Conditions: Venous Thromboembolism Multiple Myeloma
Keywords: venous thromboembolism multiple myeloma anticoagulation
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 50
Healthy volunteers: no

Brief summary:
Patients living with multiple myeloma (MM) have an increased risk of venous thromboembolism (VTE) due to the disease itself and the use of targeted therapies, including immunomodulatory drugs (IMiDs). Prevention of VTE has become a major management challenge during MM treatment. There is a paucity of data with respect to the non-vitamin K oral anticoagulants (NOACs) in the cancer population. However, the NOACs offer comparable efficacy but improved safety compared with warfarin. Apixaban has shown excellent safety and efficacy for treatment and prevention of recurrent VTE (1,2). The safety and efficacy of apixaban for primary prevention of VTE in MM patients has not been established.

Aim #1: To quantify the 6-month rate of major and clinically relevant non-major bleeding in MM patients receiving IMiDs who are prescribed apixaban 2.5 mg orally twice daily for primary prevention of VTE.

Hypothesis #1: The 6-month rate of major and clinically relevant non-major bleeding in MM patients receiving IMiDs who are prescribed apixaban 2.5 mg orally twice daily for primary prevention of VTE will be ≤3% (2). Although the MM population, in general, has a higher medical acuity than that of the previous large randomized controlled trials of apixaban, we will be selecting a stable population of MM patients who are appropriate for immunomodulatory therapy.

Aim #2: To quantify 6-month rate of symptomatic VTE in MM patients receiving IMiDs who are prescribed apixaban 2.5 mg orally twice daily for primary prevention of VTE.

Hypothesis #2: The 6-month rate of symptomatic VTE in MM patients receiving IMiDs who are prescribed apixaban 2.5 mg orally twice daily for primary prevention of VTE will be \<7% (3). Although additional therapies for MM such as dexamethasone and erythropoietin-stimulating agents may further increase the risk of VTE, the rate of incident VTE should be reduced to \<7% with apixaban.

Detailed description:
MM is associated with an increased risk of venous thromboembolism (VTE). The use of targeted therapies, including immunomodulatory drugs (IMiDs), has improved outcomes for patients with MM but also increases the risk of VTE. Prevention of VTE has become a major management dilemma during MM treatment. There is a paucity of data with respect to the non-vitamin K oral anticoagulants (NOACs) in the cancer population, including patients with MM. However, the NOACs have been shown to offer comparable efficacy but improved safety compared with warfarin. Apixaban has shown excellent safety and efficacy for treatment and prevention of recurrent VTE (1,2). Compared with injectable thromboprophylactic regimens such as enoxaparin, apixaban offers the advantages of being orally administered and less reliant on renal clearance. The safety and efficacy of apixaban for primary prevention of VTE in MM patients has not been established. The current study will evaluate apixaban (2.5 mg twice daily) in a patient population without a history of prior VTE. Although the current study population is high risk for VTE, it is likely to be lower risk for VTE than those of the prior randomized controlled trials of apixaban for secondary prevention. Furthermore, current practice is to provide MM patients receiving IMiDs with prophylactic doses (not treatment doses) of low-molecular weight heparin (such as enoxaparin 40 mg injected daily). Accordingly, the rationale to test apixaban (2.5 mg twice daily) is consistent with the standard practice of prophylactic anticoagulation.

The current study will provide event rates that will inform the design of a larger randomized controlled trial. If safe and effective, apixaban will satisfy a critical unmet need and will represent a substantial advance and "game changer" in the prevention of VTE in this high risk patient population.

Arms:
arm 1: apixaban 2.5 mg orally twice daily for primary prevention of VTE for a duration of 6 months

Interventions: intervention 1: Apixaban
Intervention descriptions: intervention 1: apixaban 2.5 mg orally twice daily for primary prevention of VTE for a duration of 6 months

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
Apixaban for Primary Prevention of Venous 
Thromboembolism in Patients with Multiple Myeloma 
Receiving Immunomodulatory Therapy 
 
Version 17.0 
 
Protocol Version Date: November 8, 2017 
 
 
 
 
 
 
 
Gregory Piazza, MD, MS 
Brigham and Women’s Hospital 
Cardiovascular Division 
75 Francis Street 
Boston, MA 02115 
(617) 732-6984 (Phone) 
(617) 738-7652 (Fax) 
gpiazza@partners.org 
 
 
 
 
 
 
 
 
 


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Protocol Version Record 
 
Version 1.0 
January 25, 2016 
Version 2.0 
January 26, 2016 
Version 3.0 
January 31, 2016 
Version 4.0 
February 2, 2016 
Version 5.0 
February 14, 2016 
Version 6.0 
March 4, 2016 
Version 7.0 
March 7, 2016 
Version 8.0 
April 8, 2016 
Version 9.0 
April 19, 2016 
Version 10.0 
April 24, 2016 
Version 11.0 
April 26, 2016 
Version 12.0 
May 16, 2016 
Version 13.0 
June 26, 2017 
Version 14.0 
July 30, 2017 
Version 15.0 
Version 16.0 
October 9, 2017 
October 26, 2017 
Version 17.0 
November 8, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
 
 
Section 
Page 
Protocol Summary   
4 
Study Flow Diagram  
5 
Abbreviations and Definitions 
6 
Study Contacts  
7 
Specific Aims 
9 
Introduction and Background 
10 
Rationale for the Proposed Study 
12 
Study Objectives 
12 
Study Design 
13 
Study Duration 
13 
Study Population 
13 
Study Inclusion Criteria 
13 
Study Exclusion Criteria 
14 
Screening Procedures 
15 
Treatment Description 
16 
Safety Outcomes 
16 
Efficacy Outcomes 
17 
Follow-up 
18 
Assessment and Reporting of Adverse 
Events 
18 
Data Reporting, Processing, and 
Quality Control 
23 
Statistical Methods 
25 
Investigator Responsibilities 
26 
Feasibility  
28 
Potential Risks and Benefits 
29 
Ethical Considerations 
31 
References 
33 
Case Report Form 
34 
Appendix  
45 
 
 
 
 
 
 


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Protocol Summary 
 
Title:   
Apixaban for Primary Prevention of Venous Thromboembolism in 
Patients with Multiple Myeloma Receiving Immunomodulatory Therapy 
 
 
Design: 
U.S.-based, single-center, single-arm, open-label, proof-of-concept 
study 
 
 
Brief Treatment Description: 
Direct anti-factor Xa inhibition with apixaban 
2.5 mg orally twice daily for primary prevention of VTE 
 
 
Purpose: 
To determine the rate of major and clinically relevant non-major 
bleeding and the rate of symptomatic VTE in MM patients on immunomodulatory 
drugs (IMiDs) who are receiving apixaban 2.5 mg orally twice daily. This study 
will provide event rates that could inform the design of a larger randomized 
controlled trial. 
 
 
Population: Outpatients with MM receiving IMiDs (i.e., thalidomide [Thalomid], 
lenalinomide [Revlimid], and pomalidomide [Pomalyst]). 
 
 
Enrollment: 50 subjects  
 
 
Clinical Site Locations: 1 center (Vanderbilt University Medical Center) 
 
 
Study Duration: 
22 months; enrollment period of up to 16 months with 6-
month follow-up. 
 
 
Primary Safety and Efficacy Outcomes: 
 
 
Primary Safety Outcome:   The 6-month rate of International Society on 
Thrombosis and Haemostasis major and clinically relevant non-major bleeding in 
MM patients receiving IMiDs who are prescribed apixaban 2.5 mg orally twice 
daily for primary prevention of VTE. 
 
Secondary Safety Outcome:  All-cause mortality at 6 months will be recorded.  
Cause of death will be classified as related to cancer, myocardial infarction, PE, 
or other disease state.   
 


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Primary Efficacy Outcome:  The 6-month rate of symptomatic VTE in MM 
patients receiving IMiDs who are prescribed apixaban 2.5 mg orally twice daily 
for primary prevention of VTE. 
 
 
Secondary Efficacy Objectives:  The 6-month rate of myocardial infarction and 
stroke will also be calculated. 
 
Follow-Up:  Follow-up will consist of Electronic Health Record review at 6-
months from study enrollment. 
 
 
Study Flow Diagram 
 
 
 
IMiDs, immunomodulatory drugs; VTE, venous thromboembolism 
 
 
 
 
 
 
 
 


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Abbreviations and Definitions 
 
Listed in alphabetical order 
 
DVT, deep vein thrombosis 
 
eCRF, electronic case report form 
 
IMiDs, immunomodulatory drugs (i.e., thalidomide [Thalomid], lenalinomide 
[Revlimid], and pomalidomide [Pomalyst]) 
 
ISTH, International Society on Thrombosis and Haemostasis 
 
LMWH, low-molecular weight heparin 
 
MM, multiple myeloma 
 
NOACs, non-vitamin K oral anticoagulants 
 
PE, pulmonary embolism 
 
PI, Proteasome inhibitors 
 
SAE, significant adverse event 
 
UADE, unanticipated adverse drug effect  
 
VTE, venous thromboembolism 
 
 
 
 
 
 
 
 
 
 
 


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Study Contacts 
 
Study Coordinating 
Center Principal 
Investigator: 
 
Gregory Piazza, MD, MS 
Brigham and Women’s Hospital 
75 Francis Street  
Boston MA  02115 
Phone: (617) 732-6984 
Fax: (617) 738-7652 
Email: gpiazza@partners.org 
 
Study Coordinating 
Center Co-Principal 
Investigator: 
 
Samuel Z. Goldhaber, MD 
Brigham and Women’s Hospital 
75 Francis Street  
Boston MA  02115 
Phone: 857-307-1932 
Fax: (857) 307-1955 
Email: sgoldhaber@partners.org  
 
Study Enrollment 
Center Principal 
Investigators: 
 
Javid Moslehi, MD 
Vanderbilt University Medical Center 
2220 Pierce Avenue 
Nashville, TN 37232 
Phone: (615) 322-2318 
Fax: (615) 936-6414 
Email: javid.moslehi@vanderbilt.edu  
 
R. Frank Cornell, MD, MS 
Division of Hematology and Oncology 
Vanderbilt University Medical Center 
777 Preston Research Building 
Nashville, TN 37232 
Office: (615) 936-8422 
Fax: (615) 936-1812 
Email: robert.f.cornell@vanderbilt.edu  
 
Clinical Trial 
Monitoring 
Lindsay Harrigan, BS 
Thrombosis Research Group 
1620 Tremont Street 


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Boston, MA  02115 
Phone: (617) 732-6984 
Fax: (617) 738-7652 
Email: lharrigan@partners.org  
 
Data Coordinating 
Center: 
 
Lindsay Harrigan, BS 
Thrombosis Research Group 
1620 Tremont Street 
Boston, MA  02115 
Phone: (617) 732-6984 
Fax: (617) 738-7652 
Email: lharrigan@partners.org   
 
Study Safety 
Monitor: 
 
Dale Adler, MD 
Cardiovascular Division 
Brigham and Women’s Hospital 
Boston, MA 02115 
Phone: (617) 525-8359 
Fax: (617) 732-7170 
Email: DADLER2@PARTNERS.ORG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Specific Aims 
 
Patients living with multiple myeloma (MM) have an increased risk of venous 
thromboembolism (VTE) due to the disease itself and the use of targeted 
therapies, including immunomodulatory drugs (IMiDs).  Prevention of VTE has 
become a major management challenge during MM treatment. There is a paucity 
of data with respect to the non-vitamin K oral anticoagulants (NOACs) in the 
cancer population.  However, the NOACs offer comparable efficacy but improved 
safety compared with warfarin.  Apixaban has shown excellent safety and 
efficacy for treatment and prevention of recurrent VTE (1,2).  The safety and 
efficacy of apixaban for primary prevention of VTE in MM patients has not been 
established.   
 
Aim #1:  To quantify the 6-month rate of major and clinically relevant non-major 
bleeding in MM patients receiving IMiDs who are prescribed apixaban 2.5 mg 
orally twice daily for primary prevention of VTE. 
 
Hypothesis #1:  The 6-month rate of major and clinically relevant non-major 
bleeding in MM patients receiving IMiDs who are prescribed apixaban 2.5 mg 
orally twice daily for primary prevention of VTE will be ≤3% (2).  Although the MM 
population, in general, has a higher medical acuity than that of the previous large 
randomized controlled trials of apixaban, we will be selecting a stable population 
of MM patients who are appropriate for immunomodulatory therapy. 
 
Aim #2:  To quantify 6-month rate of symptomatic VTE in MM patients receiving 
IMiDs who are prescribed apixaban 2.5 mg orally twice daily for primary 
prevention of VTE. 
 
Hypothesis #2:  The 6-month rate of symptomatic VTE in MM patients receiving 
IMiDs who are prescribed apixaban 2.5 mg orally twice daily for primary 
prevention of VTE will be <7% (3).  Although additional therapies for MM such as 
dexamethasone and erythropoietin-stimulating agents may further increase the 
risk of VTE, the rate of incident VTE should be reduced to <7% with apixaban. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Introduction and Background 
 
Multiple myeloma (MM) is a plasma cell malignancy characterized by clonal 
proliferation of malignant plasma cells in the bone marrow microenvironment, 
monoclonal protein in the blood or urine, and associated organ dysfunction (4). 
Overall survival has improved due to the advent of novel targeted therapies, 
including immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs).  As 
with other hematological malignancies, MM is associated with an increased risk 
of venous thromboembolism (VTE).  The risk of VTE is further increased in the 
setting of IMiDs.  Currently used IMiDs include thalidomide (Thalomid), 
lenalinomide (Revlimid), and pomalidomide (Pomalyst).  A meta-analysis of more 
than 3000 MM patients showed that the risk of VTE increased nearly 3-fold when 
the IMiD thalidomide was prescribed and nearly 8-fold when thalidomide was 
combined with other chemotherapeutics (5).  The risk of VTE is amplified when 
IMiDs are combined with a novel proteasome inhibitor, carfilzomib, that was 
recently approved by the U.S. Food and Drug Administration (6).  Due to the 
increasing use of IMiD-based regimens, prevention of VTE has become a major 
management challenge during MM treatment (Table 1) (7).  A systematic 
analysis of MM patients treated with IMiDs, especially in combination with other 
therapies, shows that VTE risk remains an important complication in this 
population (Piazza G and Moslehi J, unpublished data).   
 
 
Table 1. VTE incidence in IMiDs trials (7). 
 
Treatment Regimen 
VTE incidence (%) 
without 
thromboprophylaxis 
VTE incidence (%) with 
thromboprophylaxisa 
Thalidomide 
 
 
Alone 
2-10 
NA 
Plus dexamethasone  
2-26 
8-25 
Plus chemotherapyb 
3-58 
3-31 
Lenalidomide 
 
 
Alone 
0-33 
NA 
Plus dexamethasone  
8-75 
3-14 
Plus chemotherapyb 
14 
5-9 
Pomalidomide 
 
 
Alone 
NA 
2 
Plus dexamethasone 
NA 
2-5 
VTE, venous thromboembolism; NA, not applicable 
aAspirin (81-325mg daily), low molecular weight heparin (LMWH), fixed warfarin 
(1-1.25mg daily) and full-dose of warfarin (target INR 2-3) have been used for 
prophylaxis. Choice of thromboprophylaxis was largely based on physicians’ 
discretion.   
 


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bThalidomide and lenalidomide were used in combination with other therapeutic 
agents, including melphalan, doxorubicin and cyclophosphamide.  
 
 
MM patients also have a higher risk of arterial thromboembolic events, including 
myocardial infarction and stroke (7).  IMiDs also appear to increase the risk for 
arterial thromboembolic events.  In the long-term follow-up of 704 MM patients in 
two phase 3, randomized clinical trials, the frequency of myocardial infarction and 
cerebrovacular events were 1.98% and 3.4%, respectively, in patients treated 
with lenalidomide and dexamethasone compared with 0.57% and 1.7%, in 
patients treated with dexamethasone alone (https://www.gov.uk/drug-safety-
update/lenalidomide-risk-of-thrombosis-and-thromboembolism).  Lenalidomide 
carries a black box warning of significant myocardial infarction and stroke risks in 
MM patients receiving lenalidomide and dexamethasone treatment. 
 
Currently, there are no guidelines regarding the optimal thromboprophylactic 
regimen for MM patients receiving IMiDs.  A broad-based VTE prevention 
guideline for cancer patients is too general to be of practical use in MM patients 
(8).  In the case of MM, aspirin (81-325 mg daily), low-molecular weight heparin 
(LMWH), and warfarin (target INR 2-3) have all been prescribed for VTE 
prophylaxis.  However, the specific prophylactic regimen is ultimately based on 
the treating clinician’s best clinical judgment (7,9).  The choice of VTE 
prophylaxis is further complicated due to frequent renal dysfunction in MM 
patients.  Furthermore, these patients are often reluctant to undertake an 
extended duration prophylactic LMWH regimen of daily self-injections due to 
anxiety and injection-site discomfort.  An unintended consequence of LMWH 
injections is that injectable prophylactic anticoagulant regimens are associated 
with decreased medication adherence (10).   
 
There is a paucity of data with respect to the non-vitamin K oral anticoagulants 
(NOACs) in the cancer population.  However, the NOACs have been shown to 
offer comparable efficacy but improved safety compared with warfarin.  Apixaban 
has shown excellent safety and efficacy for treatment and prevention of recurrent 
VTE (1,2).   
 
In a randomized, double-blind study (AMPLIFY), apixaban (administered as a 
loading dose of 10 mg twice daily for 7 days, followed by 5 mg twice daily) was 
compared with subcutaneously-administered enoxaparin followed by warfarin in 
5395 patients with acute venous thromboembolism (1).  The primary efficacy 
outcome of recurrent symptomatic VTE or VTE-related death occurred in 59 of 
2609 patients (2.3%) in the apixaban group compared with 71 of 2635 (2.7%) in 
the warfarin group (relative risk, 0.84; 95% confidence interval [CI], 0.60 to 1.18; 
p < 0.001 for non-inferiority).  Major bleeding occurred in 0.6% of patients who 
received apixaban and in 1.8% of those who received warfarin (relative risk, 0.31; 
95% CI, 0.17 to 0.55; p<0.001 for superiority).  A composite outcome of major 
bleeding and clinically relevant nonmajor bleeding occurred in 4.3% of the 


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patients in the apixaban group compared with 9.7% of those in the conventional-
therapy group (relative risk, 0.44; 95% CI, 0.36 to 0.55; p<0.001).  
 
In the randomized, double-blind AMPLIFY-EXT study, two doses of apixaban 
(2.5 mg and 5 mg, twice daily) were compared with placebo in patients with VTE 
who had completed 6 to 12 months of anticoagulation therapy and for whom 
there was clinical equipoise regarding the continuation or cessation of 
anticoagulation therapy (2).  A total of 2486 patients underwent randomization.  
Symptomatic recurrent venous thromboembolism or death from venous 
thromboembolism occurred in 73 of the 829 patients (8.8%) who were receiving 
placebo versus 14 of the 840 patients (1.7%) who were receiving 2.5 mg of 
apixaban and 14 of the 813 patients (1.7%) who were receiving 5 mg of apixaban 
(p<0.001 for both comparisons). The rate of major and clinically relevant non-
major bleeding in patients receiving apixaban 2.5 mg orally twice daily for 
extended-duration prevention of recurrent VTE was similar to that of placebo.   
 
Though the stroke prevention in atrial fibrillation population is different, the 
AVERROES Trial also demonstrated the strong safety profile of apixaban, which 
had the same major bleeding rate as aspirin (11).   
 
 
Rationale for the Proposed Study 
 
MM is associated with an increased risk of venous thromboembolism (VTE).  The 
use of targeted therapies, including immunomodulatory drugs (IMiDs), has 
improved outcomes for patients with MM but also increases the risk of VTE.  
Prevention of VTE has become a major management dilemma during MM 
treatment. There is a paucity of data with respect to the non-vitamin K oral 
anticoagulants (NOACs) in the cancer population, including patients with MM.  
However, the NOACs have been shown to offer comparable efficacy but 
improved safety compared with warfarin.  Apixaban has shown excellent safety 
and efficacy for treatment and prevention of recurrent VTE (1,2).  Compared with 
injectable thromboprophylactic regimens such as enoxaparin, apixaban offers the 
advantages of being orally administered and less reliant on renal clearance.  The 
safety and efficacy of apixaban for primary prevention of VTE in MM patients has 
not been established.  The current study will evaluate apixaban (2.5 mg twice 
daily) in a patient population without a history of prior VTE.  Although the current 
study population is high risk for VTE, it is likely to be lower risk for VTE than 
those of the prior randomized controlled trials of apixaban for secondary 
prevention.  Furthermore, current practice is to provide MM patients receiving 
IMiDs with prophylactic doses (not treatment doses) of low-molecular weight 
heparin (such as enoxaparin 40 mg injected daily).  Accordingly, the rationale to 
test apixaban (2.5 mg twice daily) is consistent with the standard practice of 
prophylactic anticoagulation. 
 


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The current study will provide event rates that will inform the design of a larger 
randomized controlled trial.  If safe and effective, apixaban will satisfy a critical 
unmet need and will represent a substantial advance and “game changer” in the 
prevention of VTE in this high risk patient population. 
 
 
Study Objectives 
 
 
Primary Safety Objective:  To quantitatively assess the 6-month rate of major 
and clinically relevant non-major bleeding in MM patients receiving IMiDs who 
are prescribed apixaban 2.5 mg orally twice daily for primary prevention of VTE. 
 
Primary Efficacy Outcome:  To quantitatively assess the 6-month rate of 
symptomatic VTE in MM patients receiving IMiDs who are prescribed apixaban 
2.5 mg orally twice daily for primary prevention of VTE. 
 
Secondary Efficacy Outcome:  To quantitatively assess the 6-month rate of 
myocardial infarction and stroke. 
 
 
Study Design 
 
50-patient U.S.-based, single-center, single-arm, open-label, proof-of-concept 
study of apixaban 2.5 mg orally twice daily for primary prevention of VTE. 
 
 
Study Duration 
 
The study will be completed in 24 months:  3 months for start-up (including 
Human Research Committee approval, hiring of additional staff, and finalizing the 
Case Report Form), 18 months for patient enrollment and data collection, and 3 
months for data analysis and writing up the results (Table 2). 
 
Table 2.  Study timeline. 
Milestone 
Duration (months) 
Start-up 
3 
Patient enrollment 
12 
Completion of data collection 
6 
Data analysis and completion of study 
report 
3 
TOTAL 
24 
 
 
Study Population 
 


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Patients who are > 18 years of age or older with newly diagnosed MM, relapsed 
MM, MM on maintenance therapy and receiving IMiDs (i.e., thalidomide 
[Thalomid], lenalinomide [Revlimid], and pomalidomide [Pomalyst]). 
 
Study Inclusion Criteria 
 
• Men and women 
• Age > 18 years 
• Current or prior diagnosis of symptomatic MM based on International 
Myeloma Working Group (IMWG) guidelines 
(http://imwg.myeloma.org/category/guidelines-2/) and will be starting or 
already receiving IMiD therapy with thalidomide [Thalomid], lenalinomide 
[Revlimid], or pomalidomide [Pomalyst] 
• IMiD therapy given in the setting of newly diagnosed MM, relapsed MM, 
progressive MM, maintenance therapy or consolidation therapy as per 
IMWG criteria 
 
Patients must have had measurable disease as defined by at least one of 
the following**:  
• Serum M-protein ≥ 0.5 g/dL by serum electrophoresis (SPEP) or for IgA 
myeloma, by quantitative IgA (>750 mg/dl) 
• Urinary M-protein excretion at least 200 mg/24 hours 
• Serum Free Light Chain (FLC) whereby the involved light chain measures 
≥ 10 mg/dL and with an abnormal light chain ratio. 
 
**The patient must have met criteria for measurable disease at some point.  
Criteria do not have to be met at time of enrollment. 
 
• Willing to provide written informed consent 
• Eastern Cooperative Oncology Group (ECOG) functional status ≤ 2 
• Providers must plan to treat the patient with IMiD therapy for a minimum of 
6 cycles  
 
Study Exclusion Criteria 
 
• Pregnancy 
• Breastfeeding 
• Women of child-bearing potential who are unwilling or unable to use an 
acceptable method of birth control (such as oral contraceptives, other 
hormonal contraceptives [vaginal products, skin patches, or implanted or 
injectable products], or mechanical products such as an intrauterine 
device or barrier methods [diaphragm, condoms, spermicides]) to avoid 
pregnancy for the entire study 
• Any prior venous thromboembolism 
• Contraindication to anticoagulant therapy 


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• Conditions for which serious bleeding may occur including: 
o Current or within last 6 months: intracranial bleeding, intraocular 
bleeding, gastrointestinal bleeding, endoscopically documented 
ulcer disease 
o Current or within last month: head trauma or other major trauma, 
major surgery 
o Current or within last 2 weeks:  stroke, neurosurgical procedure 
o Current: gross hematuria, major unhealed wound, major surgery 
planned during the trial period, intracranial mass, vascular 
malformation, or aneurysm, overt bleeding, blood dyscrasia 
o CNS involvement of MM or other history of CNS malignancy 
• Active and clinically significant liver disease 
• Uncontrolled hypertension: systolic blood pressure >180 mm Hg or 
diastolic blood pressure >100 mm Hg 
• Current endocarditis 
• Requirement for ongoing anticoagulant therapy, including mechanical 
heart valve replacement and atrial fibrillation 
• Severe valvular heart disease, including rheumatic heart disease and 
mitral stenosis 
• Bioprosthetic heart valve replacement  
• Requirement for dual antiplatelet therapy or single agent antiplatelet 
therapy with clopidogrel, prasugrel, or ticagrelor 
• Requirement for aspirin at a dose higher than 165 mg daily.  
• Hemoglobin < 9 mg/dL at time of screening 
• Platelet count < 100,000/mm3 at time of screening 
• Serum calculated creatinine clearance (CrCl) < 25 ml/m at time of 
screening 
• Alanine aminotransferase or aspartate aminotransferase level > 2 times 
the upper limit of the normal at time of screening 
• Total bilirubin level > 1.5 times the upper limit of the normal at time of 
screening 
• Life expectancy < 12 months or hospice care 
• Prisoners or subjects who are involuntarily incarcerated 
• Subjects who are compulsorily detained for treatment of either a 
psychiatric or physical (e.g., infectious disease) illness 
• Receiving concurrent non-FDA-approved or investigational agents or has 
received an investigational agent within the past 30 days prior to the first 
dose of study treatment (with the exception of approved medications being 
used for an approved indication, e.g., investigating a new dosing regimen 
for an approved indication).  
• Any condition, which in the opinion of the investigator, would put the 
subject at an unacceptable risk from participating in the study 
• Any other medical, social, logistical, or psychological reason, which in the 
opinion of the investigator, would preclude compliance with, or successful 
completion of, the study protocol 


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Enrollment of Women of Childbearing Potential and Partners 
 
Although it is highly unlikely that a male or female patient of childbearing 
potential would be enrolled in this trial, the following criteria must be met for 
women of childbearing potential and their partners:   
 
a) Women of childbearing potential must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of 
HCG) within 24 hours prior to the start of study drug. 
b) Women must not be breastfeeding. 
c) Women of childbearing potential must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study 
drug 6 months plus 5 half-lives of study drug (2.5 days) plus 30 days 
(duration of ovulatory cycle) for a total of 212.5 days post-treatment 
completion. 
d) Males who are sexually active with women of childbearing potential must 
agree to follow instructions for method(s) of contraception for the 
duration of treatment with study drug 6 months plus 5 half-lives of the 
study drug (2.5 days) plus 90 days (duration of sperm turnover) for a 
total of 272.5 days post-treatment completion. 
e) Azoospermic males and women of childbearing potential who are 
continuously not heterosexually active are exempt from contraceptive 
requirements.  However, women of childbearing potential who are 
continuously not heterosexually active must still undergo pregnancy 
testing. 
 
Investigators will counsel women of childbearing potential and male subjects who 
are sexually active with women of childbearing potential on the importance of 
pregnancy prevention and the implications of an unexpected pregnancy 
Investigators will advise women of childbearing potential and male subjects who 
are sexually active with women of childbearing potential on the use of highly 
effective methods of contraception. Highly effective methods of contraception 
have a failure rate of < 1% when used consistently and correctly. 
 
At a minimum, subjects must agree to the use of one method of highly effective 
contraception as listed below: 
• 
Male condoms with spermicide 
• 
Hormonal methods of contraception including combined oral 
contraceptive pills, vaginal ring, injectables, implants and hormone-
impregnated intrauterine devices (IUDs) by women of childbearing 
potential subject.  Female partners of male subjects participating in the 
study may use hormone based contraceptives as one of the acceptable 
methods of contraception since they will not be receiving study drug.  
• 
IUDs 


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• 
Tubal ligation 
• 
Vasectomy 
• 
Complete Abstinence* 
 
*Complete abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all study drugs. 
Female subjects must continue to have pregnancy tests. Acceptable alternative 
methods of highly effective contraception must be discussed in the event that the 
subject chooses to forego complete abstinence 
 
A woman of childbearing potential is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or 
bilateral oophorectomy) and is not postmenopausal. Menopause is defined as 12 
months of amenorrhea in a woman over age 45 years, in the absence of other 
biological or physiological causes. In addition, females under the age of 55 years 
must have a serum follicle stimulating hormone, (FSH) level > 40mIU/mL to 
confirm menopause. 
 
*Females treated with hormone replacement therapy, (HRT) are likely to have 
artificially suppressed FSH levels and may require a washout period in order to 
obtain a physiologic FSH level. The duration of the washout period is a function 
of the type of HRT used. The duration of the washout period below are 
suggested guidelines and the investigators should use their judgement in 
checking serum FSH levels. If the serum FSH level is >40 mIU/ml at any time 
during the washout period, the woman can be considered postmenopausal: 
• 
1 week minimum for vaginal hormonal products (rings, creams, 
gels) 
• 
4 week minimum for transdermal products 
• 
8 week minimum for oral products 
 
Other parenteral products may require washout periods as long as 6 months. 
 
 
Screening Procedures 
 
When a potential study subject is identified, the following screening procedures 
will be followed: 
1. The Principal Investigator or designee at the study site where the 
potentially eligible patient is receiving care will be contacted by the 
responsible provider to initiate screening. 
 
2. The Principal Investigator or designee will confirm that patient is > 18 
years of age or older, has MM, and is receiving an IMiD (i.e., thalidomide 
[Thalomid], lenalinomide [Revlimid], and pomalidomide [Pomalyst]). 
 


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3. The Principal Investigator or designee will also confirm the absence of all 
exclusion criteria. 
 
4. The Principal Investigator or designee will provide the potential study 
subject with the study Informed Consent Form to review, sign, and date.  
Informed consent must be obtained from a subject with the capacity for 
medical decision-making and/or the subject’s legally authorized 
representative.  The process for obtaining informed consent must be in 
compliance with the local ethics committee guidelines and policies.  
Informed consent may be obtained by the Principal Investigator, co-
investigators, study coordinators, or an appointed designee.  Potential 
study subjects will not be enrolled if informed consent cannot be obtained.  
A copy of the signed Informed Consent Form must be provided to the 
subject or the subject’s legally authorized representative.  Signed 
Informed Consent Forms must remain in each subject’s study file and 
must be available for verification at all times.   
 
5. The study coordinator will enter the patient demographic data into the 
screening portion of the electronic case report form (eCRF). 
 
6. Subjects who agree to participate in the study and sign the Informed 
Consent Form will be considered for enrollment in the study and 
should undergo baseline data acquisition which includes:  
a. History and physical examination 
b. Serum (β-HCG) or urine pregnancy test (u-HCG) for women of 
child-bearing potential 
 
7. If the potential study subject does not meet all of the inclusion criteria or 
meets any of the exclusion criteria, the rationale for exclusion from the 
study will be recorded in the screening section of the electronic case 
report form (eCRF). 
 
 
Treatment Description   
 
Patients will begin prophylactic anticoagulation within 3 weeks of passing the 
screening procedure.  Patients with MM receiving IMiDs will be assigned to 
receive apixaban 2.5 mg orally twice daily for primary prevention of VTE for a 
duration of 6 months.   
 
If patients come off IMiD therapy during the 6-month study period due to 
progression of disease or therapy failure, apixaban will be discontinued. 
 
If during the study period the patient requires an invasive procedure or surgery 
that necessitates the discontinuation of anticoagulation (study drug), apixaban 
should be held as per the prescribing guidelines (Appendix, 


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http://packageinserts.bms.com/pi/pi_eliquis.pdf).  If appropriate based on the 
judgment of the responsible clinician, apixaban should be restarted when safe to 
do so postoperatively. 
 
 
Safety Outcomes 
 
Primary Safety Outcome 
 
The primary safety outcome is the 6-month rate of major and clinically relevant 
non-major bleeding in MM patients receiving IMiDs who are prescribed apixaban 
2.5 mg orally twice daily for primary prevention of VTE. 
 
Using the ISTH classification, bleeding is defined as major if it is overt and 
associated with a decrease in the hemoglobin level of 2 g/dL or more, requires 
the transfusion of 2 or more units of blood, occurs into a critical site, or 
contributes to death (12).   
 
Using the ISTH classification, clinically relevant nonmajor bleeding is defined as 
overt bleeding not meeting the criteria for major bleeding but associated with 
medical intervention, surgical intervention, or interruption of the study drug.  
 
Secondary Safety Outcome 
 
All-cause mortality at 6 months will be recorded.  Cause of death will be 
classified as related to cancer, myocardial infarction, PE, other cardiovascular or 
other disease state.  Death will be attributed to PE if there is evidence to support 
an association with PE. 
 
 
 
Efficacy Outcomes 
 
Primary Efficacy Outcome 
 
The primary efficacy outcome is the 6-month rate of symptomatic VTE in MM 
patients receiving IMiDs who are prescribed apixaban 2.5 mg orally twice daily 
for primary prevention of VTE. 
 
DVT is diagnosed as a noncompressible venous segment or segments on 
ultrasonography or a filling defect on computed tomographic (CT) venography, 
magnetic resonance (MR) venography, or contrast venography.   
 
PE is diagnosed on the basis of a mismatched perfusion defects on ventilation 
perfusion scan, the presence of a pulmonary artery filling defect on contrast-


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enhanced chest CT, a finding of intraluminal filling defect on invasive pulmonary 
angiography, or evidence of PE at autopsy. 
 
Secondary Efficacy Outcome 
 
MM patients have an increased risk of atherothrombotic events, including 
myocardial infarction and stroke.  The risk of atherothrombotic events is further 
increased with IMiDs.  Accordingly, the 6-month rates of myocardial infarction 
and stroke will also be calculated. 
 
An acute MI is defined as the presence of at least 2 of the 3 following conditions 
(13): 
• The detection of a rise and/or fall of cardiac biomarkers, with at least one 
of the values being elevated [preferably cardiac troponin (cTn) with at 
least one value above the 99th percentile upper reference limit] and with 
at least one of the following:   
(1) symptoms of myocardial ischemia;  
(2) new (or presumably new) significant ST-segment/T-wave 
changes or left bundle branch block;  
(3) development of pathological Q waves on ECG;  
(4) new loss of viable myocardium or regional wall motion 
abnormality by imaging; 
(5) identification of intracoronary thrombus by angiography or 
autopsy 
 
An acute stroke was defined as a new, focal neurologic deficit of sudden onset, 
lasting at least 24 hours, not due to a readily identifiable nonvascular cause (i.e. 
brain tumor, trauma), as confirmed by a neurologist (2). All strokes during the 
study were assessed by imaging or autopsy, and classified as primary 
hemorrhagic, non-hemorrhagic, infarction with hemorrhagic conversion, or 
unknown, as defined by the American College of Cardiology. 
• Primary hemorrhagic: a stroke with documentation on imaging (e.g., 
CT scan or magnetic resonance imaging) of hemorrhage in the cerebral 
parenchyma, or subarachnoid hemorrhage. Evidence of hemorrhagic 
stroke obtained from lumbar puncture, neurosurgery, or autopsy can also 
confirm the diagnosis.  
• Non-hemorrhagic: an ischemic focal neurological deficit (and not due to 
hemorrhage) that appears and is still partially evident at 24 hours. 
• Infarction with hemorrhagic conversion: no evidence of hemorrhage 
on an initial scan, but found on a subsequent scan and is clinically 
relevant to the event, as determined by a neurologist. 
• Unknown type/no imaging performed: the type of stroke could not be 
determined by imaging or other means (lumbar puncture, neurosurgery). 
 
 
Follow-up 


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Follow-Up Evaluation 
 
Routine follow-up visits with study personnel will not be required.  Study patients 
will be encouraged to follow-up with their primary care providers and other 
appropriate clinicians, including oncologists.  Data regarding study outcomes will 
be abstracted from the Electronic Health Record. 
 
We will assess medication adherence via pill count.  Medication adherence will 
be calculated as the total number of doses taken divided by the total number of 
doses prescribed ([ x / 336] x 100 = medication adherence [%]). 
 
Subjects will be given a study diary to fill out at home each day.  Subjects will 
write down the time they take their study drug and any side effects.  The study 
diary will be collected at a regularly scheduled office visit at conclusion of the 
study period. 
 
Subject Retention, Withdrawal, and Termination 
 
Continued participation of study subjects will be encouraged at the time of 
outpatient evaluation through the 6-month follow-up interval.  However, study 
subjects will be informed that they retain the right to withdraw from the study at 
any time without compromise to their current or subsequent medical care.  
Subjects will be terminated from the study if they expire or elect to withdraw.   
 
If study subjects elect to withdraw, they will be asked for permission to do the 
following: 
1. Be contacted by telephone AND 
2. Have a family member contacted AND 
3. Have their physicians contacted 
 
Withdrawal criteria will include: 
1. Patient requests to withdraw 
2. Reasons related to SAE: 
a. Initiating or continuing study drug places the subject at undue 
hazard as determined by the Investigator;   
b. SAE or other safety concern that is related to study drug treatment;   
c. Major or life-threatening bleeding (as defined in the protocol)  
d. ALT or AST ≥ 3 ULN, if suspected to be due to the study drug  
e. Calculated CrCL decreased to < 30 mL/min confirmed by repeat 
testing at least one week later, or need for dialysis 
f. Subjects in whom multiple myeloma is felt to be refractory to 
therapy or who have transitioned to a palliative treatment strategy  
3. Pregnancy; 
4. Patient develops severe hepatic impairment (Child-Pugh class C) during 
the trial; 


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5. Death; 
6. Lost to follow-up (every attempt will be made by the Investigator not to 
have subjects “lost to follow-up”); 
7. Study terminated by sponsor (termination of all or part of the study by the 
sponsor, in concert with the study leadership) 
 
 
Assessment and Reporting of Adverse Events 
 
Definitions 
 
Adverse events 
 
An adverse event (AE) is defined as any new untoward medical occurrence or 
worsening of a pre existing medical condition in a patient or clinical investigation 
subject administered an investigational (medicinal) product and that does not 
necessarily have a causal relationship with this treatment.  An AE can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of 
investigational product, whether or not considered related to the investigational 
product.  The causal relationship to study drug is determined by a physician and 
should be used to assess all AEs.  
 
Adverse events can be spontaneously reported or elicited during open-ended 
questioning, examination, or evaluation of a subject. (In order to prevent 
reporting bias, subjects should not be questioned regarding the specific 
occurrence of one or more adverse events). 
 
All SAEs that occur following the subject’s written consent to participate in the 
study through 30 days of discontinuation of dosing will be reported to BMS 
Worldwide Safety. 
 
Serious Adverse Events 
 
A serious adverse event (SAE) is any untoward medical occurrence at 
any dose that: 
  
• results in death 
• is life-threatening (defined as an event in which the subject was at risk 
of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe) 
• requires inpatient hospitalization or causes prolongation of existing 
hospitalization  
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 


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• is an important medical event, defined as a medical event that may not 
be immediately life-threatening or result in death or hospitalization but, 
based on appropriate medical and scientific judgment, may jeopardize 
the subject or may require intervention (e.g., medical, surgical) to 
prevent one of the other serious outcomes listed above. Examples of 
such events include but are not limited to intensive treatment in an 
emergency department or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization. 
 
Suspected transmission of an infectious agent (eg, pathogenic or non-
pathogenic) via the study drug is an SAE.  Although pregnancy, overdose, and 
cancer are not always serious by regulatory definition, these events must be 
handled as SAEs. 
 
 The following hospitalizations are not considered SAEs:  
• A visit to the emergency room or other hospital department lasting 
less than 24 hours that does not result in admission (unless 
considered an “important medical event” or a life-threatening event) 
• Elective surgery planned before signing consent 
• Admissions as per protocol for a planned medical/surgical 
procedure 
• Routine health assessment requiring admission for 
baseline/trending of health status (eg, routine colonoscopy) 
• Medical/surgical admission other than remedying ill health state 
that was planned before study entry. Appropriate documentation is 
required in these cases 
• Admission encountered for another life circumstance that carries no 
bearing on health status and requires no medical/surgical 
intervention (e.g., lack of housing, economic inadequacy, caregiver 
respite, family circumstances, administrative reason) 
 
Adverse Events of Special Interest 
 
In this study, the following adverse events will to be reported to BMS, regardless 
of whether these reports are classified as serious or unexpected. 
 
• Potential or suspected cases of liver injury including but not limited 
to liver test abnormalities, jaundice, hepatitis or cholestasis. 
 
Pre-Existing Medical Conditions 
 
A pre-existing medical condition is one that is present at the start of the study.  
Pre-existing medical conditions should be recorded in the baseline and 
demographic data section of the electronic case report form (eCRF).  Pre-
existing medical conditions should be reassessed during the trial and reported as 
an adverse event or severe adverse event only if the frequency, severity, or 


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character of the conditions worsens significantly or unexpectedly during the 
study.  When reporting such adverse events, the description should convey that 
the pre-existing condition has changed by including applicable descriptors (for 
example, “more frequent” headaches).  Previously scheduled hospitalizations 
and hospitalizations required for diagnostic or elective surgical procedures for the 
management of unchanged pre-existing medical condition should not be 
considered adverse events. 
 
Serious Adverse Event Collecting and Reporting 
 
Following the subject’s written consent to participate in the study, all SAEs, 
whether related or not related to study drug, must be collected, including those 
thought to be associated with protocol-specified procedures. All SAEs must be 
collected that occur during the screening period and within 30 days of 
discontinuing dosing. If applicable, SAEs must be collected that relate to any 
later protocol-specific procedure (such as follow-up skin biopsy).  The 
investigator should report any SAE occurring after these time periods that is 
believed to be related to study drug or protocol-specified procedure.  An SAE 
report should be completed for any event where doubt exists regarding its status 
of seriousness.  If the investigator believes that an SAE is not related to study 
drug, but is potentially related to the conditions of the study (such as withdrawal 
of previous therapy, or a complication of a study procedure), the relationship 
should be specified in the narrative section of the SAE Report Form. 
 
SAEs, whether related or unrelated to the study drug, and pregnancies must be 
reported to BMS within 24 hours:  
 
SAE Email Address: Worldwide.Safety@BMS.com 
SAE Fax Number: 609-818-3804 
 
SAEs must be recorded on the FDA MedWatch Form 3500A. Pregnancies must 
be reported on a Pregnancy Surveillance Form. 
 
If only limited information is initially available, follow-up reports are required. 
(Note: Follow-up SAE reports should include the same investigator term(s) 
initially reported.)  
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 
hours to the BMS (or designee) using the same procedure used for transmitting 
the initial SAE report. All SAEs should be followed to resolution or stabilization. 
 
SAE Reconciliation 
 
The investigator will reconcile the clinical database SAE cases transmitted to 
BMS Global Pharmacovigilance (GPV&E). Frequency of reconciliation will be 


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done every three months and once prior to study database lock. BMS GPV&E 
will e-mail upon request from the investigator, the GPV&E reconciliation report. 
Requests for reconciliation should be sent to aepbusinessprocess@bms.com. 
The data elements listed on the GPV&E reconciliation report will be used for 
case identification purposes. If the investigator determines a case was not 
transmitted to BMS GPV&E, the case will be sent immediately. 
 
Health Authority Reporting (US FDA IND) 
 
Investigators must adhere to local Health Authority Reporting Requirements. For 
studies conducted under an investigator sponsored US FDA IND, provide details 
of the following: 
 
• Any event that is both serious and unexpected must be reported to the 
Food and Drug Administration (FDA) as soon as possible and no later 
than 7 days (for a death or life-threatening event) or 15 days (for all 
other SAEs) after the investigator’s or institution’s initial receipt of the 
information.  
• BMS will be provided with a simultaneous copy of all adverse events 
filed with the FDA. SAEs should be reported on MedWatch Form 
3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/medwatch/. 
 
MedWatch SAE forms should be sent to the FDA at: 
 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
 
All SAEs should simultaneously be faxed or e-mailed to BMS at: 
 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
 
 
Non-Serious Adverse Events  
 
A non-serious adverse event is an AE not classified as serious. 
 
Non-Serious Event Collecting and Reporting 
 


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The collection of non-serious adverse event (NSAE) information should begin at 
initiation of study drug. Nonserious AEs should be followed to resolution or 
stabilization, or reported as SAEs if they become serious.  Follow-up is also 
required for nonserious AEs that cause interruption or discontinuation of study 
drug, or those that are present at the end of study treatment as appropriate.  
 
Nonserious Adverse Events are provided to BMS via annual safety reports (if 
applicable), and interim or final study reports. 
 
 
Laboratory Test Abnormalities 
 
The following laboratory abnormalities should be captured and reported as 
appropriate: 
 
• Any laboratory test result that is clinically significant or meets the definition 
of an SAE 
• Any laboratory test result abnormality that required the subject to have 
study drug discontinued or interrupted 
• Any laboratory test result abnormality that required the subject to receive 
specific corrective therapy.  
 
It is expected that wherever possible, the clinical rather than the laboratory term 
will be used by the reporting investigator (e.g., use the term anemia rather than 
low hemoglobin value).  Laboratory test abnormalities are provided to BMS via 
annual safety reports (if applicable), and interim or final study reports. 
 
 
Pregnancy 
 
If, following initiation of apixaban, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of apixaban exposure, 
including during at least 5 half-lives after product administration, the 
investigational product will be permanently discontinued in an appropriate 
manner.  The investigator must immediately notify WorldwideSafety@BMS.com 
of this event via the Pregnancy Surveillance Form within 24 hours and in 
accordance with SAE reporting procedures. 
 
 
Follow-up information regarding the course of the pregnancy, including perinatal 
and neonatal outcome and, where applicable, offspring information must be 
reported on a Pregnancy Surveillance Form. 
 
Any pregnancy that occurs in a female partner of a male study participant should 
be reported to BMS. Information on this pregnancy may also be collected on the 
Pregnancy Surveillance Form. 


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Protocol-required procedures for study discontinuation and follow-up must be 
performed on the subject unless contraindicated by pregnancy.  Other 
appropriate pregnancy follow-up procedures should be considered if indicated. 
 
 
Overdose  
 
An overdose is defined as the accidental or intentional administration of any dose 
of a product that is considered both excessive and medically important. All 
occurrences of overdose must be reported as SAEs. 
 
 
Other Safety Considerations 
 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, X-rays, and any other potential safety assessments, whether 
or not these procedures are required by the protocol, should also be recorded as 
a non-serious or serious adverse event, as appropriate, and reported 
accordingly. 
 
 
Documentation of Adverse Events 
 
Information about potential adverse events should be reviewed during the 6-
month follow-up period.  Subjects should be encouraged to report adverse 
events spontaneously or in response to non-directed questioning by their usual 
healthcare providers.  If it is determined that an adverse event has occurred, the 
study staff member entering data into the eCRF should obtain all of the 
information necessary to complete the Adverse Event section.  All observed or 
reported adverse events, regardless of the suspected causal relationship to study 
treatment must be recorded in the Adverse Event section of the eCRF.  The 
Sponsor will be notified when an event has been entered into the database. 
 
 
Duration of Adverse Event Reporting Period 
 
Bleeding adverse events and other serious adverse events must be reported 
throughout the 6-month follow-up period.  All observed or reported serious 
adverse events occurring through the 6-month follow-up period, regardless of the 
suspected causal relationship with treatment, must be recorded in the 
appropriate section of the eCRF.  Procedures to expedite reporting serious 
adverse events are described later in this section.   
 
 
Specific Adverse Event Reporting Guidelines 


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Study investigators should follow the following guidelines to ensure the quality 
and precision of adverse event reporting: 
1. Use recognized medical terms. 
2. Avoid the use of colloquialisms and non-standard abbreviations 
3. If known at the time of adverse event reporting, a diagnosis should be 
reported instead of individual symptoms and signs (for example, record 
only “pneumonia” rather than “productive cough” and “elevated white 
blood cell count”). 
4. If the reported symptoms and signs cannot be medically characterized as 
a single diagnosis or syndrome at the time of adverse event reporting, the 
information that is available should be reported.  If a diagnosis is 
subsequently established, it should be reported as follow-up information 
as described earlier. 
5. A cascade of clinical events (such as sequelae of an adverse event) 
should be identified as the primary, causative event.  The cascade of 
events can be further described in the adverse event narrative.  For 
example, when recording a death, the event or condition that caused or 
contributed to the fatal outcome should be reported as the serious adverse 
event.  If the cause of death is unknown and cannot be determined at the 
time of reporting, “unknown cause of death” should be recorded. 
6. Any adverse event that results in inpatient hospitalization or prolongs a 
hospitalization should be reported as a serious adverse event.  If a subject 
is hospitalized to undergo a medical or surgical procedure as a result of an 
adverse event, the event responsible for the procedure (not the procedure 
itself) should be reported as the serious adverse event.  For example, if a 
subject is hospitalized to undergo exploratory surgery as a result of a 
major bleeding event, record the major bleeding event that necessitated 
surgery as the serious adverse event. 
 
All Serious Adverse Events (SAEs) that occur following the subject’s written 
consent to participate in the study through 30 days of discontinuation of dosing 
must be reported to BMS Worldwide Safety. 
 
Categorization of Adverse Events 
 
All adverse events must be classified according to intensity or severity, 
expectedness, relatedness, outcome, and treatment or action taken. 
 
Intensity or Severity 
 
The following categories for intensity or severity of an adverse event should be 
used in reporting: 
 
Mild  
Awareness of a symptom or sign that does not interfere with the 
patient’s usual activity or is transient and resolves without 


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treatment and without sequelae 
Moderate 
Interferes with the patient’s usual daily activities, but he or she is 
still able to function 
Severe 
Interrupts a patient’s usual daily activities and generally requires 
medication, surgery, or other intervention for treatment 
 
Expectedness 
 
Each adverse event should be evaluated as to whether it was expected or 
unexpected as follows: 
 
Expected 
The specificity and severity of the event is consistent with 
applicable information on apixaban. 
Unexpected 
The specificity or severity of the event is not consistent with 
applicable information on apixaban.               
Unanticipated 
Adverse 
Device Effect 
(UADE) 
Any serious adverse effect on health or safety or any life-
threatening problem or death caused by, or associated with, 
apixaban, if that effect, problem, or death was not previously 
identified in nature, severity, or degree of incidence in the 
investigational plan or application or any other unanticipated 
serious problem associated with apixaban that relates to the 
rights, safety, or welfare of subjects.  
 
 
Relatedness 
 
Each adverse event should be evaluated as to whether it was related to the study 
procedures or apixaban as follows: 
 
Definite 
An adverse event is clearly related to apixaban 
Probable 
An adverse event has a reasonable causal relationship to the 
use of apixaban; another etiology is significantly less likely 
Possible 
An adverse event has a reasonable causal relationship to the 
use of apixaban; an alternative etiology is equally or less likely  
Unlikely 
An adverse event has little or no causal relationship to the use 
of apixaban; an alternative etiology is more likely 
Not related 
An adverse event is not related to the use of apixaban; there is 
no temporal relationship or a much more likely alternative 
etiology exists 
 
The term “reasonable causal relationship” means there is evidence to suggest a 
causal relationship.  
 
 
Outcome 
 


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The clinical course of all adverse events should be followed until a medical 
outcome is determined (resolution, stabilization, or determination that it was 
unrelated to study participation).  If a subject is pregnant or becomes pregnant 
within 30 days of receiving apixaban, follow-up should be obtained from the 
medical record to determine the outcome of the pregnancy (successful live-birth, 
etc.).  The clinical outcome of all adverse events should be recorded as follows: 
 
Death 
Patient expired 
Recovered 
Patient returned to baseline health and functional 
status 
Not yet recovered 
Patient did not recover and symptoms or 
sequelae persist 
Recovered with sequelae 
Patient did recover but continues to experience 
clinical sequelae from the adverse event 
 
Treatment or Action Taken 
 
Adverse events and serious adverse events will be categorized by the actions 
taken in response to the event: 
 
Intervention 
Surgery or other invasive procedure 
Non-surgical treatment 
Drug initiation, interruption, dose reduction, dose 
increase, or discontinuation 
None 
No action was taken 
 
Expedited Reporting of Serious Adverse Events (SAE) 
 
The study investigators must use the following procedure for reporting serious 
adverse events: 
1. Report any serious adverse event that occurs to the Sponsor within 24 
hours of knowledge of the event (Monday through Friday).  If the 
investigator does not have all information regarding the SAE, he/she will 
not wait to receive additional information before notifying the 
Sponsor of the event and completing the eCRF.  The investigator shall 
provide an event update when additional information is received. 
NOTE:  The Sponsor will automatically be notified when an adverse event 
or serious adverse event has been entered into the database when the 
investigator fills in an eCRF.  
 
2. In the reporting of serious adverse events, the study investigator shall 
provide any potentially relevant information including: 
a. Subject demographics 
b. Pre-existing conditions 
c. The complete description of the adverse event. 
d. Date and time of adverse event onset 
e. Severity 


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f. Treatment 
g. Results of diagnostic testing 
h. Duration of sequelae 
i. Outcome (if known) 
j. Date and time of adverse event resolution. 
k. Information on suspected medications including dose, route of 
administration, frequency, dates, lot number, expiration date, and 
concomitant medications 
 
3. When reporting a death, the primary event or condition that caused or 
contributed to the fatal outcome shall be reported as the serious adverse 
event.  Death will be reported as the outcomes of the serious adverse 
event.  If the cause of death is unknown at the time of reporting, report 
“unknown cause of death.” 
 
4. The investigator shall report unanticipated adverse device effects 
(UADEs) to the sponsor and Institutional Review Board within 10 working 
days after the investigator first learns of the event.   
 
Sponsor Unanticipated Adverse Drug Effects (UADEs) Reporting Responsibilities 
 
Any serious adverse event determined to be caused by apixaban will be 
reviewed for possible reporting to the U.S. Food and Drug Administration and 
IRBs.  Upon notice of an unanticipated adverse drug effect (UADE), the sponsor 
shall immediately conduct an evaluation of the UADE and report the results of 
the evaluation to the FDA, all reviewing IRBs, and participating investigators 
within 10 days of first receiving the report.   
 
 
Data Reporting, Processing, and Quality Control 
 
Data Acquisition, Monitoring, and Quality Control 
 
Subject data will be collected using a web-based centralized electronic case 
report form (eCRF).  Database monitoring and quality control will be performed 
by the Study Coordinating Center (BWH).   
Monitoring Plan 
 
Monitoring procedures will consist of the following: 
 
Site Initiation  
 
At the initial site visit, the Study Coordinating Center shall conduct a full site 
qualification and training.  Study Coordinating Center shall review the terms of 
the protocol with the site investigator and confirm the investigators access to 


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facilities required to conduct the study.  The Study Coordinating Center will 
answer any questions the investigator may have concerning the clinical study or 
protocol and instruct the investigator on how to complete the eCRFs. 
 
During the Study 
 
During the study, the Study Coordinating Center shall perform monthly random 
reviews of data submitted by investigators with checks for accuracy and 
completeness and document that corrective actions have been taken in response 
to protocol deviations or other forms of non-compliance.  Investigators will be 
contacted and asked to submit any missing information or clarify any 
questionable data.  Notes from telephone conversations and copies of written 
correspondence between the Study Coordinating Center and the Investigators 
will be maintained in the Study File.   
 
Independent Study Safety Monitor    
 
A physician with relevant expertise whose primary responsibility is to protect the 
safety of study subjects and to provide ongoing, critical, and unbiased 
evaluation of the progress of the study will be appointed as an independent study 
safety monitor for the duration of the study.  The safety monitor will operate in a 
manner similar to that of a Clinical Events Committee/Data and Safety Monitoring 
Board. 
 
The safety monitor will: 
• Provide independent safety evaluation of events and adjudicate all actual and 
potential serious adverse events experienced by study subjects during this 
study;  
• Review aggregate safety data including the frequency of adverse safety 
outcomes, particularly death, symptomatic VTE and major bleeding; and can 
recommend premature stopping of the study to the Sponsor and Principal 
Investigator at any time. 
 
Interim Safety and Efficacy Analysis 
 
The safety monitor will review the safety and efficacy outcomes for the first 10 
patients enrolled in the study.  The need for dose adjustment will be made based 
in this interim analysis.  The safety monitor will review the safety and efficacy 
outcomes again at the completion of the study. 
 
Stopping Criteria 
 
The study will be terminated by the safety monitor, sponsor, and principal 
investigator if the following stopping criterion is met: 
 


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• An excess of morbidity or mortality is observed in patients receiving 
apixaban. 
a. When 2 patients receiving apixaban experience an unprovoked 
intracranial hemorrhage, confirmed by independent adjudication, 
and did not have a protocol violation such that he/she cannot be 
considered as representative of the intended patient population. 
b. When 3 of the subjects receiving apixaban experience an 
unprovoked major bleed (including fatal hemorrhagic events) and 
did not have a protocol violation such that he/she cannot be 
considered as representative of the intended patient population. 
 
 
Protocol Violations 
 
The Study Coordinating Center will rapidly and firmly address any protocol 
violations. If a protocol violation is detected or suspected, the study site 
investigator(s) will first be asked to provide a written explanation.  After 
reviewing the available information, the Study Coordinating Center will 
categorize protocol violations as either major (eligibility or primary/secondary 
endpoint determination compromised or indefinite) or minor (data still able to be 
used for endpoint determination), and will record and track them. 
 
The Study Coordinating Center will communicate with the study enrollment site 
personnel to confirm that a process is in place to ensure that further protocol 
violations do not recur. 
 
Data Confidentiality 
 
Hardcopy and electronic subject data will be maintained in a locked office at each 
investigational site and will only be available to the study site personnel and 
sponsor personnel during monitoring visits.  Patient identifiers including names 
and other personal information will be kept separate from the study data. 
 
Compliance with Laws and Regulations 
 
The study will be conducted in accordance with this protocol, Title 21 Code of 
Federal Regulations, Parts 10, 50, 54,56 and 812, International Harmonized 
Standards- E6 Good Clinical Practices Guidance, and local ethical and legal 
requirements. 
 
 
 
 
 
 
 


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Statistical Methods 
 
Sample Size Calculation 
 
The sample size estimate is completed using the 95% confidence interval (CI) 
method. We propose a sample size of 50 patients. It generates a half-width of CI 
less than 10% if the blood clot rate is <15%. Since our study expects an 80% risk 
reduction in VTE, our estimated VTE rate is about 5%. If based on the 5% VTE 
incidence rate, the half-width CI will be <6%. Therefore, the precision will be 
improved with narrower CI, since we expect an incidence much lower than 15%.  
 
Statistical Analysis Plan 
 
For this proof-of-concept study, we will calculate: 
1) the 6-month rate of major and clinically relevant non-major bleeding 
2) the 6-month rate of symptomatic VTE 
 
We will also calculate 6-month rates of myocardial infarction and stroke. 
 
The primary analysis will be intention-to-treat.  Although study eligibility criteria 
warrant that the provider plans to treat the patient with IMiDs for at least 6 cycles, 
we will include any patient who has received at least 2 cycles in a modified 
intention-to-treat analysis. 
 
Means, medians, and frequency distributions will be calculated for continuous 
variables.  Number and percentages will be reported for binary and categorical 
variables.  Differences between subgroups of interest will be examined using the 
chi-square or Fisher’s exact test for binary and categorical variables and t-test or 
Wilcoxon Rank Sum for continuous variables (if the subgroups are of sufficient 
size for statistical comparison).  Potential subgroup analysis will include patients 
newly diagnosed vs. recurrent/relapsed disease and concomitant medications 
(dexamethasone, etc.). 
 
All tests will be two tailed and a p-value of <0.05 assumed to represent statistical 
significance.  All analyses will be performed using SAS software.   
 
 
Investigator Responsibilities 
 
Study Initiation 
 
Before enrollment of the first subject at the study site, the following documents 
must be on file with the Study Sponsor: 
1. Current curriculum vitae of the principal investigator and all co-
investigators 
2. Current, dated Institutional Review Board (IRB) membership list 


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3. Written documentation of IRB protocol approval (protocol number/title and 
approval date) and Informed Consent Form (protocol number/title and 
approval date) 
4. A copy of the IRB-approved Informed Consent Form (The Informed 
Consent Form must be reviewed by the study Principal Investigator prior 
to IRB submission.) 
 
Study Completion 
 
The following data and materials must be on file at the study site before the study 
can be considered complete or terminated: 
1. Completed electronic case report forms (eCRFs) for all study subjects. 
2. All regulatory documents including: 
a. Curriculum vitae for each investigator and study staff member. 
b. Signed confidentiality agreement 
c. Study protocol and protocol amendments 
d. Institutional Review Board approval letter (s) for initial protocol and 
any protocol amendments; as well as continuing review approval 
letters. 
e. All Institutional Review Board correspondence  
f. Study termination letter 
g. Institutional Review Board membership list 
h. Site personnel signature list 
i. Financial Disclosure and Conflict of Interest forms for all site 
investigators 
j. Patient screening and enrollment logs 
k. Signed study Informed Consent Forms for each subject 
l. Supporting source documentation for values and responses in case 
report forms 
m. Supporting source documentation for adverse events 
 
 
Informed Consent 
 
A template for the Informed Consent Form will be provided to the study site by 
the Study Coordinating Center.  The Informed Consent Form must be signed by 
the subject or his or her legally authorized representative before enrollment into 
the study.  A hardcopy of the Informed Consent Form must be provided to the 
subject or his or her legally authorized representative.  If applicable, informed 
consent should be obtained using Interpreter Services.  If an interpreter is 
required to explain the study, the informed consent presented to the patient for 
signature must be in the language in which the patient is literate. 
 
Signed Informed Consent Forms must remain in each subject’s study file and be 
available for verification by the Study Sponsor at all times.  Documentation of the 
date informed consent was obtained and a notation that a signed copy of the 


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Informed Consent Form was provided to the study subject should be recorded.  
The informed consent process must always be conducted in a non-coercive 
manner. 
 
Disclosure of Data 
 
Subject data obtained for this study will be maintained as confidential, and 
disclosure to parties other than study personnel will be prohibited.  Upon the 
study subject’s permission, medical information may be given to his or her 
physician or other medical personnel for his or her welfare. 
 
Retention of Records 
 
Records and documents pertaining to the conduct of this study including case 
report forms, signed informed consent forms, protocol and amendments, 
supporting source documentation for values and responses in the case report 
forms, and supporting documentation for adverse events must be retained by the 
investigators for at least two years after conclusion of the study.   
 
 
Feasibility 
 
Brigham and Women’s Hospital 
 
Brigham and Women’s Hospital (BWH) is a 777-bed acute tertiary care facility 
providing medical and surgical care for patients with general medical, 
cardiothoracic, orthopedic, oncologic, neurologic, obstetric, gynecologic, and 
gastrointestinal conditions.  BWH’s affiliation with the Dana Farber Cancer 
Institute (DFCI) has resulted in a large population of oncology patients receiving 
care in the inpatient wards and in the Cardiovascular Medicine clinics.  DFCI 
provides care to a large population of MM patients who travel from around the 
world.  With the opening of the Heart and Vascular Center in 2014, BWH has 
solidified its position as a world leader in cardiovascular care and research, 
supporting an integrated care model in a single location.  BWH is one of the 
world-leaders in the rapidly growing field of cardio-oncology.  Dr. Piazza’s 
cardiovascular medicine outpatient practice, which is based in the Heart and 
Vascular Center, includes a large number of referrals for thrombosis in the 
setting of malignancy.   
 
The BWH Thrombosis Research Group 
 
The Thrombosis Research Group, directed by Samuel Z. Goldhaber, MD, 
Professor of Medicine, Harvard Medical School and Section Head of Vascular 
Medicine at Brigham and Women’s Hospital, is based at BWH and Harvard 
Medical School.  The Thrombosis Research Group has a decades-long 


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commitment to improving the care for patients with cancer and increased 
thrombosis risk. 
 
The Thrombosis Research Group has an infrastructure of experienced 
leadership, with trained personnel in a multidisciplinary academic team 
(pharmacists, fellows, research nurses, research coordinators, biostatisticians, 
administrators, and medical informatics specialists).  Data storage and computing 
resources, as well as a network of regional, national, and international 
collaborating investigators, facilitate our execution of ongoing research projects 
and our planning of future research projects.  The Thrombosis Research Group 
has studied all aspects of thrombosis in malignancy, including epidemiology, 
diagnosis, and VTE prevention.  According to www.pubmed.gov, the Group has 
authored more than 90 Original Reports since 2010.  Dr. Piazza appreciates the 
burden of thrombosis on the cancer population through registries that he has led 
(14) and high-impact reviews that he has published on the subject (7,15).  Drs. 
Piazza and Goldhaber have extensive experience leading large randomized 
controlled trials focused on prevention of thromboembolic disease.  Examples of 
major Thrombosis Research Group-led trials in thrombosis prevention include the 
2500-patient multicenter Electronic Alert Trial (16), the 2500-patient multicenter 
Physician Alert Trial (17), and the 2500-patient Discharge Alert Trial (18).   
 
For this trial, the Clinical Coordinating Center of the Thrombosis Research Group 
will draft and finalize the study protocol, informed consent, and case report form, 
obtain Institutional Review Board approval, create an electronic data repository, 
assist the clinical centers with local IRB approval, file the IND, ensure scientific 
and financial integrity, approve site payments, plan and host an Investigators 
Meeting, perform the data analysis, and draft and submit for publication the study 
manuscript. 
 
Vanderbilt Cardio-Oncology Program 
 
Vanderbilt University Medical Center will be the Study Enrollment Center.  The 
proposed study will be feasible because Vanderbilt is a large Center of 
Excellence for MM care with active clinical research programs. Specifically, the 
Vanderbilt Cardio-Oncology program, directed by Dr. Javid Moslehi, brings 
together physicians and scientists with a focus on cardiac, vascular and 
thrombotic complications that occur as a result of cancer and cancer therapies. 
The integrative and collaborate nature of the Vanderbilt Cardio-Oncology 
program is illustrated by the care of MM patients. The laboratory of Dr. Moslehi is 
investigating the mechanisms of vascular and thrombotic toxicity associated with 
IMiDs and PIs. At the same time, the group is already embarking on several 
clinical and translation studies focused on cardiovascular effects of MM 
treatments. Dr. Javid Moslehi, Director of Cardio-Oncology at Vanderbilt 
University Medical Center will work closely with colleagues in oncology, including 
Dr. Robert. F. Cornell in spearheading the recruitment effort. 
 


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Potential Risks and Benefits 
 
Potential benefits to the subject 
 
The potential benefit of prophylaxis with apixaban in patients with MM receiving 
IMiDs is prevention of VTE, including fatal PE. 
 
Potential Benefits to Society 
 
The major potential benefit to society of the proposed trial of apixaban for primary 
prevention of VTE in patients with MM receiving IMiDs is that if successful, the 
study will provide the foundation for a novel regimen that avoids the discomfort of 
the currently used injectable anticoagulant strategies.  The data acquired from 
the current study will inform the design of a larger randomized controlled trial 
focused on clinical outcomes.   
 
Potential Risks to the Subject 
 
The foreseeable risk of apixaban for primary prevention of VTE in patients with 
MM receiving IMiDs is major or clinically relevant non-major bleeding. 
 
Risks of Research Procedures Performed on Subjects 
 
The risk of research procedures include psychological discomfort from 
participating in a clinical trial (less likely) and loss of confidentiality of medical 
records or economic data (rare).   
 
Women of childbearing potential (able to get pregnant) must have a negative 
pregnancy test before being considered for the study.  It is not known how 
apixaban could affect an unborn child.  Women of childbearing potential must 
use an effective method of birth control while participating in this research, as 
directed by their physician.   
 
Anticipated Risks of Drug 
 
Anticipated risks of apixaban are categorized as likely, less likely, and rare. 
 
Likely 
1. Anxiety related to participating in a clinical trial 
2. Discomfort or bruising at sites for blood draws 
 
Less likely 
1. Major bleeding requiring transfusion of blood products 
2. Clinically-relevant non-major bleeding 
3. Nausea and vomiting 


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4. Non-severe adverse drug reaction to apixaban 
 
Rare 
1. Severe allergic reaction (such as anaphylaxis) to apixaban 
2. Thromboembolism 
3. Fatal, life-threatening, or intracranial hemorrhage or stroke 
4. Severe internal bleeding (such as gastrointestinal or retroperitoneal) that 
requires surgical or interventional laboratory intervention 
5. Death 
6. Other rare or unforeseen adverse effects 
 
Protection of Subjects against the Risks of Research Procedures 
 
Before Study Enrollment 
 
A rigorous screening process will be utilized to ensure that subjects with an 
increased risk of harm due to enrollment in the study are excluded from the 
study.  This will include performing a detailed history and physical examination 
(to ensure that enrolled subjects truly fulfill all eligibility criteria) and carefully 
reviewing the results of laboratory testing (in particular, hematocrit, platelet count, 
INR, and serum creatinine).   
 
During Follow-Up 
 
Changes in health status during the 6-month follow-up period will be evaluated 
by the patient’s primary physician, oncologist, and other routine providers.  As 
apixaban is an FDA-approved drug commonly used for thromboprophylaxis and 
does not require routine follow-up clinical or laboratory monitoring for toxicity, the 
study will not mandate any follow-up visits or procedures other than those 
required for the patient’s routine myeloma care. 
 
Protection against Loss of Confidentiality 
 
Subject confidentiality will be protected by maintaining all paper records in locked 
file cabinets in locked offices and all electronic records in password-protected 
computer files.  All study data will be de-identified for storage in the electronic 
data repository.  In addition, any identifying information will be removed from 
images or other data used in publication or presentations.  All database 
information will be stored on computer systems that are located behind an 
electronic firewall, which will only permit access to certified study personnel.  
Access to study data files will be password-protected.   
 
Use of Information and Publication 
 


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All information concerning and relating to the study is considered confidential 
information.  This information includes the clinical investigational plan, case 
report forms (CRFs), training materials, and scientific data.   
 
 
Ethical Considerations 
 
In this prospective, single-arm, single-center clinical study, we will be evaluating 
the impact of apixaban for primary prevention of VTE in patients with MM 
receiving IMiDs.  The benefits of apixaban for primary prevention of VTE in 
patients with MM receiving IMiDs have not been assessed.  The risk of bleeding 
in MM patients receiving apixaban has not been determined.  Currently used 
thromboprophylactic regimens for primary prevention of VTE in MM patients 
receiving IMiDs largely consist of injectable anticoagulant regimens, such as 
enoxaparin and dalteparin.  These regimens have not been well-evaluated for 
primary prevention of VTE in the MM population and are associated with patient 
discomfort, inconvenience, and limited medication adherence. Apixaban 2.5 mg 
orally twice daily has been shown to be safe and effective for prevention of VTE 
in a large general medical population.  Therefore, a solid foundation for 
investigation of this thromboprophylactic regimen and equipoise for the proposed 
clinical trial exist.  A successful trial has the potential to provide clinicians and 
patients with a more convenient, more comfortable, and potentially safer 
prophylactic regimen. 
 
Because the proposed clinical trial involves a novel application of a U.S. FDA-
approved anticoagulant, we will obtain written consent from all study subjects 
and Institutional Review Board approval at all study sites. 
 


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References 
 
 
1. 
Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of 
acute venous thromboembolism. The New England journal of medicine 
2013;369:799-808. 
2. 
Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of 
venous thromboembolism. The New England journal of medicine 
2013;368:699-708. 
3. 
Osman K, Comenzo R, Rajkumar SV. Deep venous thrombosis and 
thalidomide therapy for multiple myeloma. The New England journal of 
medicine 2001;344:1951-2. 
4. 
Palumbo A, Anderson K. Multiple myeloma. The New England journal of 
medicine 2011;364:1046-60. 
5. 
El Accaoui RN, Shamseddeen WA, Taher AT. Thalidomide and 
thrombosis. A meta-analysis. Thrombosis and haemostasis 2007;97:1031-
6. 
6. 
Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, 
lenalidomide, and dexamethasone for relapsed multiple myeloma. The 
New England journal of medicine 2015;372:142-52. 
7. 
Weijuan L, Cornell RF, Lenihan D, et al. Cardiovascular Complications of 
Multiple Myeloma Treatment. Circulation 2016; in press. 
8. 
Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE 
disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: 


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42 
 
American College of Chest Physicians Evidence-Based Clinical Practice 
Guidelines. CHEST 2012;141:e419S-94S. 
9. 
Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of 
thalidomide- and lenalidomide-associated thrombosis in myeloma. 
Leukemia 2008;22:414-23. 
10. 
Fanikos J, Stevens LA, Labreche M, et al. Adherence to pharmacological 
thromboprophylaxis orders in hospitalized patients. The American journal 
of medicine 2010;123:536-41. 
11. 
Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial 
fibrillation. The New England journal of medicine 2011;364:806-17. 
12. 
Schulman S, Kearon C. Definition of major bleeding in clinical 
investigations of antihemostatic medicinal products in non-surgical 
patients. J Thromb Haemost 2005;3:692-4. 
13. 
Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of 
myocardial infarction. Circulation 2012;126:2020-35. 
14. 
Piazza G, Rao AF, Nguyen TN, et al. Venous thromboembolism in 
hospitalized patients with active cancer. Clinical and applied 
thrombosis/hemostasis : official journal of the International Academy of 
Clinical and Applied Thrombosis/Hemostasis 2013;19:469-75. 
15. 
Piazza G. Venous thromboembolism and cancer. Circulation 
2013;128:2614-8. 


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16. 
Kucher N, Koo S, Quiroz R, et al. Electronic alerts to prevent venous 
thromboembolism among hospitalized patients. The New England journal 
of medicine 2005;352:969-77. 
17. 
Piazza G, Rosenbaum EJ, Pendergast W, et al. Physician alerts to 
prevent symptomatic venous thromboembolism in hospitalized patients. 
Circulation 2009;119:2196-201. 
18. 
Piazza G, Anderson FA, Ortel TL, et al. Randomized trial of physician 
alerts for thromboprophylaxis after discharge. The American journal of 
medicine 2013;126:435-42. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1. Study Calendar 
Procedure 
Screeninga 
6-month 
Visit 
Informed Consent 
X 
Inclusion/Exclusion 
X 
Demographics 
X 
Medical History  
X 
 
Prior/Concomitant Medications  
X 
 
Urine Pregnancy (if clinically 
indicated) 
X 
Multiple Myeloma History 
X 
Cardio-vascular History 
X 
 
Thrombosis Evaluation 
X 
Bleeding Evaluation 
X 
Pill Diary Collection 
 
X 
aScreening is D-21 through D1 prior to enrollment 
 
 
Case Report Form 
 
Screening 
Inclusion criteria (all 
must be checked) 
[ ] Diagnosis of multiple myeloma 
[ ] Receiving immunomodulatory therapy (either thalidomide 
[Thalomid], lenalinomide [Revlimid], and pomalidomide 
[Pomalyst]) 
[ ] 18 years of age or older 
[ ] Willing and able to provide written informed consent 
 
Exclusion criteria 
(NONE must be 
checked) 
[ ] Pregnancy 
[ ] Breastfeeding 
[ ] Women of child-bearing potential who are unwilling or 
unable to use an acceptable method of birth control to avoid 
pregnancy for the entire study 
[ ] Any prior venous thromboembolism 
[ ] Contraindication to anticoagulant therapy 
[ ] Conditions for which serious bleeding may occur 
including: 
o Current or within last 6 months: intracranial 
bleeding, intraocular bleeding, gastrointestinal 
bleeding, endoscopically documented ulcer 
disease 
o Current or within last month: head trauma or 
other major trauma, major surgery 
o Current or within last 2 weeks:  stroke, 
neurosurgical procedure 
o Current: gross hematuria, major unhealed 
wound, major surgery planned during the trial 
period, intracranial mass, vascular 


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malformation, or aneurysm, overt bleeding, 
blood dyscrasia 
[ ] Active and clinically signficant liver disease 
[ ] Uncontrolled hypertension: systolic blood pressure >180 
mm Hg or diastolic blood pressure >100 mm Hg 
[ ] Current endocarditis 
[ ] Requirement for ongoing anticoagulant therapy including 
mechanical heart valve replacement and atrial fibrillation 
[ ] Severe valvular heart disease, including rheumatic heart 
disease and mitral stenosis 
[ ] Bioprosthetic heart valve replacement  
[ ] Requirement for dual antiplatelet therapy or single agent 
antiplatelet therapy with clopidogrel, prasugrel, or ticagrelor 
[ ] Requirement for aspirin at a dose higher than 165 mg 
daily.  
[ ] Hemoglobin < 9 mg/dL 
[ ] Platelet count < 100,000/mm3 
[ ] Calculated creatinine clearance (CrCl) < 25 ml/m 
[ ] Alanine aminotransferase or aspartate aminotransferase 
level > 2 times the upper limit of the normal 
[ ] Total bilirubin level > 1.5 times the upper limit of the 
normal 
[ ] Life expectancy < 12 months or hospice care 
[ ] Prisoners or subjects who are involuntarily incarcerated 
[ ] Subjects who are compulsorily detained for treatment of 
either a psychiatric or physical (eg, infectious disease) 
illness 
[ ] Receiving concurrent investigational agents or has 
received an investigational agent within the past 30 days 
prior to the first dose of study treatment (with the exception 
of approved medications being used for an approved 
indication, e.g., investigating a new dosing regimen for an 
approved indication).  
[ ] Any condition, which in the opinion of the investigator, 
would put the subject at an unacceptable risk from 
participating in the study 
[ ] Any other medical, social, logistical, or psychological 
reason, which in the opinion of the investigator, would 
preclude compliance with, or successful completion of, the 
study protocol 
 
STOP HERE AND DO NOT ENROLL PATIENT IF ANY OF THE INCLUSION 
CRITERIA ARE ABSENT OR ANY EXCLUSION CRITERIA ARE PRESENT 
Eligible 
 
[ ] Yes 
[ ] No 
Written informed 
[ ] Yes 


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consent signed 
[ ] No 
 
 
Patient Demographics 
Study ID number 
_ _ _ _ _ _ 
Date of enrollment 
           ______/______/________ 
              MM             DD               YYYY 
Date of birth 
           ______/______/________ 
              MM             DD               YYYY 
Gender 
 
[ ] Male                                         
[ ] Female 
Ethnicity 
[ ] Hispanic/Latino 
[ ] Non-Hispanic/Non-Latino 
Race 
[ ] American Indian or Alaskan Native 
[ ] Asian 
[ ] White 
[ ] Hispanic or Latino 
[ ] Native Hawaiian or Pacific Islander 
[ ] Black or African-American 
[ ] Mixed race 
[ ] Other, specify:___________ 
Weight (enter either 
weight and height OR 
BMI) 
 
             ___________________(kg) 
Height 
             ___________________(cm) 
BMI calculated 
             ___________________(kg/m²) 
 
 
Multiple Myeloma Characteristics 
Date of diagnosis 
           ______/______/________ 
              MM             DD               YYYY 
Diagnosis status 
[ ] New diagnosis (diagnosis within the last 30 days) 
[ ] Recurrent/relapsed disease 
Diagnostic criteria 
International Myeloma Working Group (IMWG) criteria  
 
Must have at least one of the following:  
[ ] Serum M-protein ≥ 0.5 g/dL by serum electrophoresis 
(SPEP) or for IgA myeloma, by quantitative IgA (>750 mg/dl) 
[ ] Urinary M-protein excretion at least 200 mg/24 hours 
[ ] Serum Free Light Chain (FLC) whereby the involved light 
chain measures ≥ 10 mg/dL and with an abnormal light chain 
ratio. 
Stage 
[ ] R-ISS I – ISS stage I (B2M <3.5 mg/L and serum albumin 
≥3.5 g/dL) and normal LDH and no del(17p), t(4;14), or 


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t(14;16) by FISH.  
[ ] R-ISS II – Neither stage I nor stage III.  
[ ] R-ISS III – ISS stage III (B2M ≥5.5 mg/L) plus LDH above 
normal limits and/or detection of one of the following by FISH: 
del(17p), t(4;14), or t(14;16).  
Immunomodulatory 
therapy (check one) 
[ ] thalidomide [Thalomid] 
[ ] lenalinomide [Revlimid] 
[ ] pomalidomide [Pomalyst] 
Other therapies 
[ ] proteasome inhibitors (PIs) (i.e., bortezomib [Velcade] and 
carfilzomib [Kyprolis]) 
[ ] corticosteroids (including dexamethasone) 
If yes, provide specific regimen (drug, dose, and 
frequency):___________________________________ 
[ ] chemotherapy 
[ ] hematopoietic cell transplantation 
[ ] erythropoiesis stimulating agents 
[ ] other 
 
 
Comorbid Conditions 
Cardiovascular disease 
[ ] Cardiomyopathy/diminished left ventricular 
systolic function 
If yes, EF (%) ____ 
[ ] Heart failure 
[ ] Coronary artery disease 
If yes,  
CABG [ ] 
Coronary stent(s) [ ] 
Prior MI [ ] 
Unstable angina [ ] 
Stable angina [ ] 
[ ] Rheumatic heart disease 
[ ] Valvular heart disease 
[ ] Atrial fibrillation or atrial flutter 
[ ] Congenital cardiac abnormality  
[ ] Pulmonary hypertension 
[ ] Other structural cardiac disease 
 
Valvular disease 
[ ] Aortic Stenosis 
[ ] Aortic regurgitation 
[ ] Mitral regurgitation 
[ ] Mitral Stenosis 
[ ] Other 
 
If yes, 
Any severe valve disease?   


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[ ] Yes 
[ ] No 
Hypertension 
[ ] Yes                                             
[ ] No 
Peripheral 
vascular/artery disease 
[ ] Yes                                             
[ ] No 
Carotid occlusive 
disease 
[ ] Yes                                             
[ ] No 
Cerebrovascular 
accident (strokes or 
TIAs) 
[ ] Yes                                             
[ ] No 
Family history of VTE 
[ ] Yes 
[ ] No 
History of bleeding 
[ ] Yes                                             
[ ] No 
Hypercholesterolemia 
[ ] Yes                                             
[ ] No 
Current alcohol 
consumption 
[ ] None                                             
[ ] 1-2 drinks per day 
[ ] >2 drinks per day 
Chronic liver disease 
(as noted in chart) 
[ ] Yes                                             
[ ] No  
If yes, cirrhosis 
[ ] yes 
[ ] no 
History of falls 
[ ] Yes                                             
[ ] No 
Cigarette smoking 
(check only 1) 
[ ] Current smoker           
[ ] Former smoker     
[ ] Never smoker             
Major surgery within 
the past 3 months 
[ ] Yes                                             
[ ] No 
If yes, date            ______/______/________ 
              MM             DD               YYYY 
 
If within the last month, patient should not be enrolled. 
Prior hospitalization 
within 30 days 
[ ] Yes                                             
[ ] No  
COPD 
[ ] Yes                                             
[ ] No 
Diabetes mellitus  
(Type I or II) 
[ ] Yes                                             
[ ] No 
Serum creatinine  > 2.5 
mg/dL  
[ ] Yes                                             
[ ] No                        
 If yes, is patient on dialysis?  
[ ] Yes                                             


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[ ] No 
 
If yes, patient should not be enrolled. 
 
If no, creatinine clearance (Cockroft-Gault) = _ _ _ mg/dL 
Concomitant 
medications 
[ ] aspirin 
If yes, dose = _ _ _ mg/daily 
 
If > 165 mg/daily, patient should not be enrolled. 
 
[ ] daily NSAID use 
 
Prior 
thromboprophylaxis 
regimen 
[ ] Yes 
[ ] No 
 
If yes, check all that apply: 
[ ] LMWH 
[ ] Fondaparinux 
[ ] Unfractionated heparin 
[ ] Warfarin 
[ ] NOAC 
[ ] Aspirin 
[ ] Other: _________ 
 
 
 
 
Study Treatment 
Date study drug 
started 
____/____/_____        
MM     DD     YYYY              
Date study drug 
stopped  
____/____/_____        
MM     DD     YYYY    
 
Completed full 6 months of study drug? 
[ ] Yes 
[ ] No 
 
If did not stay on drug for 6 months, reason why not? 
[ ] Fulfilled criteria for a primary study outcome (VTE or 
major/clinically relevant non-major bleed) 
[ ] Patient expired 
[ ] Adverse drug event or side-effect 
[ ] Change in clinical status (such as change in goals of care, 
comfort measures, hospice care) 
[ ] Patient preference/withdrawal of consent           
 


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Medication 
adherence (via pill 
count) 
Total doses taken/total doses prescribed = ( __ / 336) x 100  
= _ _ _ % 
 
 
Six-Month Study Outcomes 
Deep vein 
thrombosis 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Confirmed by diagnostic imaging: 
[ ] Yes 
[ ] No 
If yes, by? 
[ ] Ultrasound 
[ ] CT 
[ ] MRI 
[ ] Venography 
 
Location: 
[ ] Upper extremity 
If checked: 
[ ] Right 
[ ] Left 
[ ] Bilateral or SVC 
 
[ ] Lower extremity 
If checked: 
[ ] Right 
[ ] Left 
[ ] Bilateral or IVC 
[ ] Proximal (popliteal or higher) 
[ ] Calf 
 
Hospitalized? 
[ ] Yes 
[ ] No 
 
Treatment: 
[ ] Anticoagulation 
[ ] Pharmacomechanical (catheter-based) therapy 
[ ] Surgery 
[ ] IVC filter 
 


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Superficial vein 
thrombosis 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Other venous 
thrombosis 
(mesenteric, cerebral 
sinus, gonadal, etc.) 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Pulmonary embolism [ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Confirmed by diagnostic imaging: 
[ ] Yes 
[ ] No 
If yes, by? 
[ ] CT 
[ ] MRI 
[ ] Pulmonary angiography 
[ ] V/Q scan 
 
Location: 
[ ] Left 
[ ] Right 
[ ] Bilateral 
 
RV dysfunction on echocardiogram or CT? 
[ ] Yes 
[ ] No 
 
Associated with hemodynamic instability (syncope, shock, 
hypotension, cardiac arrest)? 
[ ] Yes 
[ ] No 
 
Fatal? 
[ ] Yes 
[ ] No 
 
Hospitalized? 


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[ ] Yes 
[ ] No 
 
Treatment: 
[ ] Anticoagulation 
[ ] Systemic fibrinolysis 
[ ] Pharmacomechanical (catheter-based) therapy 
[ ] Surgical embolectomy 
[ ] IVC filter 
 
Death 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Cause of death: 
[ ] PE 
[ ] Myocardial infarction 
[ ] Other cardiovascular  
[ ] Cancer-related 
[ ] Non-cardiovascular, non-cancer 
 
Major or clinically 
relevant non-major 
bleed 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Major bleed 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Location: 
[ ] Intracranial 
[ ] Surgical/operative site 
[ ] Gastrointestinal 
[ ] Genitourinary 
[ ] Retroperitoneal 
[ ] Pericardial 
[ ] Pulmonary 
[ ] Other thoracic 
[ ] Musculoskeletal 
[ ] Nasopharyngeal 


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[ ] Hematocrit or hemoglobin decrease without clear source 
[ ] Other 
 
Fatal? 
[ ] Yes 
[ ] No 
 
Hospitalized? 
[ ] Yes 
[ ] No 
 
Associated with hemodynamically instability? 
[ ] Yes 
[ ] No 
 
Treatment: 
[ ] Blood products 
[ ] Surgery 
[ ] Invasive procedure 
[ ] Medical therapy (PCC, andexanet, etc.) 
 
Clinically relevant 
non-major bleed 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Location: 
[ ] Intracranial 
[ ] Surgical/operative site 
[ ] Gastrointestinal 
[ ] Genitourinary 
[ ] Retroperitoneal 
[ ] Pericardial 
[ ] Pulmonary 
[ ] Other thoracic 
[ ] Musculoskeletal 
[ ] Nasopharyngeal 
[ ] Hematocrit or hemoglobin decrease without clear source 
[ ] Other: _______________ 
 
Hospitalized? 
[ ] Yes 
[ ] No 
 
Treatment: 


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[ ] Blood products 
[ ] Surgery 
[ ] Invasive procedure 
[ ] Medical therapy (PCC, andexanet, etc.) 
 
Non-bleed adverse 
drug reaction 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Type of reaction: 
[ ] Anaphylaxis 
[ ] Cutaneous (rash, etc.) 
[ ] Liver function abnormalities 
[ ] Other: _______________ 
 
Hospitalized? 
[ ] Yes 
[ ] No 
 
Study drug discontinuation? 
[ ] Permanent stop 
[ ] Temporary stop 
[ ] Not discontinued 
 
Myocardial infarction 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Type: 
[ ] ST elevation 
[ ] Non-ST elevation 
 
Fatal? 
[ ] Yes 
[ ] No 
 
Treatment: 
[ ] Systemic fibrinolysis 
[ ] Percutaneous coronary intervention (angioplasty, stenting, 
etc.) 
[ ] CABG 
[ ] Medical management 


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55 
 
 
Stroke/TIA 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
TIA? 
[ ] Yes 
[ ] No 
 
Stroke? 
[ ] Yes 
[ ] No 
 
If yes, type of stroke: 
[ ] Ischemic 
[ ] Hemorrhagic 
[ ] Other 
 
Fatal stroke? 
[ ] Yes 
[ ] No 
 
Treatment: 
[ ] Systemic fibrinolysis 
[ ] Percutaneous thrombectomy 
[ ] Surgery 
[ ] Other 
 
 
 
 
Appendix 
 
1. Apixaban Package Insert 
 
2. Informed Consent