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Neoplasm Reports in Patients with Multiple Sclerosis Treated with Disease-Modifying Therapies: An Analysis of the EudraVigilance Database

An analysis of the EudraVigilance database suggests that most multiple sclerosis disease-modifying therapies are not significantly associated with increased neoplasm reports, with the notable exception of mitoxantrone, which demonstrated a marked disproportionality in cancer-related adverse events.

Original authors: R. Kułakowski, M. Chrzanowski, I . Rosciszewska-Żukowska, M. Niewada, D. Mirowska-Guzel

Published 2026-10-14

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CC BY 4.0

Original authors: R. Kułakowski, M. Chrzanowski, I . Rosciszewska-Żukowska, M. Niewada, D. Mirowska-Guzel

Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). ✨ This is an AI-generated explanation of the paper below. It is not written or endorsed by the authors. For technical accuracy, refer to the original paper. Read full disclaimer

Multiple sclerosis is a condition where the body's own immune system mistakenly attacks the protective covering of nerves in the brain and spinal cord, leading to a wide range of physical and cognitive challenges. For decades, the medical community has relied on a class of medicines known as disease-modifying therapies to calm this overactive immune response, slow the progression of the disease, and reduce the frequency of flare-ups. However, because these drugs work by suppressing the immune system, a long-standing question has lingered: could this necessary dampening of the body's defenses inadvertently open the door to other serious health issues, such as the development of cancer? As newer, more powerful treatments have emerged, the need to understand their long-term safety profile has become increasingly urgent, not just for the patients taking them, but for the doctors who prescribe them and the families who rely on them.

To address this concern, a team of researchers from Poland turned to a massive, pan-European database that collects spontaneous reports of adverse events from millions of patients. This database, known as EudraVigilance, acts as a vast, real-world ledger where doctors and patients can report any unexpected health problems that occur after taking a medication. The researchers sifted through data collected up to April 2024, looking specifically for reports of tumors or cancers in patients with multiple sclerosis who were being treated with various disease-modifying therapies. Their goal was not to prove that a drug causes cancer, but to see if certain medicines were being reported alongside cancer cases far more often than would be expected by chance, which would signal a need for closer investigation.

The analysis covered thousands of reports involving a wide array of treatments, from older injectable medications to newer oral drugs and monoclonal antibodies. In total, the team identified over 12,000 reports linking these therapies to neoplasms, a medical term for any new and abnormal growth of tissue, which can be either benign or malignant. When they compared the frequency of these reports across different drugs, the results were largely reassuring for the vast majority of modern treatments. Most of the drugs currently used to manage multiple sclerosis did not show a pattern suggesting they were linked to a higher risk of cancer reports compared to the others in the group. This finding aligns with broader scientific consensus that these therapies do not inherently increase cancer risk for the general population of patients.

However, the study did uncover one significant exception that stood out clearly from the rest. The researchers found that a drug called mitoxantrone, which was approved for use in Europe in the early 2000s, showed a distinct and strong signal. The data indicated that reports of tumors associated with mitoxantrone were disproportionately high compared to all other multiple sclerosis treatments analyzed. This drug, which is now rarely used due to other serious long-term risks like heart damage, was the only medication in the study to meet every statistical criterion for a safety signal, suggesting a genuine link between its use and the reporting of neoplasms.

For the other medications, the picture was more nuanced but ultimately less alarming. Five drugs, including fingolimod, interferon beta-1a, natalizumab, ocrelizumab, and mitoxantrone, showed a slightly higher number of cancer reports than the average, but they did not meet the strict thresholds required to declare a definitive safety signal. For instance, while fingolimod and interferon beta-1a had reporting rates that were somewhat elevated, the statistical evidence was not strong enough to confirm a causal relationship. The researchers noted that these drugs are often used by patients who are under constant, vigilant medical supervision, which can sometimes lead to the detection of cancers that might otherwise go unnoticed in the general population. This intense monitoring, combined with the fact that patients with multiple sclerosis are often older or have been living with the disease for a long time, can complicate the picture, as age itself is a major risk factor for cancer.

The study also highlighted that the database has limitations. Because the reports are voluntary and come from many different sources, it is impossible to know exactly how many people took each drug or to perfectly match the age and health history of every patient. This means the data cannot prove that a drug causes cancer, but it can highlight where doctors should look more closely. The researchers emphasized that while the current evidence suggests most modern treatments are safe regarding cancer risk, the nature of these drugs means that long-term monitoring remains essential. As the population of patients grows and new therapies are introduced, the continuous flow of real-world data remains the most valuable tool for ensuring that the benefits of treatment continue to outweigh the risks.

In the end, this large-scale review of European safety data offers a clear message: for the overwhelming majority of patients with multiple sclerosis, the disease-modifying therapies they rely on do not appear to be driving an increase in cancer reports. The one notable outlier, mitoxantrone, serves as a reminder of the importance of rigorous safety monitoring, but it does not cast doubt on the safety profile of the newer, more widely used medications. The findings suggest that the current landscape of treatment is safe, provided that doctors and patients remain attentive to the long-term health of those living with the disease.

Technical Summary: Neoplasm Reports in Patients with Multiple Sclerosis Treated with Disease-Modifying Therapies

Problem Statement
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system affecting approximately 2.9 million people globally. While the introduction of numerous high-efficacy disease-modifying therapies (DMTs) has significantly reduced relapse rates and slowed disease progression, their immunosuppressive properties have raised concerns regarding potential carcinogenic risks. Although previous studies and meta-analyses have yielded inconclusive or conflicting results regarding the overall cancer risk in MS patients, specific agents have been suspected of increasing the incidence of malignancies, particularly brain and urinary tract cancers. Furthermore, the aging MS population and the presence of comorbidities complicate the assessment of drug safety. There is a need for robust post-marketing surveillance to evaluate the real-world risk of carcinogenesis associated with the expanding array of available DMTs, as clinical trials often exclude older patients or those with long disease durations.

Methodology
This study conducted a pharmacovigilance analysis using data from the EudraVigilance database, the European Medicines Agency's system for monitoring adverse drug reactions (ADRs). The dataset included reports collected up to the end of April 2024.

Data Scope: The analysis focused on spontaneous reports of neoplasms (including benign, malignant, and unspecified tumors) associated with MS DMTs. The search utilized Medical Dictionary for Regulatory Activities (MedDRA) terms covering a broad spectrum of neoplastic conditions (e.g., carcinoma, lymphoma, leukemia, sarcoma).
Drug Classes Analyzed: The study evaluated reports for five main categories of DMTs: Interferons (beta-1a, beta-1b, pegylated), Fumarates (dimethyl-fumarate), Sphingosine-1-phosphate (S1P) receptor modulators (fingolimod, ozanimod, siponimod, ponesimod), Monoclonal antibodies (ocrelizumab, ofatumumab, natalizumab, alemtuzumab), and other agents (glatiramer acetate, teriflunomide, cladribine, mitoxantrone).
Statistical Approach: The study employed disproportionality analysis to identify potential safety signals. The primary metrics calculated were:
- Reporting Odds Ratio (ROR): Calculated as $(a/c) / (b/d)$ , where $a$ is the number of neoplasm reports for the drug of interest, $b$ is other reports for that drug, $c$ is neoplasm reports for other drugs, and $d$ is other reports for other drugs.
- Proportional Reporting Ratio (PRR): Calculated as $[a/(a+b)] / [c/(c+d)]$ .
- Chi-square ( $\chi^2$ ) test: To assess statistical significance.
Signal Detection Criteria: A "positive signal" was defined strictly by meeting five predefined criteria simultaneously:
1. PRR $\ge$ 2
2. Number of reported cases ( $a$ ) $\ge$ 3
3. $\chi^2$ value $\ge$ 4
4. ROR lower 95% Confidence Interval (CI) > 1
5. ROR > 1
Limitations: The study acknowledged inherent limitations of spontaneous reporting systems, including underreporting, the inability to calculate incidence rates due to unknown total exposed populations, and the lack of granular age stratification in the exported data.

Key Results
The analysis identified a total of 12,565 neoplasm-related ADR reports associated with MS DMTs. The demographic distribution showed a male-to-female ratio of approximately 0.27, reflecting the higher prevalence of MS in women.

Mitoxantrone: This agent was the only drug to meet all five signal detection criteria, indicating a strong disproportionality in neoplasm reporting.
- ROR: 8.63 (95% CI: 7.29–10.20)
- PRR: 5.55
- $\chi^2$ : 952.26
- Total neoplasm reports: 241 out of 597 total ADRs.
Other Agents with Elevated RORs: Five DMTs met the ROR-based criteria (ROR > 1 with lower 95% CI > 1 and at least three reports) but failed to meet the PRR threshold ( $\ge$ $\geq$ 2) or other flags required for a "positive signal":
- Fingolimod: ROR = 1.50 (95% CI: 1.42–1.58), PRR = 1.45.
- Interferon beta-1a: ROR = 1.35 (95% CI: 1.29–1.40), PRR = 1.31.
- Natalizumab: ROR = 1.29 (95% CI: 1.23–1.35), PRR = 1.26.
- Ocrelizumab: ROR = 1.09 (95% CI: 1.01–1.17), PRR = 1.08.
Agents with Reduced Reporting: Several drugs, including dimethyl-fumarate, cladribine, siponimod, interferon beta-1b, glatiramer acetate, alemtuzumab, ozanimod, teriflunomide, ofatumumab, and ponesimod, demonstrated ROR values below 1, suggesting no disproportionate increase in neoplasm reporting compared to the reference group.

Significance and Claims
The paper concludes that, based on the EudraVigilance database, most DMTs used for MS are not associated with a significantly increased number of neoplasm reports, with the notable exception of mitoxantrone.

Mitoxantrone: The study confirms a marked disproportionality in neoplasm reporting for mitoxantrone, consistent with its known history of severe long-term complications, including therapy-related acute leukemia and cardiotoxicity. The authors note that while the drug is rarely used in current clinical practice due to these risks, the signal remains robust in the database.
Other DMTs: For agents such as fingolimod, interferon beta-1a, natalizumab, and ocrelizumab, while RORs were slightly elevated, they did not meet the rigorous criteria for a positive safety signal (specifically the PRR $\ge$ 2 threshold). The authors suggest these results do not confirm an increased risk of carcinogenesis but indicate a need for continued monitoring.
Real-World Context: The study emphasizes that spontaneous reporting data is crucial for post-marketing surveillance, particularly for detecting rare or long-term adverse events that may not be evident in clinical trials. The authors caution that the observed signals reflect reporting patterns rather than established causality and that factors such as patient age, disease duration, and increased medical surveillance in MS cohorts may influence reporting rates.

The authors assert that their findings align with recent systematic reviews suggesting DMTs generally do not increase overall cancer risk in MS patients, though they highlight that class-level estimates in meta-analyses may obscure risks associated with specific agents like mitoxantrone. The study underscores the necessity of ongoing pharmacovigilance as the landscape of MS treatments evolves.

Technical Summary: Neoplasm Reports in Patients with Multiple Sclerosis Treated with Disease-Modifying Therapies

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