Multiple Myeloma Patients SAVED from Thrombosis

Introduction

Multiple myeloma is an incurable malignancy involving the proliferation of plasma cells within the bone marrow, and is the second most common hematologic cancer in the United States.1,2 Rather than producing healthy functional antibodies, plasma cells produce abnormal monoclonal proteins or immunoglobulins that can be referred to as myeloma proteins (M-protein).3 In addition to structural bone damage, these non-functional proteins can accumulate in the blood and urine to cause organ damage and reduce overall immunity.2 The Veterans Health Administration identified Agent Orange exposure as a common risk factor in developing multiple myeloma.4 Other risk factors include exposure to radiation or chemicals (e.g. asbestos, benzene, pesticides, herbicides), age >60 years old, male gender, race (Middle East, Black, Mediterranean decent), and personal history of solitary plasmacytoma or monoclonal gammopathy of undetermined significance (MGUS).1,3


Effects of Multiple Myeloma on the Coagulation Cascade

Multiple myeloma patients have a greater risk for venous thromboembolism (VTE) compared to other solid cancers due to the pathology of the malignancy and treatment-related factors.5 About one in three multiple myeloma patients will experience a VTE within the first year of treatment.3 The molecular mechanism that links thrombosis to malignancy differs between solid cancers and multiple myeloma.5 IL-6, which is involved in the coagulation cascade, is elevated in myeloma patients. This cytokine aids as an anti-apoptotic factor for myeloma cells and in the growth of malignant clones. IL-6 increases activity of plasminogen activator inhibitor-1 (PAI-1), thus decreasing fibrinolytic activity.6 The abnormal levels of immunoglobulins produced in myeloma increases blood viscosity and impairs fibrin polymerization. Due to their thin shape and small size, these fibrin structures are resistant to plasmin degradation. The M-protein itself may be associated with intrinsic pro-thrombotic properties as found in Belloti, et al study.7,8 Three patients were shown to have immunoglobulins with lupus anticoagulant-like activity against thromboplastin phospholipid.8 The incidence of acquired activated protein-C resistance (aAPCR) without factor-V Leiden mutation was studied in a large population (n= 1178) of multiple myeloma patients.6,9 A high incidence of aAPCR was initially discovered in solid cancer patients.6,10 In myeloma, 6% of the patients contained abnormal APCR at baseline and was statistically associated with an increased VTE risk (Odds Ratio 3.45, 95% CI 1.86-6.42; p<0.001).9 aAPCR was found to be the most frequent single coagulation abnormality associated with thrombosis.6,9 In inflammatory disorders, protein S, an important cofactor for the inactivation of factor-Va and factor-VIIIa, is generally reduced.11 A study confirmed aAPCR and decreased protein S activity in 27% (n= 78) of newly diagnosed myeloma patients (p=0.012). These mechanisms contribute to the hypercoagulable state and manifestation of multiple myeloma.


Treatment-Related Effects on Thrombosis

Immunomodulatory drugs (IMiDs) are major components of multiple myeloma therapy. As thalidomide analogues, they possess anti-angiogenic and anti-neoplastic properties. This class of medications inhibits proliferation and induces apoptosis of hematopoetic tumor cells. By altering cytokine production, these agents regulate T cell co-stimulation and enhance NK-cell cytotoxicity.12,13 Cytokines generally influence gene activation and growth and differentiation of cell surface molecule expression. Interactions involving cytokines and antibodies result in tumor destruction. IMiDs potentiate cytokine production which influence interactions among myeloma cells, bone marrow stromal cells, and endothelial cells.13 These events cause an elevation in factor VIII, von Willebrand factor, fibrinogen, and D-dimer which lead to endothelial cell dysfunction, platelet activation, and thrombosis formation.13 IMiD therapy alone has a 4% risk for VTE, which when combined with dexamethasone increases up to 12% with low-dose dexamethasone (40 mg per week) or 26% with high-dose dexamethasone (160 mg per week).14,15 Due to this risk, lenalidomide and pomalidomide each carry a black-box warning for venous thromboembolism with concomitant dexamethasone use.

Lenalidomide

A second-generation IMiD, lenalidomide, is used in triplet therapy regimens for initial management in transplant and non-transplant eligible patients.2 Single-agent lenalidomide is the preferred maintenance therapy after autologous stem cell transplant or initial treatment in non-transplant patients, for which it has shown to improve progression free survival. Lenalidomide in combination with dexamethasone is approved as treatment for relapsed or refractory multiple myeloma. A synergistic effect was shown with this combination therapy which effectively inhibited cell proliferation and induced apoptosis.12

In 2006, Weber D, et al. evaluated the combination of lenalidomide and dexamethasone against placebo and dexamethasone.16 This multicenter, phase III trial (n= 177) included patients with relapsed/refractory multiple myeloma. Patients received dexamethasone 160 mg/week for four cycles, then 160 mg/month starting at cycle five. No thromboprophylactic therapy was given during the study. The incidence of thromboembolic events was 26 (14.7%)in the lenalidomide-group and 6 (3.4%)in the placebo-group (p<0.001). Although lenalidomide and dexamethasone was therapeutically effective, the incidence of thromboembolic events indicated that prophylactic therapy should be considered in myeloma patients.

A non-inferiority trial by Rajkumar S, et al published in 2010 compared the efficacy and safety of lenalidomide with high-dose versus low-dose dexamethasone in newly diagnosed multiple myeloma (n= 445).17 The high-dose group was defined as receiving dexamethasone 480 mg/month and the low-dose group as 160 mg/month. Patients were excluded if they had a history of deep venous thromboembolism (DVT). Thromboprophylaxis was not mandated; however, due to the high rates of DVT in the study, prophylactic aspirin 81-325 mg was added in order to continue the trial.17 The incidence of DVT in the high-dose group was 57 (26%) versus 27 (12%) in the low-dose group (p= 0.003). Pulmonary embolism occurred in 20 (9%) of high-dose patients vs. 9 (4%) of low-dose patients. The greatest incidence of thrombosis occurred in the first four months of treatment in the high-dose group compared to the low-dose group, 20% vs. 9%.17 Thromboembolic events caused deaths in both groups, 9% vs. 2%. Overall, high-dose dexamethasone resulted in a greater incidence of thromboembolic events and the greater number of deaths within the first four months of treatment.

Pomalidomide

As a third-generation IMiD, pomalidomide is reserved for patients after at least two prior therapies, including lenalidomide, with disease progression within 60 days from the last treatment.2 Pomalidomide possesses an unique ability to inhibit the proliferation of lenalidomide-resistant myeloma cell lines.18Combination therapy with dexamethasone also demonstrated a therapeutic synergistic effect in multiple myeloma.

Pomalidomide is associated with fewer thromboembolic events than lenalidomide; however, this data may reflect the mandatory or increased thromboprophylaxis use in subsequent pomalidomide trials.14 A randomized, multicenter, phase II study assessed the efficacy and safety of pomalidomide with or without dexamethasone in relapsed/refractory multiple myeloma.19 All patients (n= 219) received aspirin 81-100 mg/day, or LMWH based on health care facility protocol if aspirin was contraindicated. The incidence of DVT was low with or without dexamethasone, 2 (2%) vs. 3 (3%). The majority of patients were using aspirin; therefore, even with simple thromboprophylactic therapy there was minimal risk for a DVT.


Literature Review of Thromboembolism Prophylaxis in Multiple Myeloma

Due to the increase in thromboembolic complications in multiple myeloma patients, studies were conducted to assess appropriate thromboembolism prophylactic therapy. A prospective, phase III trial by Larocca A, et al in 2012, compared the efficacy and safety of aspirin 100 mg/day (n= 176) or low-molecular weight heparin (LMWH) enoxaparin 40 mg/day (n= 166) in newly diagnosed multiple myeloma.20 Patients were treated with lenalidomide and low-dose dexamethasone followed by melphalan, prednisone and lenalidomide consolidation therapy. The incidence of VTE between aspirin and LMWH was 2.27% vs. 1.20%, respectively (p= 0.452). Pulmonary embolism occurred in 1.70% of patients with aspirin and zero patients in the LMWH group. Only one event of minor gastrointestinal bleeding occurred in the LMWH group, which completely resolved. No arterial thrombosis, acute cardiovascular events, sudden deaths, or major hemorrhagic complications were reported in either group. Therefore, aspirin was found to be an effective and less-expensive alternative to LMWH in previously untreated myeloma patients on lenalidomide therapy.

Direct oral anticoagulants (DOACs) were studied in a retrospective review by Man L, et al in 2017, as thromboprophylaxis in myeloma patients on concurrent IMiD therapy.21 Patients received either therapeutically dosed warfarin (n= 16) or therapeutic or prophylactic doses of dabigatran, rivaroxaban, or apixaban (n= 21). Four non-major bleeds occurred in both groups, however two major bleeds occurred in the warfarin-group. No venous thromboembolisms (VTE) occurred in either group.

A larger retrospective review in 2019, evaluated the use of apixaban for VTE prevention in myeloma patients.22 Seventy patients received apixaban 2.5 mg twice daily with concomitant IMiD-based therapy. Patients were included with a history of a pulmonary embolism (n= 2), stroke (n= 2), or myocardial infarction (n= 3). No VTE events occurred in the first six months of therapy. Overall, two patients had arterial thrombosis, one patient had non-ST-elevation myocardial infarction with known ischemic heart disease, and one patient had major bleeding with known severe thrombocytopenia. VTE risk assessment scores are not available for this cohort. Apixaban was shown to be a safe, effective, and convenient alternative as thromboembolism prophylaxis during IMiD therapy.


Guideline-Directed Thromboembolism Prophylaxis

The National Comprehensive Cancer Network (NCCN) recently updated the guidelines for thromboembolism prophylactic therapy in multiple myeloma patients receiving IMiDs.23 The recommendations are supported by the SAVED score (Table 1), an algorithm developed in 2019 from retrospective data.23 The SAVED score determines appropriate thromboprophylactic therapy based on the patient’s total score; the higher the score, the greater risk of a thromboembolic event. Three points are given if patient has history of VTE. Two points are given for each: surgery within 90 days or if taking high-dose dexamethasone (>160 mg/cycle). One point is added for age of greater than or equal to 80 years old or if taking standard dose dexamethasone (120-160 mg/cycle). If the patient is of Asian race, then three points are deducted. Patients of high-risk (score of >2) should receive enoxaparin, dalteparin, warfarin, or apixaban. Patients of low-risk (score of <2) are recommended to receive aspirin 81-325 mg, or have no intervention per clinical judgment.

Table 1: SAVED score for Patients Treated with IMiDsa,b

Variable

Point Score

Calculate Risk

Surgery within 90 days

+ 2

High risk (>2 points)

• Enoxaparin 40 mg SC daily

• Dalteparin 5000 units SC daily (category 2B)

• Warfarin PO INR 2-3

• Apixaban 2.5 mg PO BID

Asian race

- 3


VTE history

+ 3

Low risk (<2 points)

• No intervention

• Aspirin 81-325 mg PO daily

Age >80 years

+ 1

Dexamethasone dose

Standard dose (120-160 mg per cycle)

High dose (>160 mg per cycle)


+ 1

+ 2

a Agent selection based on: renal failure (CrCL < 30 ml/min), FDA approval, cost, ease of administration, monitoring, and ability to reverse anticoagulation.

b Adapted from NCCN guidelines.23


The SAVED score was developed based on the evidence from a large population-based cohort study (n= 2,397) in 2019 using the SEER-Medicare and Veterans Health Administration (VHA) databases.24 The purpose of the study was to create and validate a new risk assessment model for IMiD-associated VTE. Patients with newly diagnosed multiple myeloma on IMiD therapy were included. The five independent risk factors for VTE as described above were identified through multivariable regression. Sensitivity analyses were conducted in the derivation cohort and validation cohort. About 30% of patients were high-risk in both cohorts. The SAVED score resulted in hazard ratio (HR) 1.85 (p<0.01) in the derivation cohort and HR 1.98 (p<0.01) in the validation cohort between high versus low risk patients. This algorithm serves as a new clinical tool to identify multiple myeloma patients at high risk for thromboembolism on IMiD therapy.

The NCCN also refers to the IMPEDE score to assess VTE risk and thromboembolism prophylaxis in cancer patients.23 The IMPEDE score was developed in 2019 based on retrospective data.22 Patients receiving IMiD therapy automatically receive four points, thus making them high-risk (score >3). Patients considered high-risk should receive enoxaparin, dalteparin, or warfarin. Additional criteria included in the IMPEDE score are the following: BMI >25 kg/m2, pelvic/hip/femur fracture, erythropoiesis stimulating agent, dexamethasone dose (<160 or >160 mg/month), doxorubicin, ethnicity, history of VTE before myeloma diagnosis, tunneled line/central venous catheter, and existing thromboprophylaxis therapy. Low-risk patients (score <3), should consider aspirin 81-325 mg. The American Society of Clinical Oncology (ASCO) guidelines refer to the Khorana score to assess VTE risk in all outpatient cancer patients including those with multiple myeloma.25 The Khorana score identifies the site of primary cancer, prechemotherapy platelet count, hemoglobin level, prechemotherapy leukocyte count, and BMI to stratify patients into low risk (0.3-1.5%), intermediate risk (1.8-4.8%), or high risk (6.7-12.9%) risk for VTE.2,24 According to ASCO and the Khorana score, all multiple myeloma patients on IMiD therapy with chemotherapy and/or dexamethasone should receive thromboprophylaxis. Low-risk patients (score of <2) should receive aspirin or LMWH, and high-risk patients (score of >3) should receive LMWH as prophylaxis.


Conclusion

The diagnosis of multiple myeloma itself is a risk factor for a thromboembolism and is exacerbated with the use of IMiD therapy. Risk assessment models have established clinical benefit in assessing thrombosis risk in cancer patients. The unique, multifaceted nature of thrombosis in myeloma patients have led to the development of the most recent SAVED score. Robust clinical data to support the use of superior thromboembolism prophylactic agents, especially direct oral anticoagulants (DOACs), in multiple myeloma is missing. Furthermore, research is warranted using DOACs due to their convenience and oral administration. For use in practice, the SAVED score is a valuable tool to stratify myeloma patients. Selecting an appropriate thromboembolism prophylactic agent would require assessing patient-specific safety, efficacy, and convenience of use.


Prepared by:

Demetra M. Mylonas, PharmD

PGY-2 Oncology Pharmacy Resident

Southern Arizona VA Health Care System

Tucson, AZ


References:


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