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Thalidomide and
Cardiovascular Complications
in Multiple Myeloma
Maurizio Zangari
Myeloma Institute for Research and Therapy
University of Arkansas for Medical Sciences
Little Rock, Arkansas

Thalidomide
(-(N-phthalimido) glutarimide),
synthetic glutamic-acid derivative
Clinical use of thalidomide:
Late 1950s: insomnia, morning sickness in pregnant women, nausea
associated with influenza (never approved in US by FDA).
Teratogenic effects led to market withdrawal in early 1960.
1965: Jacob Sheskin reported efficacy in reducing lesions and
systemic symptoms in a patient with Erythema Nodosum Leprosum
(ENL).
A double blind WHO study confirmed this observation, leading to
approval of thalidomide for moderate to severe cutaneous
complications of ENL.

Thalidomide-related Thrombosis
5 patients with dermatologic diseases (lupus, severe atopic
dermatitis) developed 2 arterial occlusive events and 3
venous thrombotic events.
(Flageul et al, Ann Dermatol Venerol, 2000)
84 relapsing multiple myeloma (MM) patients treated with
escalating doses of thalidomide: < 5% of deep venous
thrombosis (DVT) reported .
(Singhal et al, 1999)
4/15 (27%) of untreated MM patients enrolled in a Phase II
trial with thalidomide, doxorubicin and dexamethasone
developed deep vein thrombosis (DVT).
(Osman et al, NEJM 2001)

Total Therapy II Protocol for Newly
Diagnosed Myeloma Patients
Thalidomide
VAD
DCEP
Randomization
MEL 200
DCEP
Randomization
Interferon
X 2
No
CAD
DCEP/CAD
Thalidomide
DCEP

Incidence of DVT in myeloma
patients treated with thalidomide
and chemotherapy
(n= 122)
(n= 134)

VTE in MGUS and Multiple Myeloma
Srkalovic et al, Cancer 2004

Baseline Hypercoagulable Panel in Newly
Diagnosed MM Patients
Normal Range
n
Median
Min
Max
Abnormal
(%)
anticardiolipin-IgG
<23 GPL
78
4.72
1.02
52.54
2.6
anticardiolipin-IgM
<11 MPL
78
0.9
0.10
5.64
0
activated protein C
>2.0
78
2.18
1.3
2.58
24.3
ratio
ATIII
90-127%
78
99.5
58.0
128.0
32
fibrinogen
197-447 mg/dL
78
361
113
689
67.9
homocysteine
m= <15.5, f= <12
78
9.28
3.86
34.69
21.8
protein C
70-160%
78
106.5
48.0
197.0
8.9
protein S
65-140%
78
76.5
14.0
130.0
26.9
quantative D-dimer
<0.4 mg/dL
78
0.55
0.05
2.83
62.8
Von Willebrand
60-150%
78
150
27
524
48.7
antigen

Baseline Hypercoagulable Panel in Previously
Treated MM Patients
Normal Range
n
Median
Min
Max
Abnormal
(%)
anticardiolipin-IgG
<23 GPL
38
3.37
1.11
37.6
3
anticardiolipin-IgM
<11 MPL
38
0.81
0.17
4.37
0
activated protein C
>2.0
38
2.16
1.55
2.52
13
ratio
ATIII
90-127%
38
91
55
134
45
fibrinogen
197-447 mg/dL
38
351
139
723
68
homocysteine
m= <15.5, f=
38
9.73
3.2
49.96
16
<12
protein C
70-160%
38
103.5
24
257
18
protein S
65-140%
38
64
22
161
53
quantative D-dimer
<0.4 mg/dL
38
0.65
0.07
3.6
71
Von Willebrand
60-150%
38
140
63
349
39
antigen

Activated Protein C Pathway
FXII
FXI
FVII
FIX
FVIIIa
APC
FVa
FX
Thrombin
Fibrinogen
Fibrin

Acquired APC resistance in
cancer patients
ˇ Cancer patients have an increased prevalence of
acquired APC resistance, that is associated with VTE:
54% in cancer patients with VTE and 17% in those
without VTE.
(Haim et al, Am J Med 2001)
ˇ Significant increased incidence of acquired resistance
to APC was found in women with breast cancer
compared to healthy subjects (P< 0.001).
(Nijziel et al, BJH 2003)

APC Resistance in Multiple Myeloma
Patients
1137 myeloma patients were tested for APC resistance
(2nd generation assay):
2/3: no mutation
97 pts (8.5%)
with APC< 2
1/3: FV Leiden

Incidence of DVT by Acquired
APC Status
1
P = 0.04
0.8
DVT
Normal APC:
n=48
0.6
Abnormal APC:
n=14
0.4
i
ve Incidence of
0.2
Cumulat
0
0
6
12
18
24
30
36
42
weeks after VAD
Zangari et al, Blood Coagul Fibrinolysis 2002

Transient Nature of Aquired APC
Resistance in Myeloma Patients
24 patients repeated APC ratio test:
23 pts (no mutation)
APC normalized
1 pt (no mutation)
APC still abnormal

Incidence of DVT in myeloma
patients with FV Leiden mutation
27 myeloma patients heterozygous
for FV Leiden mutation
8 DVT (30%)
4 patients treated
4 patients treated
with Thalidomide
without
Thalidomide

Cumulative Incidence of DVT in 535 Patients
Enrolled on Thalidomide-containing Protocols
50%
1-Year
Events / N Estimate
All Patients
82 / 535
15%
40%
30%
20%
10%
0% 0
12
24
36
48
60
Months After Starting Therapy
(Zangari et al, Clin Lymphoma 2003)

Multivariate Odds of Developing DVT
(n=535)
OR (95% CI)
P-value
Thalidomide + Adriamycin
4.3 (2.0, 9.2)
<0.001
Newly Diagnosed MM
2.5 (1.4, 4.3)
0.001
Chromosome 11 Abnormality
1.8 (1.0, 3.1)
0.048
(Zangari et al, Clin Lymphoma 2003)

Thalidomide and Adriamycin Effect on
DVT Incidence
N = 192
N = 40
(Zangari et al, Blood 2002)

Incidence of DVT in thalidomide-treated
myeloma patients without prophylaxis
Regimen
Incidence
Patients
Reference
of VTE
Thal 200-800 mg
3% - 4%
Newly
Weber et al, 2002
diagnosed
Rajkumar et al, 2003
Thal 100-400 mg +
18% - 26% Newly
Cavo et al, 2002
dexamethasone
diagnosed
Rajkumar, ASH 2004
Thal + doxo-containing
26% - 34% Newly
Zangari et al, 2004
chemotherapy
diagnosed
Thal 100-800 mg
< 2% - 3%
Relapsed or
Barlogie et al, 2001
refractory
Tosi et al, 2002
Kumar et al, 2003
Thal 100-400 mg +
2% - 7%
Relapsed or
Palumbo, 2004
dexamethasone
refractory
Dimopoulos, 2001
Thal + chemotherapy
4.2%
Relapsed or
Moehler, ASH 2002
without doxorubicin
refractory
(CED)
Thal + doxo-containing
16%
Relapsed or
Zangari et al, 2002
chemotherapy (DT-PACE)
refractory

Thrombosis and Survival in Cancer
Patients with cancer and primary venous thromboembolism may have
a worse prognosis than cancer patients without thrombosis.
In a group of 668
patients with
cancer at the
same time of
VTE, 12% were
alive after one
year as
compared to 36%
in the control
group (P < 0.001)
(Sorensen et al, NEJM 2000)

Overall Survival and Thalidomide-related
DVT in Newly Diagnosed MM Patients
100%
80%
60%
40%
3-Year
20%
Deaths / N
Estimate
No DVT within 6 months
13 / 79
81% (72,91)
DVT within 6 months
5 / 35
80% (62,97)
Logrank P-value = .74
0% 0
12
24
36
48
Months from 6-Month Landmark

Total Therapy II (TTII) Schema
Thalidomide
VAD
DCEP
Randomization
MEL 200
DCEP
Randomization
Interferon
X 2
No
CAD
DCEP/CAD
Thalidomide
DCEP

Newly Diagnosed Multiple Myeloma
Patients enrolled on Total Therapy II
n=256
Cohort I
Cohort II
Cohort III
(No anticoagulation)
(Coumadin prophylaxis)
n = 130
n =221
n = 35
Chemotherapy
Chemotherapy +Thal
Chemotherapy + Thal +
Chemotherapy +
Chemotherapy
n = 134
n = 87
Coumadin
Thal + LMWH
n = 62
n = 35
n = 68
DVT
DVT
n = 19
DVT
n = 30 (34%)
DVT
DVT
n = 11 (31%)
n =10
n = 9
19 DVT
DVT = 41
Continue Treatment
+ Anticoagulant
36 DVT
Continue Treatment
Thalidomide Resumed
DVT
+ Anticoagulant
Recurrence
n = 1 (5%)
DVT Recurrence
n = 4 (11%)
(Zangari et al, BJH 2004)

Coumadin Effect on DVT
0.4
n=35
0.3
n=221
0.2
No Coumadin
Coumadin
Log-rank P = 0.7
0.1
Cumulative DVT Incidence
0
0
3
6
9
12
15
18
21
24
27
30
Months After VAD

Thromboprophylaxis with LMWH
in the Total Therapy II protocol
ˇ Patients randomized to thalidomide
received Lovenox 40 mg daily for the
entire duration of the induction phase.
ˇ Lovenox was continued till platelets
<30,000/ľl and resumed when platelets
50,000/ľl.

Newly Diagnosed Multiple Myeloma
Patients enrolled on Total Therapy II
n=256
Cohort I
Cohort II
Cohort III
(No anticoagulation)
(Coumadin prophylaxis)
n = 130
n =221
n = 35
Chemotherapy
Chemotherapy +Thal
Chemotherapy + Thal +
Chemotherapy +
Chemotherapy
n = 134
n = 87
Coumadin
Thal + LMWH
n = 62
n = 35
n = 68
DVT
DVT
DVT
n = 19
n = 30
DVT
n = 11
DVT
n =10 (15%)
n = 9
19 DVT
DVT = 41
Continue Treatment
+ Anticoagulant
36 DVT
Continue Treatment
Thalidomide Resumed
DVT
+ Anticoagulant
Recurrence
n = 1 (5%)
DVT Recurrence
n = 4 (11%)
(Zangari et al, BJH 2004)

Effect of LMWH on DVT incidence

HOVON-50/GMMH-HD3 study
ˇ Phase III multicenter study with upfront randomization to:
VAD: vincristine (0.4 mg i.v. days 1-4), doxorubicin and dex (n = 201)
or
TAD: thalidomide (200-400 mg/d), doxorubicin and dex (n = 211)
ˇ LMWH nadroparin (2850 IE anti-Xa or 5700 anti-Xa in case of weight
above 90 kg) was prophylactically given to the TAD arm throughout
the induction phase of the protocol.
(Minnema et al, Leukemia 2004)

Effect of LMWH on DVT incidence
AD +thal + LMWH
VTE incidence
Time from randomization to VTE
(Minnema et al, Leukemia 2004)

DVT Recurrence on Thalidomide
treatment
ˇ In a population of patients with active cancer, recurrence
rate of VTE after the first acute event was 17% with oral
anticoagulant prophylaxis and 9% with dalteparin
prophylaxis.
(Lee et al, NEJM 2003)
ˇ Myeloma patients enrolled in the Total Therapy II
protocol, cumulative follow-up 792 months:
5% recurrence rate in the non-thalidomide arm
13.8% recurrence rate in patients who resumed
thalidomide while on oral anticoagulation.
(Zangari et al, BJH 2004)

Strategies for Thromboprophylaxis in
Thalidomide Treated MM Patients
Aspirin
Warfarin
Warfarin
Therapy
No prophylaxis
LMWH
(81
1mg/daily
(INR 2-3)
mg/d)
25% Weber,
26% Cavo, 2002 (19 pts)
T+D in newly
2002 (24 pts)
7% Weber,
diagnosed
2002
18% Rajkumar, 2004
patients
13%
(46 pts)
Cavo, 2004
(102 pts)
(52 pts)
15% Zangari,
T+dox in
2004 (68 pts)
newly
34% Zangari, 2004 (87
31% Zangari,
18%
diagnosed
pts)
2004 (35 pts)
7% Minnema, Baz,
patients
2004 (412 pts) 2004
(103 pts)
T+dox at
16% Zangari, 2002 (192
relapse
pts)

Thalidomide and Sinus Bradycardia
Regimen
Reference
Incidence of bradycardia
Singhal, 1999; 84 pts
6%
Thalidomide
Kumar, 2003; 32 pts
6% grade 3-4
single agent
Rajkumar, 2003; 29 pts
23% grade 1-2; 3% grade 3-4
Thal +
2% gr. 3-4 arrhythmia
dexamethasone
Rajkumar, 2002; 50pts
53% with < 60 beats per minute
Fahdi, 2004; 200 pts
4% with 30 beats per minute
Thal +
chemotherapy
16% with 50-60 beats per minute
Schütt, 2005; 31 pts
13% with 40-50 beats per minute
3.2% with < 40 beats per minute
Post-marketing
Clark, 2001
0.12%
surveillance

Effect of thalidomide on bradycardia
during the treatment for multiple myeloma
200 patients enrolled in the Total Therapy II protocol
were analyzed:
96 pts. received thalidomide
104 pts. did not receive thalidomide
No significant difference in gender, race, prevalence of
cardiac risk factors, diabetes and cardiac medications
between the two groups.
Fahdi et al, Am J Cardiol 2004

Bradycardia in Total Therapy II
No thalidomide
Thalidomide

Bradycardia in Total Therapy II
ˇ Overall incidence of bradycardia in the thalidomide
group: 53%, grade 2: 19%
ˇ 5 pts. (2.5%) in the thalidomide group required
pacemaker implantation.
ˇ No statistically significant difference in the PR
interval, QRS duration and QTc interval between the
two groups.
ˇ No correlation between development of bradycardia
and use of -blockers, digoxin, calcium channel
blockers.
Fahdi et al, Am J Cardiol 2004

Conclusions
Development of thromboembolism in multiple
myeloma is multifactorial.
In patients receiving thalidomide, newly diagnosed
status and thalidomide/doxorubicin combination
are the most important factors associated with
VTE.
Prophylaxis with LMWH can abrogate the
increased incidence of DVT observed with
thalidomide/chemotherapy combinations.

Conclusions
Perturbance in the Protein C function is common
in multiple myeloma patients and is associated
with venous thromboembolism.
In myeloma patients treated with a thalidomide
containing regimen, the development of DVT
does not appear to affect overall survival.