In the Journals

VTE risk substantial, despite thromboprophylaxis, with lenalidomide-based regimens for multiple myeloma

Rajshekhar Chakraborty, MD
Rajshekhar Chakraborty

Patients with multiple myeloma who received lenalidomide-based regimens appeared to have considerable risk for venous thromboembolism, regardless of adequate thromboprophylaxis, according to study results published in Cancer.

“Despite using risk-stratified thromboprophylaxis [for patients with] multiple myeloma receiving lenalidomide [Revlimid, Celgene]-based combination regimens, we still encounter VTE in the clinic, including deep vein thrombosis and pulmonary embolism,” Rajshekhar Chakraborty, MD, hematology and oncology fellow at Cleveland Clinic’s Taussig Cancer Institute, told Healio. “Recent observational studies suggest the risk for VTE remains substantial — between 7% and 12% — and that aspirin may not be enough to mitigate VTE risk in some patients with multiple myeloma treated with lenalidomide-based regimens.”

Chakraborty and colleagues conducted a systematic review and meta-analysis to assess cumulative risk for VTE among patients with newly diagnosed and relapsed or refractory multiple myeloma treated with contemporary lenalidomide-based regimens combined with protocol-mandated thromboprophylaxis.

Researchers pooled data from 51 clinical trials with 9,069 patients included in the Ovid MEDLINE, Embase and Cochrane databases. A random effects model was used to estimate the pooled incidence rate of VTE.

Most patients (70%) in the trials were aged 65 years or older. Regimens evaluated in the trials included lenalidomide with low-dose dexamethasone (35%), lenalidomide maintenance (17%), and lenalidomide with low-dose dexamethasone and a proteasome inhibitor (15%). Aspirin, low-molecular-weight heparin and warfarin were the most common thromboprophylaxis agents administered.

Results — excluding maintenance trials — showed a pooled VTE incidence of 6.2% (95% CI, 5.4-7.1) with median treatment durations of two to 34 cycles. This corresponded to 1.2 (95% CI, 0.9-1.7) VTE events per 100 patient-cycles.

VTE risk appeared lowest with lenalidomide plus low-dose dexamethasone (0.2 [95% CI, 0.1-0.6] events per 100 patient-cycles) and lenalidomide maintenance therapy (0.0 [95% CI, 0.0-0.7] events per 100 patient-cycles). VTE risk was highest with lenalidomide and low-dose dexamethasone plus proteasome inhibitors (1.3 [95% CI, 0.7-2.3] events per 100 patient-cycles), with a cumulative rate of 8.4% (95% CI, 6-11.6).

Researchers observed a VTE incidence rate in trials of lenalidomide plus low-dose dexamethasone and monoclonal antibodies of 7.1% (95% CI, 2.4-19.3), which translated to 0.9 (95% CI, 0.1-9.9) events per 100 patient-cycles. The VTE incidence rate was 4.5% (95% CI, 3.5-5.8) with lenalidomide plus prednisone combined with alkylating agents, which corresponded to 0.5 (95% CI, 0.2-1.3) events per 100 patient-cycles.

Researchers acknowledged study limitations, including publication bias, the inability to ascertain thromboembolic events for all studies and the fact investigators could not address the effect of different thromboprophylaxis strategies on VTE risk.

“We need better risk-stratification tools in contemporaneously treated patients to identify patient-related, disease-related and treatment-related risk factors for VTE,” Chakraborty told Healio. “We should also design clinical trials testing new thromboprophylaxis strategies targeting patients at high risk for VTE.”

Current recommendations include low-molecular-weight heparin or therapeutic warfarin for patients at high VTE risk. However, those with newly diagnosed myeloma already are overwhelmed with the diagnostic workup and cancer treatments, Chakraborty said.

“Hence, adding a daily injection or frequent visits for international normalized ratio monitoring can increase the therapeutic burden and lower compliance,” he said. “With promising early data on efficacy and safety of direct oral anticoagulants in this population, clinical trials targeting patients at high risk for VTE are urgently needed. The cumulative incidence of VTE with individual regimens reported in our study can serve as a benchmark for evaluation of VTE risk with future [immunomodulatory drug]-based combination regimens.”

Chakraborty and colleagues are evaluating cumulative incidence and risk factors of VTE in a large cohort of patients with multiple myeloma who have received treatment at Cleveland Clinic since 2008.

“We will validate the two recently published risk-stratification tools — the SAVED and IMPEDE-VTE scores — for VTE in contemporaneously treated [patients with] myeloma,” Chakraborty said. “Availability of robust risk-stratification tools will eventually help clinicians in routine practice and help design clinical trials targeting high-risk patients, such as the CASSINI trial, which assessed rivaroxaban [Xarelto, Janssen] for thromboprophylaxis in high-risk ambulatory [patients with] cancer.” – by Jennifer Southall

For more information:

Rajshekhar Chakraborty, MD, can be reached at Cleveland Clinic Taussig Cancer Institute, 10201 Carnegie Ave., Cleveland, OH 44195; email: chakrar2@ccf.org.

Disclosures: Chakraborty reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

Rajshekhar Chakraborty, MD
Rajshekhar Chakraborty

Patients with multiple myeloma who received lenalidomide-based regimens appeared to have considerable risk for venous thromboembolism, regardless of adequate thromboprophylaxis, according to study results published in Cancer.

“Despite using risk-stratified thromboprophylaxis [for patients with] multiple myeloma receiving lenalidomide [Revlimid, Celgene]-based combination regimens, we still encounter VTE in the clinic, including deep vein thrombosis and pulmonary embolism,” Rajshekhar Chakraborty, MD, hematology and oncology fellow at Cleveland Clinic’s Taussig Cancer Institute, told Healio. “Recent observational studies suggest the risk for VTE remains substantial — between 7% and 12% — and that aspirin may not be enough to mitigate VTE risk in some patients with multiple myeloma treated with lenalidomide-based regimens.”

Chakraborty and colleagues conducted a systematic review and meta-analysis to assess cumulative risk for VTE among patients with newly diagnosed and relapsed or refractory multiple myeloma treated with contemporary lenalidomide-based regimens combined with protocol-mandated thromboprophylaxis.

Researchers pooled data from 51 clinical trials with 9,069 patients included in the Ovid MEDLINE, Embase and Cochrane databases. A random effects model was used to estimate the pooled incidence rate of VTE.

Most patients (70%) in the trials were aged 65 years or older. Regimens evaluated in the trials included lenalidomide with low-dose dexamethasone (35%), lenalidomide maintenance (17%), and lenalidomide with low-dose dexamethasone and a proteasome inhibitor (15%). Aspirin, low-molecular-weight heparin and warfarin were the most common thromboprophylaxis agents administered.

Results — excluding maintenance trials — showed a pooled VTE incidence of 6.2% (95% CI, 5.4-7.1) with median treatment durations of two to 34 cycles. This corresponded to 1.2 (95% CI, 0.9-1.7) VTE events per 100 patient-cycles.

VTE risk appeared lowest with lenalidomide plus low-dose dexamethasone (0.2 [95% CI, 0.1-0.6] events per 100 patient-cycles) and lenalidomide maintenance therapy (0.0 [95% CI, 0.0-0.7] events per 100 patient-cycles). VTE risk was highest with lenalidomide and low-dose dexamethasone plus proteasome inhibitors (1.3 [95% CI, 0.7-2.3] events per 100 patient-cycles), with a cumulative rate of 8.4% (95% CI, 6-11.6).

Researchers observed a VTE incidence rate in trials of lenalidomide plus low-dose dexamethasone and monoclonal antibodies of 7.1% (95% CI, 2.4-19.3), which translated to 0.9 (95% CI, 0.1-9.9) events per 100 patient-cycles. The VTE incidence rate was 4.5% (95% CI, 3.5-5.8) with lenalidomide plus prednisone combined with alkylating agents, which corresponded to 0.5 (95% CI, 0.2-1.3) events per 100 patient-cycles.

Researchers acknowledged study limitations, including publication bias, the inability to ascertain thromboembolic events for all studies and the fact investigators could not address the effect of different thromboprophylaxis strategies on VTE risk.

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“We need better risk-stratification tools in contemporaneously treated patients to identify patient-related, disease-related and treatment-related risk factors for VTE,” Chakraborty told Healio. “We should also design clinical trials testing new thromboprophylaxis strategies targeting patients at high risk for VTE.”

Current recommendations include low-molecular-weight heparin or therapeutic warfarin for patients at high VTE risk. However, those with newly diagnosed myeloma already are overwhelmed with the diagnostic workup and cancer treatments, Chakraborty said.

“Hence, adding a daily injection or frequent visits for international normalized ratio monitoring can increase the therapeutic burden and lower compliance,” he said. “With promising early data on efficacy and safety of direct oral anticoagulants in this population, clinical trials targeting patients at high risk for VTE are urgently needed. The cumulative incidence of VTE with individual regimens reported in our study can serve as a benchmark for evaluation of VTE risk with future [immunomodulatory drug]-based combination regimens.”

Chakraborty and colleagues are evaluating cumulative incidence and risk factors of VTE in a large cohort of patients with multiple myeloma who have received treatment at Cleveland Clinic since 2008.

“We will validate the two recently published risk-stratification tools — the SAVED and IMPEDE-VTE scores — for VTE in contemporaneously treated [patients with] myeloma,” Chakraborty said. “Availability of robust risk-stratification tools will eventually help clinicians in routine practice and help design clinical trials targeting high-risk patients, such as the CASSINI trial, which assessed rivaroxaban [Xarelto, Janssen] for thromboprophylaxis in high-risk ambulatory [patients with] cancer.” – by Jennifer Southall

For more information:

Rajshekhar Chakraborty, MD, can be reached at Cleveland Clinic Taussig Cancer Institute, 10201 Carnegie Ave., Cleveland, OH 44195; email: chakrar2@ccf.org.

Disclosures: Chakraborty reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.