Apixaban for Primary Prevention of Venous Thromboembolism in Patients With Multiple Myeloma

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.

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

- 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

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

- Conditions for which serious bleeding may occur including:

1. Current or within last 6 months: intracranial bleeding, intraocular bleeding,
gastrointestinal bleeding, endoscopically documented ulcer disease

2. Current or within last month: head trauma or other major trauma, major surgery

3. Current or within last 2 weeks: stroke, neurosurgical procedure

4. Current: gross hematuria, major unhealed wound, major surgery planned during the
trial period, intracranial mass, vascular malformation, or aneurysm, overt
bleeding, blood dyscrasia

5. 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