This document summarizes the risk of thrombosis/deep vein thrombosis (DVT) associated with multiple myeloma and its treatments. It finds that the risk of DVT is increased by certain drugs like thalidomide, lenalidomide, and dexamethasone, especially when combined with chemotherapy. Studies show aspirin, low molecular weight heparin, and warfarin can effectively prevent DVT when used as prophylaxis, with aspirin and heparin posing a lower bleeding risk than warfarin. A phase III trial compared aspirin, low dose warfarin, and low molecular weight heparin for DVT prevention in newly diagnosed multiple myeloma patients on thalidomide-containing regimens

2. Preventing Thromboembolism
in Multiple Myeloma
Paul G. Richardson, MD
Associate Professor of Medicine
Harvard Medical School
Clinical Director, Jerome Lipper Center for Multiple Myeloma
Dana-Farber Cancer Institute
Boston, Massachusetts

3. DVT in MM
• Incidence of DVT in MM per se
vs drug-related (IMiDs, Dex, Chemo)
• How does Dex fit into DVT risk?
• How about other drugs?
– Anthracyclines + thalidomide or lenalidomide
• Intensity of anti-coagulation
– ASA vs warfarin vs LMWH

4. Incidence and Prophylaxis of Thrombosis With
Thalidomide-Based Therapies
Rajkumar SV, et al. Mayo Clin Proc. 2005;80:1549-1551.

5. Lenalidomide:
Thrombotic Events
Len / dex
(n = 346)
Placebo / dex
(n = 345)
Thrombotic Events 12% 4%
DVT 8% 3%
PE 3% 1%
DVT = deep vein thrombosis; PE = pulmonary embolism.
• 3 deaths due to thromboembolic events
• Prophylactic anticoagulation was not required in these studies
Dimopoulos M, et al. N Engl J Med. 2010; 357:2123-2132.

6. Thrombotic Risk With Len / Dex and
Erythropoietin
Subset Analysis of MM-009 Trial Data
Subjects With ≥1 Thrombotic Episode
P Value
Epo Non-Epo
Len / Dex 20 / 87 (23%) 4 / 83 (5%) 0.022
Dex 5 / 67 (9%) 1 / 103 (1%) 0.036
Effect of Therapy
P Value
Odds Ratio 95% CI
Len / Dex vs Dex / Placebo 3.51 1.77-6.97 0.0002
Concomitant Epo 3.21 1.72-6.01 0.0066
Efficacy of ASA in MM-009 and MM-010 Trials
Subjects With ≥ 1 Thrombotic Episode
ASA during 1st mo of Tx No ASA
0 / 23 (0%) 52 / 668 (9.1%)
Knight R, et al. N Engl J Med. 2006;354:2079.
Niesvizky R, et al. J Clin Oncol. 2006;24(suppl):423s. Abstract 7506.

7. Thrombotic Risk Factors and
Risk Reduction With
Thalidomide and Lenalidomide
Risk
of DVT
Concomitant
chemotherapy
Use of Epo
Steroiduse
andDose
Antithrombotic
therapy
*ASA is effective with lenalidomide / dexamethasone or thalidomide / dexamethasone combinations.
Knight R, et al. N Engl J Med. 2006;354:2079; Rajkumar SV, et al. N Engl J Med. 2006;354:2080.
Zonder JA, et al. Blood. 2006;108:403; Rajkumar SV and Gertz MA. Blood. 2006;108:404.
Rajkumar SV, et al. Presented at: ASCO Annual Meeting; June 2-6, 2006; Atlanta, GA.
18.2
3.7
0
2
4
6
8
10
12
14
16
18
20
High-Dose Dex
(n=132)
Low-Dose Dex
(n=134)
Thromboembolic events among 266
patients enrolled in ECOG 4A03 as of
11/15/05
Steroid
dose?
ECOG 4A03
%ofPatients
Avoid Epo if possible
Use warfarin or LMWH with Epo
Avoid doxorubicin
In order of
preference:
1. Warfarin
2. LMWH
3. ASA*

8. DVT With Thalidomide in MM
No Prophylaxis With Prophylaxis
Single-Agent < 2-3% _
Thal / Dex 12-26% Low
Thal / Dex+Dox 27-58% 8-15%
Rajkumar SV. Mayo Clin Proc. 2005;80(12):1549-1551.

9. Thalidomide
Induced DVT
Baseline Risk APC Resistance
Endothelial Damage
and Healing
Risk Factors

10. Risk of DVT
Steroid Use and Dose Concomitant Chemotherapy
Antithrombotic
Prophylaxis
Use of Erythropoietin

11. IMiD +/- Steroid Use and Dose
Single agent studies
• Thalidomide
• Lenalidomide
• Addition of high-dose steroids: 18-20%
• Addition of low-dose steroids: 10%
Barlogie B, et al. Blood. 2001;98:492.
List A, et al. N Engl J Med. 2005;352:549.
Richardson P, et al. Blood. 2002;100:3063.
Richardson P, et al. Blood. 2006;108;3458-3464.
Richardson P, et al. Blood. 2009;114;772-778.
0-5%

12. Steroid Use and Dose
ECOG trial
Lenalidomide
plus dex
– 266 pts
– Low dose =
40 mg dex once
a week
Dex Dose and DVT
0
20
40
60
80
100
120
1 2
Treatment Arm
18.2% 3.7%
HD Dex LD Dex
Rajkumar S, et al. N Engl J Med. 2006;354:2080.

13. Risk Adapted Management for VTE
in Patients Receiving IMiDs
Risk Factors Actions
Individual
Obesity
Previous VTE
Central venous catheter or pacemaker 0-1 risk factor is present:
Aspirin 81-325 mg daily
≥ 2 risk factors present:
LMWH
Full dose warfarin (INR 2-3)
Combination Chemo:
LMWH
Full dose warfarin (INR 2-3)
Disease-related
Cardiac disease
Chronic renal disease
Paralysis or immobilization
Surgery
General surgery or trauma
Any anesthesia
Medication
Erythropoietin
Inherited Risk Factors for VTE
Myeloma related risk factors
Newly diagnosed
Hyperviscosity
Palumbo A, et al. Leukemia. 2008;22:414-423.

14. Chemotherapy: Addition of Doxorubicin to
Thalidomide-Based Regimens
Study Pts DVT Rate
Osman et al 15 27%
Zangari et al 87 34%
Baz et al 19 58%
Osman K, et al. N Engl J Med. 2001;344:1951.
Zangari M, et al. Br J Haematol. 2004;126:715-721.
Baz R, et al. Mayo Clin Proc. 2005;80:1568-1574.

15. Chemotherapy: Addition of Melphalan to
Thalidomide
• MPT with no prophylaxis: 20%
Palumbo A, et al. Lancet. 2006;367:825-831.

16. DVT Prophylaxis Options
• Warfarin: clearly effective, clearly more
challenging
– Fixed dose
– Therapeutic dose
• LMWH: Effective, more expensive,
cumbersome
• Aspirin: Baby vs Adult ?
– What is the data?
Antiplatelet Trialists' Collaboration. Br Med J. 1994;308:235-246.
Hansen KE, et al. Blood. 2004;104. Abstract 129.
Palumbo A, et al. Leukemia. 2008;22:414-423.

17. Appropriate Prophylaxis:
VTE Risk Factors
• Central venous line
• Concomitant
chemotherapy (eg,
alkylators)
• Doxorubicin use
• Erythropoietin use
• High-dose
dexamethasone use
• High tumor mass
• Immobilization /
orthopedic procedure
• Ongoing infection /
inflammation
• Older age
• Previous VTE
• Thrombophilia
• Family history
Palumbo A , et al. Leukemia. 2008;22:414-423.

18. Rajkumar SV, et al. Mayo Clin Proc. 2005;80:1549-1551.

19. ASA
Aspirin
100 mg/d
LMWH
Enoxaparin
40 mg/d
WAR
Warfarin
1.25 mg/d
No
prophylaxis
LMWH vs Warfarin vs ASA in Newly Diagnosed MM
Treated With Thalidomide-Containing Regimens*
*A prospective, randomized, GIMEMA phase III trial.
Thalidomide Regimens
VTD – TD – VMPT
Randomize
VMP
• VTD-TD (< 65 yr): 9 wk before ASCT
• VMPT (> 65 yr): 6 mos
Palumbo A, et al. Blood. 2007;110. Abstract 310.

20. LMWH vs Warfarin vs ASA Prophylaxis
for Thalidomide-Containing Regimens
VTE According to Risk Factors
Patients (%)
0 1 2 3 4 5 6
ASA
WAR
LMWH
> 2 risk factors 1 risk factor 0 risk factor
Palumbo A, et al. Blood. 2007;110. Abstract 310.
• Overall incidence of VTE < 10%
• 42% of VTE patients had > 2 risk factors

21. DVT Prophylaxis With LMWH
• MPT with no prophylaxis: 20%
• MPT with LMWH prophylaxis: 3%
Palumbo A, et al. Lancet. 2006;367:825-831.

22. DVT Prophylaxis With ASA
• DVd-T with no prophylaxis: 58%
• DVd-T with aspirin prophylaxis: 19%
Baz R, et al. Mayo Clin Proc. 2005;80:1568-1574.

23. Pulmonary Embolism Prevention (PEP) trial collaborators..Lancet. 2000;355:1295-1302.
The Role of Aspirin in Preventing
Thrombosis: Meta-Analysis

24. Gimema: Italian Myeloma Network
A phase III study of Enoxaparin vs Aspirin vs Low-Dose Warfarin as
Thromboprophylaxis for Newly Diagnosed Myeloma Patients Treated With
Thalidomide-Based Regimens
A. Palumbo1*, M. Cavo2*
, S. Bringhen1, M. Cavalli3
, F. Patriarca3
, D. Rossi3,
P. Tacchetti2
, N. Pescosta3
, C. Crippa3
, M. Galli3
, T. Spadano3
, A.M. Carella3
,
T. Caravita3
, C. Cellini3
, A. Ledda3
, F. Pisani3
, J. Peccatori3
, F. Elice3
, A. Nozza3
,
V. De Stefano3
, L. De Rosa3
, A.M. Liberati3
, F. Ciambelli3
, G. De Sabbata3
,
L. Catalano3
, A. Larocca1
, F. Morabito3
, E. Zamagni2
, M. Offidani3
, P. Tosi2
,
and Mario Boccadoro1
.
1Division of Hematology, University of Torino, A.O.U. San Giovanni Battista, Torino, Italy;
2Seràgnoli Institute of Hematology and Medical Oncology, Bologna University School of
Medicine, Bologna, Italy; 3Italian Multiple Myeloma Network, GIMEMA, Italy.
*First authorship equally shared.

25. Thalidomide Regimens
VTE Incidence Without Any Prophylaxis
Thalidomide Regimens VTE Incidence (%) Ref
Alone 3-4 1,2
+ Dexamethasone 14-26 3-5
+ Melphalan 10-20 6-8
+ Doxorubicin 10-27 9-11
+ Multi-agent chemo 16-34 12,13
1Zangari M, et al. Semin Thromb Hemost. 2003;29:275-282; 2Fox EA, et al. Thromb Haemost. 2005;94:362-365; 3Barlogie B, et al. Blood. 2001;98:492-494;
4Neben K, et al. Clin Cancer Res. 2002;8:3377-3382; 5Schey SA, at al. Leuk Res. 2003;27:909-914; 6Anagnostopoulos A, at al. Br J Haematol. 2003;121:768-
771; 7Palumbo A, at al. Hematol J. 2004;5:318-324; 8Dimopoulos MA, at al. Haematologica. 2006;91:252-254; 9Osman K, at al. N Engl J Med. 2001;344:1951;
10Schutt P, at al. Eur J Haematol. 2005;74:40-46; 11Zervas K, at al. Ann Oncol. 2004;15:134-138; 12Barlogie B, at al. N Engl J Med. 2006;354:1021-1030;
13Zangari M, at al. Blood. 2002;100:1168-1171.

26. Study Design 1
Newly diagnosed MM
(991 patients)
< 65 years > 65 years
Bortezomib V=Bortezomib V=Bortezomib
Thalidomide Thalidomide Melphalan Melphalan
Dexamethasone Dexamethasone Prednisone Prednisone
ThalidomideFollowed by
ASCT
Followed by
ASCT

27. Study Design 2
Thalidomide regimens
VTD – TD – VMPT
Randomize
ASA WAR LMWH
Aspirin Warfarin Enoxaparin
100 mg/day 1.25 mg/day 40 mg/day
• VTD-TD: 9 weeks before ASCT
• VMPT: 6 months

28. Trial Profile
991 patients
assessed for eligibility
67 excluded
38 clear indication for anticoagulant therapy;
26 clear indication for antiplatelet therapy;
2 high-risk of bleeding;
1 other
667 randomized
224 ASA 222 WAR 221 LMWH

29. Patient Characteristics
Risk Factors
ASA
(n = 224)
WAR
(n = 222)
LMWH
(n = 221)
Age (median)
> 65 years
VMPT
TD
VTD
Cardiac Disease
Diabetes
Inherited Conditions
61
29%
29%
36%
35%
16%
5%
N/A
60
27%
28%
37%
35%
22%
4%
N/A
62
29%
20%
35%
36%
17%
4%
N/A

30. Grade 3/4 Thromboembolic Events
0 1 2 3 4 5 6 7 8 9
Patients (%)
ASA
LMWH
WAR
P = 0.17
P = 0.02

31. Time To Onset of Thromboembolic
Events
. at Risk
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0 1 2 3 4 5 6
Months
ASA
WAR
LMWH

32. Grade 3/4 Thromboembolic Events
ASA
(N = 220)
WAR
(N = 220)
LMWH
(N = 219)
Any Thromboembolic
Event
5.9% 8.2% 3.2%
Deep Vein Thrombosis 3.6% 6.4% 2.7%
Pulmonary Embolism 1.8% 1.8% 0%
Arterial Thrombosis 0.5% 0% 0.5%

33. Grade 3/4 Thromboembolic Events
According to MM Therapy
VMPT
TD
VTD
Patients (%)
0 1 2 3 4 5 6 7 8

34. Bleeding Events
ASA
(N = 220)
WAR
(N = 220)
LMWH
(N = 219)
Major Bleeding 1.4%* 0% 0%
Minor Bleeding 2.7% 0.5% 1.4%
Total 4.1% 0.5% 1.4%
*1 urinary track, 2 gastrointestinal.

35. Combined Thrombosis, Bleeding,
C-V Events, and Sudden Deaths
Combined Toxicity
ASA
(N = 220)
WAR
(N = 220)
LMWH
(N = 219)
All Thrombosis 5.9% 8.2% 3.2%
Major Bleeding
Cardio-Vascular
Sudden Deaths
1.4%
0.5%
0.5%
0%
0%
0%
0%
1.4%
0.5%
Cumulative Incidence 8.0% 8.0% 5.0%

36. Time to Onset of Combined Events

37. Time to Onset of Combined Events

38. Multivariate Analysis for Combined Events
Risk factors HR 95% CI P Value
ASA vs LMWH 1.56 0.74-3.32 0.24
WAR vs LMWH 1.67 0.78-3.57 0.18
Age: > 60 vs ≤ 60 years 1.83 0.95-3.35 0.07
Creatinine: ≥ 2 vs < 2 mg/dL 1.67 0.22-12.56 0.62
Co-morbidities: ≥ 2 vs < 2 2.01 0.59-6.86 0.27
Bortezomib: no vs yes 2.12 0.88-5.12 0.09
Intermediate dose DEX: yes / no 1.07 0.55-2.07 0.84

39. Role of Bortezomib in
Preventing Thrombosis
• Reduction of thrombotic risk observed in
randomized trials
• Mechanism unclear (endothelial effects? Effect on
platelet aggregation?)
• Bortezomib + lenalidomide or thalidomide +/- Dex
(RVD, VTD) now a therapeutic backbone in MM with
low rates of thrombosis (5%)
Richardson P, et al. Blood. 2010 April 12. E-pub ahead of print.
Cavo M, et al Blood. 2009;114. Abstract 351.

40. Coagulation Case Challenges in Cancer
Slide unavailable

41. Summary and Conclusion
• Prevention of DVT / PE a key priority
• Newly diagnosed vs relapsed MM
• Risk evaluation
• Choice of combination therapy
• Appropriate prophylaxis
– Aspirin, warfarin, LMWH