Redefining Thromboprophylaxis in Multiple Myeloma: Early VTE Emerges as the Critical Therapeutic Challenge

Among the most clinically relevant sessions at the ISTH 2026 Congress was a presentation exploring venous thromboembolism (VTE) in patients with multiple myeloma.

The data presented by Dr. Zaulin and Dr. Franzel challenged traditional approaches to thrombosis prevention and highlighted a growing shift in clinical thinking: during modern myeloma therapy, treatment-related factors may be more important than baseline patient characteristics in determining thrombotic risk.

The session emphasized that thromboprophylaxis should be considered an integral part of first-line multiple myeloma treatment rather than an optional supportive intervention.

Modern Therapy Has Reshaped Thrombotic Risk

The introduction of triplet and quadruplet induction regimens, frequently combining immunomodulatory drugs (IMiDs) with monoclonal antibodies such as daratumumab, has significantly improved outcomes for patients with multiple myeloma.

At the same time, these advances have changed the landscape of cancer-associated thrombosis.

Historically, thalidomide- and lenalidomide-based therapies have been associated with an increased risk of VTE.

Dr. Zaulin presented ongoing analyses evaluating thrombotic outcomes with contemporary frontline regimens, including DRdand Dara-VRd, while highlighting the evolution of thromboprophylaxis strategies toward greater use of apixaban and low-molecular-weight heparin (LMWH) compared with older approaches.

Cassiopeia Study Highlights a Critical Three-Month Window

One of the central discussions focused on findings from the Cassiopeia phase III trial, which included 1,085 patients with newly diagnosed multiple myeloma.

Despite 98% of patients receiving thromboprophylaxis, the cumulative incidence of VTE remained approximately 9%, demonstrating that thrombotic complications continue to represent a significant clinical challenge.

Perhaps the most important observation was the timing of these events.

Nearly all VTE episodes occurred during the first three months after treatment initiation. After this period, the cumulative incidence curve plateaued, with very few additional thrombotic events occurring during continued therapy or following transplantation.

These findings suggest that the induction phase represents a unique period of heightened thrombogenicity, during which active myeloma, IMiD-containing therapy, inflammation, endothelial activation, and coagulation pathways combine to create the greatest risk of thrombosis.

Early Initiation of Thromboprophylaxis Matters

The timing of thromboprophylaxis emerged as another key message.

Patients who developed VTE began prophylaxis a median of six days after starting therapy, compared with two daysamong patients who remained free of thrombosis.

Although the difference appears small, the findings suggest that even the earliest days of induction therapy may be critical for preventing thrombotic events.

The speakers emphasized that thromboprophylaxis should ideally begin simultaneously with IMiD-based treatment, rather than being delayed by physician preference or prolonged risk assessment.

Current Risk Scores May No Longer Be Enough

The session also examined the performance of existing risk prediction models.

The widely used IMPEDE VTE score did not successfully distinguish between patients who developed thrombosis and those who did not within the Cassiopeia cohort.

Among baseline clinical characteristics, body mass index (BMI) was the only factor significantly associated with VTE occurrence.

These findings suggest that traditional prediction models, which rely largely on static patient characteristics, may no longer adequately reflect thrombotic risk in the era of modern combination therapy.

Future risk assessment models may need to incorporate treatment intensity together with dynamic biomarkers, inflammatory profiles, endothelial activation, and potentially genomic factors.

Choosing the Right Thromboprophylaxis Strategy

The session reviewed currently available thromboprophylaxis options while acknowledging important limitations.

Aspirin was described as having limited effectiveness in multiple myeloma.

Low-molecular-weight heparin (LMWH) remains widely used but long-term adherence can be challenging because of prolonged subcutaneous injections.

Direct oral anticoagulants (DOACs), including apixaban, represent an increasingly used option, although no large study has yet confirmed the overall net benefit of primary thromboprophylaxis in this patient population.

Within the Cassiopeia study, most patients received heparin-based prophylaxis.

What Is the Role of Daratumumab?

Researchers are also evaluating whether the addition of daratumumab influences thrombotic risk when combined with modern induction regimens.

Data from the Cassiopeia trial showed no statistically significant difference in VTE rates between patients randomized to receive daratumumab and those who did not.

Instead, the study identified thalidomide together with low-dose dexamethasone as the primary drivers of thrombosis risk rather than daratumumab itself.

From Risk Assessment to Risk Prevention

One of the most important concepts emerging from the session was a shift away from identifying individual high-risk patients toward recognizing universally high-risk treatment periods.

Rather than asking which patients require thromboprophylaxis, clinicians may increasingly focus on how quickly prophylaxis should be initiated and which anticoagulant strategy offers the greatest protection during the induction phase.

The evidence presented supports viewing the initiation of IMiD-containing therapy as a thrombotic risk state that warrants immediate preventive intervention.

Key Definitions

• Venous thromboembolism (VTE): Blood clots that develop in the venous circulation, including deep vein thrombosis (DVT).
• Multiple myeloma: A cancer of plasma cells that develops in the bone marrow.
• Immunomodulatory drugs (IMiDs): Medications such as thalidomide, lenalidomide, and pomalidomide that are effective in treating multiple myeloma but increase the risk of thrombosis.
• Cassiopeia study: A phase III clinical trial involving 1,085 patients with newly diagnosed multiple myeloma evaluating modern treatment combinations.
• Thromboprophylaxis: Preventive anticoagulant treatment used to reduce the risk of blood clot formation.
• IMPEDE VTE score: A clinical tool designed to estimate VTE risk in patients with multiple myeloma; in the Cassiopeia cohort, it showed limited ability to distinguish patients who developed thrombosis from those who did not.

Written by Heghine Khachatryan, MD, PhD, Editor-in-Chief at Hemostasis Today, Head of Hemophilia and Thrombosis Center at Yeolyan Hematology and Oncology Center, Ministry of Health, Republic of Armenia.

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