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

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

Incidence and Prophylaxis of Thrombosis With

Thalidomide-Based Therapies

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

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.

Thrombotic Risk With Len / Dex and

ErythropoietinSubset Analysis of MM-009 Trial Data

Subjects With ≥1 Thrombotic EpisodeP 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 TherapyP 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.

Thrombotic Risk Factors and

Risk Reduction With

Thalidomide and Lenalidomide

Risk

of DVT

Concomitant

chemotherapy

Use of Epo

Ste

roid

us

e

an

d D

os

e

An

tith

rom

bo

tic

the

rap

y

*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

3.70

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

% o

f P

ati

en

ts

Avoid Epo if possible

Use warfarin or LMWH with Epo

Avoid doxorubicin

In order of

preference:

1. Warfarin

2. LMWH

3. ASA*

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.

Thalidomide

Induced DVT

Baseline Risk APC Resistance

Endothelial Damage

and HealingRisk Factors

Risk of DVT

Steroid Use and Dose Concomitant Chemotherapy

Antithrombotic

ProphylaxisUse of Erythropoietin

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%

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.

Risk Adapted Management for VTE

in Patients Receiving IMiDsRisk 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.

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.

Chemotherapy: Addition of Melphalan to

Thalidomide

• MPT with no prophylaxis: 20%

Palumbo A, et al. Lancet. 2006;367:825-831.

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.

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.

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

ASAAspirin

100 mg/d

LMWHEnoxaparin

40 mg/d

WARWarfarin

1.25 mg/d

Noprophylaxis

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.

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

DVT Prophylaxis With LMWH

• MPT with no prophylaxis: 20%

• MPT with LMWH prophylaxis: 3%

Palumbo A, et al. Lancet. 2006;367:825-831.

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.

Pulmonary Embolism Prevention (PEP) trial collaborators..Lancet. 2000;355:1295-1302.

The Role of Aspirin in Preventing

Thrombosis: Meta-Analysis

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.

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.

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

Thalidomide Followed by

ASCT

Followed by

ASCT

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

Trial Profile

991 patients

assessed for eligibility

67 excluded38 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

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

Grade 3/4 Thromboembolic Events

0 1 2 3 4 5 6 7 8 9Patients (%)

ASA

LMWH

WAR

P = 0.17

P = 0.02

Time To Onset of Thromboembolic

Events

ASA

WAR

LMWH

No. at Risk

220 216 211 206 205 204 204

220 218 211 206 200 197 197

219 217 215 213 210 208 208

0.00

0.05

0.10

0.15

0.20

0.25

0.30

Cu

mul

ativ

e In

cide

nce

0 1 2 3 4 5 6Months

ASA

WAR

LMWH

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%

Grade 3/4 Thromboembolic Events

According to MM Therapy

VMPT

TD

VTD

Patients (%)

0 1 2 3 4 5 6 7 8

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.

Combined Thrombosis, Bleeding,

C-V Events, and Sudden Deaths

Combined ToxicityASA

(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%

Time to Onset of Combined Events

Time to Onset of Combined Events

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

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.

Coagulation Case Challenges in Cancer

Slide unavailable

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