Management of Venous Thromboembolism in Patients Receiving Immunomodulatory Agents
|Shaji K. Kumar, MD
Professor of Medicine
Clinical Research Office
Mayo Clinic Cancer Center
How important of an issue is venous thromboembolism (VTE) in patients with myeloma, and what are some of the contributing factors to this?
In myeloma, as with all cancers, there is an increased risk of VTE. Though the numbers vary depending on the timeframe in which studies have been done and the types of treatments used, probably about 10% of patients will develop a venous thromboembolic episode some time during the course of the disease.1 While VTE is not necessarily becoming more of a problem among patients with myeloma, the impact is significant in terms of both the cost of management as well as issues for the patients. Clearly, patients are living longer with myeloma, so we certainly need to be more cognizant of this problem.
What is currently known regarding risk factors for VTE in patients with myeloma, and how does this figure into risk stratification?
There are a variety of different risk factors identified that put patients at a higher risk of developing VTE. Broadly, these have been grouped into factors that are related to the disease itself, related to the patient, and certain factors that are related to the types of treatment that we use for the myeloma itself. Among patient-related risk factors, some of the strongest include older age, obesity, and history of VTE, but there are a number of others, including presence of a central venous catheter, hospitalization associated with fractures, pre-existing thrombophilic conditions, and a variety of other comorbidities such as chronic inflammatory bowel disease and diabetes. A lower risk of VTE has been identified in the Asian population.2 And with respect to the disease-related risk factors, patients with a newly diagnosed disease are at higher risk compared to someone with relapsed or refractory myeloma, and patients who present with very high levels of monoclonal protein also seem to be at higher risk.
In terms of treatment, we recognized that there was an increased risk of VTE when we started using the immunomodulatory drugs (IMiDs). The observation during the context of some of the phase 3 trials showed that IMiDs used in combination with a high dose of dexamethasone was associated with this significantly higher risk of VTE.3 Since then, other agents also have been associated with VTE in myeloma—for example, use of erythropoietin for anemia, use of cytotoxic chemotherapy and especially anthracyclines, and then the multi-drug combinations that are used today can have a cumulative added risk of thromboembolism as well.
How have these findings translated into risk stratification?
These risk factors have been used to develop a variety of different risk stratification systems that have been included in recommendations on prevention of thalidomide- and lenalidomide-associated thrombosis from the International Myeloma Working Group (IMWG),4 as well as guidelines from the European Myeloma Network (EMN)5 and National Comprehensive Cancer Network (NCCN).6 In general, what has been done in terms of risk stratification is identifying the number of these risk factors that are present. For example, if three or more of these risk factors are present, patients are often considered to be at a higher risk of thrombosis, and a different prophylactic approach might be called for.
Is there any one system (eg, the Khorana score) that is most useful in myeloma?
The Khorana risk score is generally useful for risk of identifying patients with cancer at high risk of thrombosis; however, it does not predict VTE very well in the setting of myeloma.7 There have been some myeloma-specific risk assessment models that have been developed. One of these that was published about a year ago is called the IMPEDE VTE score,2 which was based on data from 4,446 patients in the Veterans Administration Central Cancer Registry. Variables included in the risk score include use of an IMiD, body mass index greater than 25 kg/m2, presence of a pathologic fracture, use of an erythropoiesis stimulating agent, use of high-dose dexamethasone, use of chemotherapy like doxorubicin, ethnicity or race, previous history of VTE, presence of a tunneled line/central venous catheter, and type of thromboprophylaxis that is used. Basically, points are given to each of these different characteristics to come up with a risk assessment model that groups patients into low, intermediate, and high risk.
So, the IMPEDE VTE score is useful, but I think the main thing to keep in mind is that risk stratification systems should be used as broad guidelines. Individual patient context can be quite different, especially in myeloma as the treatments continue to change quite rapidly, which needs to be taken into account. We are using multi-drug combinations so that needs to be kept in mind as well, so from that standpoint, I think it is also important to talk about the individual drugs that have an impact on the VTE. With proteasome inhibitors, and bortezomib particularly, there seems to be a decreased risk of developing VTE. Furthermore, the combination of an IMiD plus a proteasome inhibitor to some extent might neutralize the risk, as was shown in a review of data from earlier phase 3 trials.8 However, we are lacking prospective studies using more recent multi-drug combinations, so this is somewhat of an extrapolation of the data that we have from the previous studies.
To what extent are the practice guidelines useful in terms of risk assessment and management of VTE?
The guidelines from the IMWG and NCCN are all useful, though a number of studies have shown that overall adherence has not been very consistent in clinical practice.9,10 However, the guidelines do provide a tool set to identify those patients who are at high risk of VTE, and the factors that they recommend for stratifying these patients are things that are commonly available and do not require any additional testing. From a utility standpoint, I think any of these guidelines could be considered; they differ not so much in treatment, but more in terms of risk factors being considered. That said, the risk factors they recommend are very much overlapping between guidelines, so it does not matter so much which specific guideline you follow to identify who is at a higher risk of VTE.
What are main options that you consider today when VTE prophylaxis is warranted for a patient with multiple myeloma?
The easiest approach is obviously using aspirin. There are plenty of data suggesting that aspirin decrease the risk of thrombosis in patients with multiple myeloma. For example, in the original Eastern Cooperative Oncology Group trial that looked at lenalidomide plus high- or low-dose dexamethasone (E4A03), there was a significant increase in VTE associated with steroid dose that was reduced with the addition of aspirin alone.3,11 So, for patients with a low risk of thrombosis, aspirin appears to be sufficient. There are few studies that have compared aspirin with fixed-dose warfarin versus low-molecular weight heparin (LMWH) for prophylaxis, and there did not seem to be a significant advantage of one over the other.
In patients with a higher risk of VTE, use of LMWH to decrease the risk of thrombosis is preferred, though the disadvantage of using the LMWH is obviously that it has to be given subcutaneously. There is very little data for use of LMWH in patients with renal insufficiency, so in a patient with a creatinine clearance that is less than 30 mL/min/1.73m2, we will have to monitor anti-factor Xa activity and potentially modify the dose.12 Also, there is an expense that goes with the low molecular weight heparin. The alternative for patients with renal insufficiency is to use unfractionated heparin; there, you do not have to worry about the drug accumulation because of the lack of renal clearance. The other option is to use warfarin, which can be taken orally, and certainly is the least expensive approaches outside of aspirin. However, warfarin has to be closely monitored, which can become quite problematic in patients who become cytopenic—especially if platelet counts keep dropping and going back up with treatment, it may become quite difficult to monitor and adjust the doses of warfarin.
More recently, there have been some studies looking at the direct oral anticoagulant (DOAC) agents such as apixaban. The data is mostly from retrospective analyses or pilot studies, but it appears to be quite safe to use, and it is certainly easy to monitor. Prospective studies are lacking, but there are some clinical trials that are ongoing right now, looking at the utility of apixaban in this setting.13
Putting it all together, what is your own approach in terms of evaluating a patient with multiple myeloma for VTE risk and deciding upon a strategy for prophylaxis?
Currently, the most commonly used regimen in newly diagnosed myeloma is the combination of bortezomib/lenalidomide/dexamethasone. In terms of the IMiD and dexamethasone, we know there is an increased risk of VTE there. So, if patients have at least a few VTE risk factors, such as VTE history or immobilization due to a bone fracture, we generally would start them on LMWH, at least initially, so that it becomes easier to manage them. The alternate option is trying one of the newer oral anticoagulants. We prefer not to use warfarin, especially in very old patients—there is an increased risk of bleeding in the older patients as it is, and we also want to get a sense of how much thrombocytopenia we are seeing with these drugs. Once we are sure that counts are improving and they are tolerating the treatment well, we can always switch to warfarin if need be. The choice between these three options—LMWH, DOAC, or warfarin—often depends on logistics: Are you expecting a lot of thrombocytopenia? Does the patient have renal dysfunction? How old and frail is the patient? Is there a risk of falling? All these factors need to be taken into consideration.
Then, as long as the patient is on a treatment that you think increases the VTE risk—for example, an IMiD with dexamethasone—then we will continue them on the prophylaxis until they are off that medication. I usually continue them on anticoagulation for at least a month after they stop therapy, as long as there are no other risk factors that are still persistent.
What is in store for the future in this area?
I think that in the future, we are going to be using more and more of the drugs like apixaban as we get more data. I think the DOACs are much easier to manage, and obviously convenient for the patients because they are oral.
- Zamagni E, Brioli A, Tacchetti P, Zannetti B, Pantani L, Cavo M. Multiple myeloma, venous thromboembolism, and treatment-related risk of thrombosis. Semin Thromb Hemost. 2011;37(3):209-219. doi:10.1055/s-0031-1273085
- Sanfilippo KM, Luo S, Wang T-F, et al. Predicting venous thromboembolism in multiple myeloma: Development and validation of the IMPEDE VTE score. Am J Hematol. 2019;94(11):1176-1184. doi:10.1002/ajh.25603
- Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: An open-label randomised controlled trial. Lancet Oncol. 2010;11(1):29-37. doi:10.1016/S1470-2045(09)70284-0
- Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22(2):414-423. doi:10.1038/sj.leu.2405062
- Terpos E, Kleber M, Engelhardt M, et al. European Myeloma Network Guidelines for the Management of Multiple Myeloma-related Complications. Haematologica. 2015;100(10):1254-1266. doi:10.3324/haematol.2014.117176
- NCCN Clinical Practice Guidelines in Oncology. Cancer-associated venous thromboembolic disease. Version 1.2019 – February 28, 2019. Available at https://www.nccn.org/professionals/physician_gls/pdf/vte.pdf. Accessed April 6, 2020.
- Sanfilippo KM, Wang T-F, Luo S, et al. Predictive ability of the Khorana score for venous thromboembolism (VTE) in multiple myeloma (MM). J Clin Oncol. 2018;36(15_suppl):e18733-e18733. doi:10.1200/JCO.2018.36.15_suppl.e18733
- Zangari M, Fink L, Zhan F, Tricot G. Low venous thromboembolic risk with bortezomib in multiple myeloma and potential protective effect with thalidomide/lenalidomide-based therapy: Review of data from phase 3 trials and studies of novel combination regimens. Clin Lymphoma Myeloma Leuk. 2011;11(2):228-236. doi:10.1016/j.clml.2011.03.006
- Baker HA, Brown AR, Mahnken JD, Shireman TI, Webb CE, Lipe BC. Application of risk factors for venous thromboembolism in patients with multiple myeloma starting chemotherapy, a real-world evaluation. Cancer Med. 2019;8(1):455-462. doi:10.1002/cam4.1927
- Anderson SM, Beck B, Sterud S, Lockhorst R, Ngorsuraches S. Evaluating the use of appropriate anticoagulation with lenalidomide and pomalidomide in patients with multiple myeloma. J Oncol Pharm Pract. 2019;25(4):806-812. doi:10.1177/1078155218758500
- Menon SP, Rajkumar V, Lacy M, Falco P, Palumbo A. Thromboembolic Events With Lenalidomide-based Therapy for Multiple Myeloma. Cancer. 2008;112(7):1522-1528. doi:10.1002/cncr.23336
- Kristinsson SY, Landgren O. Thromboprophylaxis in multiple myeloma: Is the evidence there? Expert Rev Anticancer Ther. 2012;12(3):291-294. doi:10.1586/era.11.214
- Cornell RF, Goldhaber SZ, Engelhardt BG, et al. Apixaban for Primary Prevention of Venous Thromboembolism in Patients With Multiple Myeloma Receiving Immunomodulatory Therapy. Front Oncol. 2019;9:45. doi:10.3389/fonc.2019.00045