pharmjournalРазработка и регистрация лекарственных средствDrug development & registration2305-20662658-5049LLC «CPHA»10.33380/2305-2066-2025-14-4-2138pharmjournal-2222Research ArticleДОКЛИНИЧЕСКИЕ И КЛИНИЧЕСКИЕ ИССЛЕДОВАНИЯPRECLINICAL AND CLINICAL STUDIESЦелевое метаболомное профилирование множественной миеломы: диагностика и оценка эффективности терапииTargeted metabolomic profiling of multiple myeloma: diagnostics and treatment efficacyhttps://orcid.org/0000-0002-9067-8717ВарзиеваВ. Г.VarzievaV. G.

119991, г. Москва, ул. Трубецкая, д. 8, стр. 2

8/2, Trubetskaya str., Mosсow, 119991

varzieva.valeria@gmail.comhttps://orcid.org/0000-0001-6554-3936ШестаковаК. М.ShestakovaK. M.

119991, г. Москва, ул. Трубецкая, д. 8, стр. 2

8/2, Trubetskaya str., Mosсow, 119991

БолдинА. А.BoldinA. A.

119991, г. Москва, ул. Трубецкая, д. 8, стр. 2

8/2, Trubetskaya str., Mosсow, 119991

https://orcid.org/0009-0001-7169-0577КуцакинаД. А.KutsakinaD. A.

119991, г. Москва, ул. Трубецкая, д. 8, стр. 2

8/2, Trubetskaya str., Mosсow, 119991

https://orcid.org/0000-0002-8271-7704КириченкоЮ. Ю.KirichenkoYu. Yu.

119991, г. Москва, ул. Трубецкая, д. 8, стр. 2

8/2, Trubetskaya str., Mosсow, 119991

https://orcid.org/0000-0002-3014-6129БеленковЮ. Н.BelenkovYu. N.

119991, г. Москва, ул. Трубецкая, д. 8, стр. 2

8/2, Trubetskaya str., Mosсow, 119991

https://orcid.org/0000-0001-6817-6270ИльгисонисИ. С.IlgisonisI. S.

119991, г. Москва, ул. Трубецкая, д. 8, стр. 2

8/2, Trubetskaya str., Mosсow, 119991

https://orcid.org/0000-0002-9394-7994ТарасовВ. В.TarasovV. V.

119991, г. Москва, ул. Трубецкая, д. 8, стр. 2

8/2, Trubetskaya str., Mosсow, 119991

https://orcid.org/0000-0002-9032-1558АпполоноваС. А.AppolonovaS. A.

119991, г. Москва, ул. Трубецкая, д. 8, стр. 2

8/2, Trubetskaya str., Mosсow, 119991

Федеральное государственное автономное образовательное учреждение высшего образования «Первый Московский государственный медицинский университет имени И. М. Сеченова» Министерства здравоохранения Российской Федерации (Сеченовский Университет)РоссияI. M. Sechenov First MSMU of the Ministry of Health of the Russian Federation (Sechenov University)Russian Federation202503122025144229248Copyright © Варзиева В.Г., Шестакова К.М., Болдин А.А., Куцакина Д.А., Кириченко Ю.Ю., Беленков Ю.Н., Ильгисонис И.С., Тарасов В.В., Апполонова С.А., 20252025Варзиева В.Г., Шестакова К.М., Болдин А.А., Куцакина Д.А., Кириченко Ю.Ю., Беленков Ю.Н., Ильгисонис И.С., Тарасов В.В., Апполонова С.А.Varzieva V.G., Shestakova K.M., Boldin A.A., Kutsakina D.A., Kirichenko Y.Y., Belenkov Y.N., Ilgisonis I.S., Tarasov V.V., Appolonova S.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmjournal.ru/jour/article/view/2222Введение

Введение. Множественная миелома (ММ) представляет собой злокачественное заболевание плазматических клеток, характеризующееся выраженной гетерогенностью клинического течения и вариабельностью ответа на лечение. Метаболомный анализ, отражающий совокупность малых молекул в биологических жидкостях, открывает новые возможности для поиска диагностических и прогностических биомаркеров.

Цель

Цель. Оценить метаболомные профили пациентов с ММ и выявить метаболические маркеры, ассоциированные с эффективностью полихимиотерапии.

Материалы и методы

Материалы и методы. Исследование проводилось с сентября 2022 года по май 2025 года на базе кафедры госпитальной терапии № 1 Сеченовского Университета. Проведен целевой анализ метаболитов плазмы крови 29 пациентов с ММ до начала лечения и 30 здоровых добровольцев (контроль). Пациенты были разделены на группы с ответом и без ответа на основании результатов проведения трех курсов терапии первой линии по протоколу VCD.

Результаты и обсуждение

Результаты и обсуждение. Обнаружены значительные различия в метаболомных профилях пациентов с ММ по сравнению с контрольной группой. У больных ММ отмечен повышенный катаболизм триптофана через кинурениновый путь (~41 % увеличение соотношения кинуренин/триптофан, ~80 % снижение уровня серотонина), изменения в метаболитах цикла мочевины и оксида азота (~28 % снижение аргинина, ~5,3-кратное увеличение асимметричного диметиларгинина), а также аминокислотный дисбаланс (снижение уровня серина, аспартата, BCAA) и значительное увеличение общего количества ацилкарнитинов (в ~1,4 раза выше, чем в контроле). Исходный метаболический профиль также отличался у пациентов с различными результатами лечения: до лечения у пациентов, у которых впоследствии наблюдался клинический ответ, были снижены уровни некоторых ацилкарнитинов и продуктов распада триптофана (например, антраниловой кислоты), в то время как у пациентов без ответа были снижены уровни 5-гидрокситриптофана, индол-3-молочной кислоты и гистидина.

Заключение

Заключение. Метаболомный анализ выявил характерные метаболические изменения при ММ, отражающие активацию иммунометаболических путей (триптофан-кинурениновый путь, метаболизм аргинина) и нарушение регуляции энергии и аминокислот. Полученные результаты указывают на потенциальную прогностическую значимость метаболитов: ряд биомаркеров (например, производные триптофана, ацилкарнитины) может быть связан с чувствительностью к химиотерапии. Полученные данные открывают перспективы для дальнейших исследований метаболических подходов в мониторинге и терапии ММ.

Introduction

Introduction. Multiple myeloma (MM) is a malignant disease of plasma cells characterized by marked heterogeneity of the clinical course and variability in response to treatment. Metabolomic analysis, which reflects the totality of small molecules in biological fluids, opens up new possibilities for the search for diagnostic and prognostic biomarkers.

Aim

Aim. To evaluate metabolomic profiles of patients with multiple myeloma (MM) and to identify metabolic markers associated with the efficacy of polychemotherapy.

Materials and methods

Materials and methods. The study was conducted from September 2022 to May 2025 at the Department of Hospital Therapy No. 1 of Sechenov University. We performed targeted analysis of plasma metabolites in 29 pre-treatment MM patients and 30 healthy volunteers (controls). Patients were divided into response and no response groups based on the results of therapy with VCD protocol after three courses.

Results and discussion

Results and discussion. Significant differences in metabolomic profiles of MM patients compared to controls were found. MM patients showed increased tryptophan catabolism via the kynurenine pathway (~41 % increase in kynurenine/tryptophan ratio, ~80 % decrease in serotonin levels), changes in urea and nitric oxide cycle metabolites (~28 % decrease in arginine, ~5.3-fold increase in asymmetric dimethylarginine), and amino acid imbalances (decrease in serine, aspartate, BCAA) and a significant increase in total acylcarnitines (~1.4-fold higher than control). The baseline metabolic profile also differed between patients with different treatment outcomes: before treatment, patients who subsequently showed a clinical response had lower levels of several acylcarnitines and tryptophan breakdown products (e.g. anthranilic acid), whereas patients without response showed decreased levels of 5-hydroxytryptophan, indole-3-lactic acid and histidine.

Conclusions

Conclusions. Metabolomic analysis revealed characteristic metabolic alterations in MM reflecting activation of immunometabolic pathways (tryptophan kynurenine pathway, arginine metabolism) and impaired energy and amino acid regulation. The results indicate the potential prognostic significance of metabolites: a number of biomarkers (e.g. tryptophan derivatives, acylcarnitines) may be associated with chemotherapy sensitivity. The findings open the prospects for further research on metabolic approaches in MM monitoring and therapy.

метаболомикамножественная миеломабиомаркерэффективность леченияпрогноздиагностикаmetabolomicsmultiple myelomabiomarkertreatment efficacyprognosisdiagnosisИсследование выполнено при финансовой поддержке Российского научного фонда: грант № 24-75-00062 «Изучение роли омных маркеров (микроРНК-155, микроРНК-146а, метаболомный профиль) как ранних предикторов васкулотоксичности полихимиотерапии».The study was supported by the Russian Science Foundation: Grant No. 24-75-00062 "Investigation of the Role of Omic Markers (MicroRNA-155, MicroRNA-146a, Metabolomic Profile) as Early Predictors of Polychemotherapy Vasculotoxicity".ReferencesCowan A. J., Green D. J., Kwok M., Lee S., Coffey D. G., Holmberg L. A., Tuazon S., Gopal A. K., Libby E. N. Diagnosis and Management of Multiple Myeloma. JAMA. 2022;327(5):464–477. DOI: 10.1001/jama.2022.0003.Cowan A. J., Green D. J., Kwok M., Lee S., Coffey D. G., Holmberg L. A., Tuazon S., Gopal A. K., Libby E. N. Diagnosis and Management of Multiple Myeloma. 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The authors declare that there are no conflicts of interest present.