bloodjourГематология и трансфузиологияRussian journal of hematology and transfusiology0234-57302411-3042ООО Издательский дом «Практика»10.18821/0234-5730-2017-62-3-140-146bloodjour-76Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESМНОЖЕСТВЕННАЯ МИЕЛОМА, ОСЛОЖНЕННАЯ СОПУТСТВУЮЩЕЙ КАРДИОЛОГИЧЕСКОЙ ПАТОЛОГИЕЙMULTIPLE MYELOMA COMPLICATED BY CONCOMITANT CARDIAC PATHOLOGYhttps://orcid.org/0000-0002-3064-5112ЮроваE. В.YurovaE. V.https://orcid.org/0000-0002-8129-8114СёмочкинС. В.SemochkinS. V.

117997, г. Москва

Сёмочкин Сергей Вячеславович, доктор мед. наук, профессор, руководитель 

Moscow, 117997

Semochkin Sergey V., MD, PhD, DSci.

semochkin_sv@rsmu.ruФГБОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава РоссииРоссияN.I. Pirogov Russian National Research Medical UniversityRussian Federation201712032019623140146Copyright © Юрова E.В., Сёмочкин С.В., 20192019Юрова E.В., Сёмочкин С.В.Yurova E.V., Semochkin S.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.htjournal.ru/jour/article/view/76

Материал и методы. В период с марта 2008 г. по май 2010 г. в исследование включены 148 больных (69 мужчин и 79 женщин) множественной миеломой (ММ). Обязательным условием было наличие у всех (100%) пациентов значимой кардиологической патологии. Медиана возраста составила 64,7 года (разброс 36,3–82,7). Работа выполнена в ГБУЗ «Городская клиническая больница им. С.П. Боткина» (Москва), которая является клинической базой ФГБОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава России. Больных разделили на две группы: 1-я – с впервые диагностированной ММ (n = 72), 2-я – с рецидивирующей или рефрактерной ММ (n = 76). По поводу ММ проводили терапию бортезомиб-содержащими схемами VCD, VMP или VD. В результате проведенного лечения получен общий ответ: частичная ремиссия у 46 (65,7%) и 44 (59,5%) соответственно, полная ремиссия у 16 (22,9%) и строгая полная ремиссия у 15 (20,3%) больных. При медиане наблюдения 4,9 года показатель 5-летней общей выживаемости (ОВ) по группам составил 22,8 ± 5,3% и 17,3 ± 4,4% (р = 0,295), медиана ОВ составила 40,0 и 31,8 мес соответственно. При многофакторном анализе только общий статус по шкале ECOG не менее 2 показал независимое негативное прогностическое значение в отношении как бессобытийной (отношение рисков – ОР 1,69; p = 0,006), так и ОВ (ОР 1,76; p = 0,003). Заключение. Применение бортезомиб-содержащих схем у больных ММ с сопутствующей кардиопатологией не приводило к ухудшению состояния сердечно-сосудистой системы.

Material and methods. 148 patients (69 males, 79 females) with multiple myeloma (MM) and cardiac pathology were included in the study during March 2008 – May 2010. The median age of patients was 64.7 years (ranges 36.3–82.7). The patients were divided in two groups. In the first group the patients with de novo with MM (n = 72) were included. The patients with relapsed or refractory MM (RR; n = 76) were included in the second group. Results. The bortezomib-containing regimens (VCD, VMP or VD) were used as anti-myeloma treatment. The overall response was documented in 65.7% and 59.5% cases including complete (CR) and strong complete remission (sCR) in 22.9% and 20.3% cases respectively. For a median follow-up of 4.9 years for the comparison groups, the 5-year overall survival (OS) was 22.8 ± 5.3% and 17.3 ± 4.4% (p = 0.295). The median OS was 40 and 31.8 months respectively. In multivariate analysis only ECOG scores ≥ 2 were demonstrated an independent negative prognostic value both for the event-free survival (Hazard ratio 1.69; p = 0.006) and OS (Hazard ratio 1.76; p = 0.003). Conclusion. The bortezomib-based treatment of MM patients with concomitant cardiac pathology was not accompanied by an increase in the incidence of cardiovascular adverse events.

множественная миеломабортезомибкардиотоксичностькардиологическая патологияmultiple myelomabortezomibcardiotoxicitycardiac pathologyReferencesКаприн А.Д., Старинский В.В., Петрова Г.В., ред. Злокачественные новообразования в России в 2015 году (заболеваемость и смертность). М.: МНИОИ им. П.А. Герцена; 2017.Kaprin A.D., Starinskiy V.V., Petrova G.V., eds. Malignant neoplasms in Russia in 2015 (morbidity and mortality). Moscow: P. Herzen Moscow Scientific Research Oncological Institute; 2017. (in Russian)Митина Т.А., Голенков А.К., Трифонова Е.В., Луцкая Т.Д., Катаева Е.В., Высоцкая Л.Л. и др. Эффективность бортезомиба, мелфалана и преднизолона (ВМП) у пациентов с впервые выявленной множественной миеломой. Medline.ru. 2013; 14(4): 1030–50. Доступна на: http://www.medline.ru/public/art/tom14/art82.htmlMitina T.A., Golenkov A.K., Trifonova E.V., Lutskaya T.D., Kataeva E.V., Vysotskaya L.L., et al. The efficacy of bortezomib, melphalan and prednisolone (VMP) in patients with newly diagnosed multiple myeloma. Medline.ru. 2013; 14(4): 1030–50. (in Russian). http://www.medline.ru/public/art/tom14/art82.htmlKaya H., Peressini B., Jawed I., Martincic D., Elaimy A.L., Lamoreaux W.T., et al. Impact of age, race and decade of treatment on overall survival in a critical population analysis of 40,000 multiple myeloma patients. Int. J. Hematol. 2012; 95(1): 64–70.Kaya H., Peressini B., Jawed I., Martincic D., Elaimy A.L., Lamoreaux W.T., et al. Impact of age, race and decade of treatment on overall survival in a critical population analysis of 40,000 multiple myeloma patients. Int. J. Hematol. 2012; 95(1): 64–70.Tim Goodnough L., Comin-Colet J., Leal-Noval S., Ozawa S., Takere J., Henry D., et al. Management of anemia in patients with congestive heart failure. Am. J. Hematol. 2017; 92(1): 88–93.Tim Goodnough L., Comin-Colet J., Leal-Noval S., Ozawa S., Takere J., Henry D., et al. Management of anemia in patients with congestive heart failure. Am. J. Hematol. 2017; 92(1): 88–93.Kwaan H.C. Hyperviscosity in plasma cell dyscrasias. Clin. Hemorheol. Microcirc. 2013; 55(1): 75–83.Kwaan H.C. Hyperviscosity in plasma cell dyscrasias. Clin. Hemorheol. Microcirc. 2013; 55(1): 75–83.Kohrt H., Logan A., Temmins C., Witteles R., Liedtke M., Medeiros B., et al. Reversible high-output cardiac failure, an unusual marker of disease status in multiple myeloma. Leuk. Lymphoma. 2008; 49(3): 581–5.Kohrt H., Logan A., Temmins C., Witteles R., Liedtke M., Medeiros B., et al. Reversible high-output cardiac failure, an unusual marker of disease status in multiple myeloma. Leuk. Lymphoma. 2008; 49(3): 581–5.Рехтина И.Г., Менделеева Л.П., Бирюкова Л.С. Диализзависимая почечная недостаточность у больных множественной миеломой: факторы обратимости. Терапевтический архив. 2015; 87(7): 72–6.Rekhtina I.G., Mendeleeva L.P., Biryukova L.S. Dialysis-dependent renal failure in patients with multiple myeloma: reversible factors. Therapeutic archive. Russian Journal (Terapevticheskiy arkhiv). 2015; 87(7): 72–6. (in Russian)Ухолкина Г.Б., Кучин Г.А., Бычкова О.П., Чихирев О.А. Амилоидоз сердца в клинической практике. Сердечная недостаточность. 2016; 17(1): 57–68.Ukholkina G.B., Kuchin G.A., Bychkova O.P., Chihirev O.A. Amyloidosis of the heart in clinical practice. Heart failure. Russian Journal (Serdechnaya nedostatochnost). 2016; 17(1): 57–68. (in Russian)Smith L.A., Cornelius V.R., Plummer C.J., Levitt G., Verrill M., Canney P., Jones A. Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomised controlled trials. BMC Cancer. 2010; 10: 337. doi: 10.1186/1471- 2407-10-337.Smith L.A., Cornelius V.R., Plummer C.J., Levitt G., Verrill M., Canney P., Jones A. Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomised controlled trials. BMC Cancer. 2010; 10: 337. doi: 10.1186/1471- 2407-10-337.Kozelj M., Zver S., Zadnik V. Long term follow-up report of cardiac toxicity in patients with multiple myeloma treated with tandem autologous hematopoietic stem cell transplantation. Radiol Oncol. 2013; 47(2): 161–5.Kozelj M., Zver S., Zadnik V. Long term follow-up report of cardiac toxicity in patients with multiple myeloma treated with tandem autologous hematopoietic stem cell transplantation. Radiol Oncol. 2013; 47(2): 161–5.Bagratuni T., Kastritis E., Politou M., Roussou M., Kostouros E., Gavriatopoulou M., et al. Clinical and genetic factors associated with venous thromboembolism in myeloma patients treated with lenalidomide-based regimens. Am. J. Hematol. 2013; 88(9): 765–70.Bagratuni T., Kastritis E., Politou M., Roussou M., Kostouros E., Gavriatopoulou M., et al. Clinical and genetic factors associated with venous thromboembolism in myeloma patients treated with lenalidomide-based regimens. Am. J. Hematol. 2013; 88(9): 765–70.Spur E.M., Althof N., Respondek D., Klingel K., Heuser A., Overkleeft H.S., Voigt A. Inhibition of chymotryptic-like standard proteasome activity exacerbates doxorubicin-induced cytotoxicity in primary cardiomyocytes. Toxicology. 2016; 353–354: 34–47.Spur E.M., Althof N., Respondek D., Klingel K., Heuser A., Overkleeft H.S., Voigt A. Inhibition of chymotryptic-like standard proteasome activity exacerbates doxorubicin-induced cytotoxicity in primary cardiomyocytes. Toxicology. 2016; 353–354: 34–47.Durie B.G., Salmon S.E. A clinical staging system for multiple myeloma: Correlation of measure Myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975; 36(9): 842–54.Durie B.G., Salmon S.E. A clinical staging system for multiple myeloma: Correlation of measure Myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975; 36(9): 842–54.Durie B.G., Harousseau J.L., Miguel J.S., Bladу J., Barlogie B., Anderson K., et al. International uniform response criteria for multiple myeloma. Leukemia. 2006; 20(9): 1467–73.Durie B.G., Harousseau J.L., Miguel J.S., Bladу J., Barlogie B., Anderson K., et al. International uniform response criteria for multiple myeloma. Leukemia. 2006; 20(9): 1467–73.U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE). Version 4.0. Published May 28, 2009. Available at: https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14._QuickReference_5x7.pdf (accessed 04.04.2017)U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE). Version 4.0. Published May 28, 2009. Available at: https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14._QuickReference_5x7.pdf (accessed 04.04.2017)The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. Boston: Brown & Co; 1994: 253–6.The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. Boston: Brown & Co; 1994: 253–6.Prentice R.L., Kalbfleisch J.D. Mixed discrete and continuous Cox regression model. Lifetime Data Anal. 2003; 9(2): 195–210.Prentice R.L., Kalbfleisch J.D. Mixed discrete and continuous Cox regression model. Lifetime Data Anal. 2003; 9(2): 195–210.Moreau P., Hulin C., Macro M., Caillot D., Chaleteix C., Roussel M., et al. VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. Blood. 2016; 127(21): 2569–74.Moreau P., Hulin C., Macro M., Caillot D., Chaleteix C., Roussel M., et al. VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. Blood. 2016; 127(21): 2569–74.Reeder C.B., Reece D.E., Kukreti V., Mikhael J.R., Chen C., Trudel S., et al. Long-term survival with cyclophosphamide, bortezomib and dexamethasone induction therapy in patients with newly diagnosed multiple myeloma. Br. J. Haematol. 2014; 167(4): 563–5.Reeder C.B., Reece D.E., Kukreti V., Mikhael J.R., Chen C., Trudel S., et al. Long-term survival with cyclophosphamide, bortezomib and dexamethasone induction therapy in patients with newly diagnosed multiple myeloma. Br. J. Haematol. 2014; 167(4): 563–5.Chng W.J., Goldschmidt H., Dimopoulos M.A., Moreau P., Joshua D., Palumbo A., et al. Carfilzomib-dexamethasone vs bortezomibdexamethasone in relapsed or refractory multiple myeloma by cytogenetic risk in the phase 3 study Available at: ENDEAVOR. Leukemia. 2017; 31(6): 1368–74. doi: 10.1038/leu.2016.390. (accessed 06.06.2017)Chng W.J., Goldschmidt H., Dimopoulos M.A., Moreau P., Joshua D., Palumbo A., et al. Carfilzomib-dexamethasone vs bortezomibdexamethasone in relapsed or refractory multiple myeloma by cytogenetic risk in the phase 3 study Available at: ENDEAVOR. Leukemia. 2017; 31(6): 1368–74. doi: 10.1038/leu.2016.390. (accessed 06.06.2017)Tuchman S.A., Moore J.O., De Castro C.D., Li Z., Sellars E., Kang Y., et al. Phase II study of dose-attenuated bortezomib, cyclophosphamide and dexamethasone (VCD-Lite) in very old or otherwise toxicity-vulnerable adults with newly diagnosed multiple myeloma. J. Geriatr. Oncol. 2017; 8(3): 165–9. Available at: http://www.geriatriconcology.net/article/S1879-4068(17)30030-9. (accessed 16.06.2017)Tuchman S.A., Moore J.O., De Castro C.D., Li Z., Sellars E., Kang Y., et al. Phase II study of dose-attenuated bortezomib, cyclophosphamide and dexamethasone (VCD-Lite) in very old or otherwise toxicity-vulnerable adults with newly diagnosed multiple myeloma. J. Geriatr. Oncol. 2017; 8(3): 165–9. Available at: http://www.geriatriconcology.net/article/S1879-4068(17)30030-9. (accessed 16.06.2017)Rosinol L., Oriol A., Mateos M.V., Sureda A., García-Sánchez P., Gutierrez N., et al. Phase II PETHEMA trial of alternating bortezomib and dexamethasone as induction regimen before autologous stemcell transplantation in younger patients with multiple myeloma: efficacy and clinical implications of tumor response kinetics. J. Clin. Oncol. 2007; 25(28): 4452–8.Rosinol L., Oriol A., Mateos M.V., Sureda A., García-Sánchez P., Gutierrez N., et al. Phase II PETHEMA trial of alternating bortezomib and dexamethasone as induction regimen before autologous stemcell transplantation in younger patients with multiple myeloma: efficacy and clinical implications of tumor response kinetics. J. Clin. Oncol. 2007; 25(28): 4452–8.Harousseau J.L., Attal M., Leleu X., Troncy J., Pegourie B., Stoppa A.M., et al. Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: results of an IFM phase II study. Haematologica. 2006; 91(11): 1498–505.Harousseau J.L., Attal M., Leleu X., Troncy J., Pegourie B., Stoppa A.M., et al. Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: results of an IFM phase II study. Haematologica. 2006; 91(11): 1498–505.Mateos M.V., Oriol A., Martínez-López J., Teruel A.I., Bengoechea E., Palomera L., et al. Outcomes with two different schedules of bortezomib, melphalan, and prednisone (VMP) for previously untreated multiple myeloma: matched pair analysis using long-term follow-up data from the phase 3 VISTA and PETHEMA/GEM05 trials. Ann. Hematol. 2016; 95(12): 2033–41.Mateos M.V., Oriol A., Martínez-López J., Teruel A.I., Bengoechea E., Palomera L., et al. Outcomes with two different schedules of bortezomib, melphalan, and prednisone (VMP) for previously untreated multiple myeloma: matched pair analysis using long-term follow-up data from the phase 3 VISTA and PETHEMA/GEM05 trials. Ann. Hematol. 2016; 95(12): 2033–41.de Waal EG., de Munck L., Hoogendoorn M., Woolthui G., van der Velden A., Tromp Y., et al. Combination therapy with bortezomib, continuous low-dose cyclophosphamide and dexamethasone followed by one year of maintenance treatment for relapsed multiple myeloma patients. Br. J. Haematol. 2015; 171(5): 720–5.de Waal EG., de Munck L., Hoogendoorn M., Woolthui G., van der Velden A., Tromp Y., et al. Combination therapy with bortezomib, continuous low-dose cyclophosphamide and dexamethasone followed by one year of maintenance treatment for relapsed multiple myeloma patients. Br. J. Haematol. 2015; 171(5): 720–5.Mai E.K, Bertsch U., Dürig J., Kunz C., Haenel M., Blau I.W., et al. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 2015; 29(8): 1721–9.Mai E.K, Bertsch U., Dürig J., Kunz C., Haenel M., Blau I.W., et al. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 2015; 29(8): 1721–9.Fu W., Delasalle K., Wang J., Song S., Hou J., Alexanian R., et al. Bortezomib-cyclophosphamide-dexamethasone for relapsing multiple myeloma. Am. J. Clin. Oncol. 2012; 35(6): 562–5.Fu W., Delasalle K., Wang J., Song S., Hou J., Alexanian R., et al. Bortezomib-cyclophosphamide-dexamethasone for relapsing multiple myeloma. Am. J. Clin. Oncol. 2012; 35(6): 562–5.Hajek R., Jarkovsky J., Bouwmeester W., Treur M., DeCosta L., Campioni M., et al. Exploration of Survival Stratification of Patients with Multiple Myeloma after First Relapse Using Real World Data. Blood. 2016; 128(22): Abstract. 2417. Available at: http://www.bloodjournal.org/content/128/22/2417 (accessed 04.06.2017)Hajek R., Jarkovsky J., Bouwmeester W., Treur M., DeCosta L., Campioni M., et al. Exploration of Survival Stratification of Patients with Multiple Myeloma after First Relapse Using Real World Data. Blood. 2016; 128(22): Abstract. 2417. Available at: http://www.bloodjournal.org/content/128/22/2417 (accessed 04.06.2017)Lenihan D.J., Potluri R., Bhandari H., Ranjan S., Chen C. Evaluation of cardiovascular comorbidities among patients with multiple myeloma in the United States. Blood. 2016; 128(22): Abstr. 4794. Available at: http://www.bloodjournal.org/content/128/22/4794?ssochecked=true (accessed 04.06.2017)Lenihan D.J., Potluri R., Bhandari H., Ranjan S., Chen C. Evaluation of cardiovascular comorbidities among patients with multiple myeloma in the United States. Blood. 2016; 128(22): Abstr. 4794. Available at: http://www.bloodjournal.org/content/128/22/4794?ssochecked=true (accessed 04.06.2017)Bahlis N.J., Lazarus H.M. Multiple myeloma-associated AL amyloidosis: is a distinctive therapeutic approach warranted? Bone Marrow Transplant. 2006; 38(1): 7–15.Bahlis N.J., Lazarus H.M. Multiple myeloma-associated AL amyloidosis: is a distinctive therapeutic approach warranted? Bone Marrow Transplant. 2006; 38(1): 7–15.Xiao Y., Yin J., Wei J., Shang Z. Incidence and risk of cardiotoxicity associated with bortezomib in the treatment of cancer: a systematic review and meta-analysis. PLoS One. 2014; 9(1): e87671. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906186 (accessed 16.06.2017)Xiao Y., Yin J., Wei J., Shang Z. Incidence and risk of cardiotoxicity associated with bortezomib in the treatment of cancer: a systematic review and meta-analysis. PLoS One. 2014; 9(1): e87671. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906186 (accessed 16.06.2017)

The authors declare that there are no conflicts of interest present.