data Coordinators
R Alexanian, M Wang
Kim Rankin, Kay Delasalle
Research nurses, PAs
Clinic Nurses
M Gavino, P Sanjorjo
R Alcid, C Samuels, J Song
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