Комментарий к теме "Исключительные долгосрочные ответные меры, полученные в ходе испытаний в ОКЕАН и ГОРИЗОН: мелфлюфен-дексаметазон в качестве расширения возможностей лечения повторной/реферативной множественной миеломы в эпоху новой иммунотерапии?".

Dear Editor,

We read with great interest the case series by Talarico et al. (Talarico et al. 2025 ), describing three patients who achieved exceptionally long responses to melflufen-dexamethasone in the OCEAN and HORIZON trials.

Statistical validity and clinical interpretation

Patient 1 had a time to progression (TTP) of 28 months after autologous stem cell transplant (ASCT), placing this case within the subgroup the OCEAN post-hoc analysis identified as faring significantly worse on melflufen-dexamethasone than on pomalidomide-dexamethasone (median OS 15.7 versus 28.7 months, HR 1.8, p = 0.033), the very data the paper cites earlier to justify restricting the current European approval to patients without prior ASCT or with a TTP of 3 years or more (Ludwig et al. 2025 ). The discussion acknowledges this discrepancy only briefly, noting the long duration of response occurred "despite" the unfavorable TTP, without addressing the tension this creates: a single case with an atypically favorable outcome is used to soften the message about a subgroup that trial-level evidence indicates is harmed, on average, by this treatment relative to the comparator. Case reports are inherently susceptible to this kind of selective emphasis, since exceptional outliers are precisely what prompt a case report (Waeber et al. 2025 ). However, presenting this case alongside the broader argument that melflufen may be considered even in patients outside the currently approved target population risks leaving readers with the impression that individual favorable responses can offset subgroup-level harm found in a randomized comparison may be misleading (Lesan et al. 2025 ). Explicitly reiterating, in the discussion of this specific case, that the OCEAN subgroup data indicate a significant survival disadvantage for TTP-under-36-months patients treated with melflufen would prevent this exceptional case from being read as evidence against the population-level finding that it actually contradicts (Acs et al. 2025 ).

Data integrity and translational context

Patient 1 received 46 cycles of melflufen-dexamethasone over approximately four years before developing a second primary myelodysplastic neoplasm. The authors attributed this largely to the patient's prior exposure to alkylators and immunomodulatory drugs, citing the low reported rate of second primary malignancies across the HORIZON and OCEAN trials as reassurance about melflufen’s mutagenic contribution (Vecina et al. 2023 ). However, the median progression-free survival among trial responders was 8.5 months in both study populations, meaning that most trial patients received a small fraction of the cumulative melflufen exposure that this patient received before their malignancy developed (Farrell et al. 2025 ). The second primary malignancy rate calculated from a population whose treatment was, on average, cut short after several months by disease progression or intolerance provides limited reassurance about mutagenic risk, specifically in patients who go on to receive several years of continuous alkylating exposure, since cumulative-dose-related carcinogenesis is a known feature of alkylating agents, and the trial population's exposure was systematically too brief to detect this risk, even if present (The impact of cytotoxic chemotherapy on somatic mutation in normal human cells. 2024 ). Because the discussion's broader argument favors considering melflufen for extended use in exceptional responders, the population capable of accumulating multi-year exposure, the reassurance drawn from short-exposure trial populations does not directly address the risk profile most relevant to the patients this recommendation would actually affect. Reporting cumulative melflufen dose or duration alongside second-primary-malignancy incidence, where available from trial or real-world follow-up data, would provide a more directly applicable estimate of the risk for long-term responders being considered for extended therapy (Shahzad et al. 2024 ).

Taken together, this case series offers a genuinely useful clinical contribution by illustrating that meaningful, durable responses to melflufen-dexamethasone are achievable in carefully selected patients, complementing trial-level data with the kind of granular, longitudinal detail that population-level reporting cannot provide, and the explicit acknowledgment that these cases were retrospectively selected for their exceptional duration of response reflects appropriate transparency about the study’s inherent selection bias (Aslani et al. 2025 ). Against this background, the clinical implication is direct: before these cases inform practical guidance about extending melflufen use beyond the currently approved target population or into multi-year continuous therapy, the discussion of patient 1 should explicitly reconcile the case with the unfavorable OCEAN subgroup data for TTP-under-36-months patients, and the reassurance about second-primary-malignancy risk during extended use should be grounded in exposure-matched safety data rather than incidence rates drawn from a trial population with a substantially shorter average treatment duration.

The online version of the original article can be found at https://doi.org/10.1007/s00432-025-06326-3 .

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Author contributions

M.R.B. contributed to the conceptualization of the commentary, literature review, critical appraisal of the published study, methodological and clinical evaluation, manuscript drafting, and interpretation of the findings. A.A. contributed to the literature review, interpretation of the pharmacological and therapeutic aspects, critical revision of the manuscript, and reference verification. S.B. contributed to literature review, clinical and pharmacological interpretation, critical revision, and editing of the manuscript. K.V.G. contributed to the conceptualization, critical appraisal, clinical and pharmacological evaluation, supervision, and critical revision of the manuscript. All authors reviewed and approved the final version of the manuscript.

Funding

No funding was received for this work.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

Not applicable, as this manuscript is a commentary on a previously published article.

Consent to participate

Not applicable.

Consent for publication

All authors have read and approved the final version of the manuscript and consent to its publication.

Generative AI statement

No generative artificial intelligence tools were used in the preparation, writing, analysis, interpretation, or revision of this manuscript.

References

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