Thrombosis and multiple myeloma

The risk of thromboembolism is increased in patients with multiple myeloma (MM) compared with the general population. A retrospective study of 4 million US veterans showed a nine-fold increase in the risk of deep vein thrombosis in patients with MM and a three-fold increased risk for those with monoclonal gammopathy of uncertain significance. Patients are most likely to develop venous thromboembolisms (VTEs) within the first year of treatment and, while treatments for MM may have improved, many of the novel agents carry an increased risk of VTE.¹

Why are patients with MM at greater risk of VTEs?

The pathophysiology of VTEs in MM is not fully understood. Patients with MM are at higher risk of VTE due to the influence of a number of competing factors split into three categories, as shown in Table 1.

Table 1. Risk factors for venous thromboembolisms in patients with multiple myeloma²

Patient-derived	Treatment-derived	Disease-derived
Increased age	Immunomodulatory agents	Surgery for fractures
Race	High-dose corticosteroid use	Hyperviscosity
Comorbidities - congestive heart failure - hypertension	Anthracyclines	Decreased mobility due to fractures
Obesity	Central venous lines	Nephrotic syndrome (if amyloidosis is present)
History of venous thromboembolism		Inflammation
Gender (male)	Active myeloma
	Erythropoiesis stimulating agents

Of note, patients with MM typically present all three factors included in the classic Virchow triad that predispose an individual to the development of VTEs²:

1. Venous stasis
2. Activation of coagulation or hypercoagulability
3. Endothelial damage

The International Myeloma Working Group (IMWG) guidelines for VTE risk assessment and thromboprophylaxis in MM were originally published in 2008 and then updated in 2014. Why is it that patients with MM continue to be at risk?

Although it is possible to identify patients at higher risk, and thromboprophylaxis is widely used, the different treatment strategies remain controversial²:

• Whether agents such as warfarin are better than low molecular weight heparin (LMWH) is unclear.
• Factors associated with administration reduce compliance in patients or prevent physicians from choosing to use them. LMWHs, for example, require daily subcutaneous injections.
• In addition, while new agents such as apixaban show promise, they have yet to be tested against the current standards of care for VTE prophylaxis in a randomized trial.
• There is also no consensus on which risk assessment model is best for selecting patients with greater risk of VTE.

How to identify patients at higher risk of VTEs

Currently, three different risk assessment models (RAMs) have been developed, as shown in Table 2.^3-5

• Each model takes into account a slightly different list of factors, although VTE history, ethnicity factors, and surgery for fractures are included in all models.
• The SAVED model only splits patients into high or low groups, whereas the other RAMs differentiate risk into three categories.
• The PRISM model is the most recent and the only one to include the impact of cytogenetics. This model does not include high-dose dexamethasone as this treatment has fallen out of favor following a randomized study that showed it resulted in increased thromboses and reduced overall survival.²

Table 2. VTE risk assessment models for patients with multiple myeloma

Risk assessment model	Factors evaluated	Score weighting	Risk score	References
IMiD, immunomodulatory drugs; LMWH, low molecular weight heparin; P-, prophylactic; T-, therapeutic; VTE, vascular thromboembolism.
SAVED	Surgery (within 90 days)	+2	High ≥ 2   Low ≤ 1	Li A, et al.3
Asian race	-3
VTE history	+3
Eighty (≥ 80 years)	+1
Dexamethasone dose:
Standard dose (120−160 mg)	+1
High dose (> 160 mg)	+2
IMPEDE-VTE	IMiD agent	4	High ≥ 8   Intermediate 4−7   Low ≤ 3	Sanfilippo KM et al.4
Body Mass index ≥ 25 kg/m2	1
Pelvic, hip or femur fracture	4
Erythropoietin-stimulating agent	1
Doxorubicin	3
Dexamethasone:
High dose	4
Low dose	2
Asian/pacific islander Ethnicity	-3
VTE history	5
Tunneled line/central venous catheter	2
Existing thromboprophylaxis:
T-LMWH or warfarin	-4
P-LMWH or aspirin	-3
PRISM	Prior VTE	8	High 7−11   Intermediate 1−6   Low 0	Chakraborty R, et al.5
Black Race	1
IMiD use	2
Surgery	5
Abnormal Metaphase cytogenetics	2

The c-statistic for each model was:

• SAVED model, 0.61
• IMPEDE-VTE, 0.64 (with its external validation cohort)
• PRISM model, 0.62

All of which compares favorably against the value for the IMWG guidelines c-statistic of 0.55.³⁻⁵

Recommended thromboprophylaxis and unmet needs

The most recently updated IMWG guidelines⁶ recommend:

• Administration of VTE prophylaxis based on the presence of risk factors in the first 4–6 months of treatment until disease is controlled or for as long as VTE risk remains high.
• In patients treated with lenalidomide or thalidomide
  • Low risk: give aspirin
  • High risk: dose-adjusted therapeutic warfarin or prophylactic LMWH (depending on renal function) for 4−6 months followed by aspirin.
• If patients develop VTE, treatment should be paused, and anticoagulant therapy should be given. Once clots are clear, chemotherapy can be restarted.

Data from the MYELOMA XI and IX trials have provided further evidence that the risk of VTE is similar when using thalidomide or lenalidomide.¹ In the MYELOMA XI trial, lenalidomide use did appear to increase the risk of VTE. However, patients underwent a median of 18 cycles, whereas thalidomide was only given for a median of 7 months as patients experienced non-VTE toxicity.¹

With the advent of novel agents in MM, such as bortezomib and carfilzomib, more work is required to assess the impact these drugs have on the risk of VTE. Prospective randomized controlled trials are needed to test which VTE prophylaxis treatments are best for patients in different categories and undergoing different anti-myeloma treatments, including assessing newer antithrombotic agents like apixaban.

Conclusion

Despite the guidelines and RAMs available, the risk of VTE remains high for patients with MM. VTE prophylaxis must be considered for all patients undergoing treatment.

Even if the best thromboprophylaxis option is not clear, the current guidelines can still reduce the risk and improve the quality of life for those with MM. It is not just a case of the efficacy of the agents used; treatment options that require fewer visits to the clinic or reduced monitoring need to be developed to aid compliance. On this front, oral anticoagulant therapies show promise, but further testing is required.