Relationship Between Markers of the Acute Phase of Inflammation, Parameters of Blood Lipid Composition and Intracardiac Hemodynamics During Chemotherapy in Patients With Multiple Myeloma

Aim      To evaluate in a pilot study time-related changes in the clinical state, indexes of the acute phase of inflammation, parameters of blood lipid profile, intracardiac hemodynamics, and disorders of cardiac rhythm/conduction in patients who are not candidates for autologous hemopoietic stem cell transplantation, during three bortezomib-containing chemotherapy courses (VCD) followed by a correlation analysis.

Material and methods  This pilot study included 20 patients diagnosed with myeloma, who were not candidates for autologous hemopoietic stem cell transplantation and who had undergone three courses of VCD chemotherapy (bortezomib, cyclophosphamide and dexamethasone). In addition to mandatory examinations, measurement of blood lipid profile, transthoracic echocardiography (EchoCG), and 24-h Holter electrocardiogram (ECG) monitoring were performed for all participants before and after a specific therapy.

Results Following three bortezomib-containing courses of chemotherapy, patients of the study group had significant increases in the neutrophil-lymphocyte ratio (NLR) (1.6±0.2 and 2.5±0.4; р=0.05), cholesterol concentration (4.8±1.1 and 5.6±1.1 mmol/l, р=0.05), and low-density lipoprotein concentration (2.8±0.4 and 3.5±0.8 mmol/l, р=0.02). In comparing the changes in parameters of intracardiac hemodynamics, criteria for genuine cardiotoxicity were not met, however, a tendency to emergence/progression of myocardial diastolic dysfunction was noted. No clinically significant disorders of cardiac rhythm/conduction were observed. The correlation analysis performed prior to the start of chemotherapy, showed significant strong, direct correlations between the C-protein concentration and left atrial (LA) volume (r=0.793; p=0.006), right atrial (RA) volume (r=0.857; p=0.002), left ventricular (LV) end-diastolic dimension (EDD) (r=0.589; p=0.043), and LV end-diastolic volume (EDV) (r=0.726; p=0.017). Following the specific treatment, significant, medium-power and strong correlations were found between NLR and EDV (r= –0.673; p=0.033), NLR and end systolic volume (ESV) (r= –0.710; p=0.021), respectively. Significant direct correlations were found between the bortezomib dose per one injection and the serum concentration of triglycerides following the treatment (r=0.78; p=0.05); a single bortezomib dose and parameters of intracardiac hemodynamics: LA (r=0.71; p=0.026), RA (r=0.74; p=0.014), EDD (r=0.837; p=0.003), EDV (r=0.749; p=0.013), ESV (r=0.553; p=0.049).

Conclusion      For the first time, a comprehensive evaluation was performed in patients with multiple myeloma, including the dynamics of blood lipid profile, intracardiac hemodynamics and disorders of cardiac rhythm/conduction during bortezomib-containing antitumor therapy, with an analysis of correlation with levels of acute inflammation phase markers. Although in the observation window for genuine cardiotoxicity, clinically significant cardiovascular complications were not detected, the found correlations may evidence a potential role of systemic inflammation activity in myocardial remodeling in the studied patient cohort.

1. Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer. Available online: https://gco.iarc.fr/today (accessed on 7 May 2020).

2. Cowan AJ, Allen C, Barac A. Global Burden of Multiple Myeloma. A Systematic Analysis for the Global Burden of Disease Study 2016. JAMA Oncol. 2018;4(9):1221-7. doi: 10,1001/jamaoncol.2018.2128

3. O.Yu. Vinogradova1,3,4, V.V. Ptushkin et all. Epidemiology of multiple myeloma in city Moscow. Terapevticheskii arkhiv. 2019; 91 (7): 83–92. DOI: 10.26442/00403660.2019.07.000305.

4. Heminki K. et. all. Epidemiology, genetics and treatment of multiple myeloma and precursor diseases. Int J Cancer. 2021 Dec 15;149(12): 1980-1996.doi: 10.1002/ijc.33762.

5. Joshua D. E., Dix C., Gibson J., Ho J. Biology and therapy of multiple myeloma. Medical Journal of Australia. 2019, mja2.50129. doi:10.5694/mja2.50129

6. Mendeleeva L.P., Votyakova O.M. et all. National clinical recommendations on diagnosis and treatment of multiple myeloma 2020 года. Association of Oncologists of Russia.

7. Montefusco V, Mussetti A, Salas MQ, Martinelli G, Cerchione C. Old and new generation proteasome inhibitors in multiple myeloma. Panminerva med 2020; 62:193-206. dOi: 10.23736/S0031-0808.20.04148-8

8. Adams J. The proteasome: structure, function, and role in the cell. cancer Treat rev 2003;29(Suppl 1):3–9.

9. Schmidt m, Finley d. regulation of proteasome activity in health and disease. Biochim Biophys acta 2014; 1843:13–25.

10. Obengea, Carlson LM, Gutman DM, Harrington WJ Jr, Lee KP, Boise LH. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood 2006; 107:4907–16.

11. Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538–48.

12. Yeh ET, Bickford CL. Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol. 2009;53(24):2231–47.

13. Willis MS, Patterson C. Proteotoxicity and cardiac dysfunction – Alzheimer’s disease of the heart? N Engl J Med. 2013;368(5): 455–64.

14. Heckmann MB, Doroudgar S, Katus HA, Lehmann LH et al. Cardiovascular adverse events in multiple myeloma patients. J Thorac Dis. 2018; 10 (Suppl 35): p. S4296–S4305.

15. Stewart AK, Rajkumar SV, Dimopoulos MA. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015; 372:142–52.

16. Siegel DS, et al. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2018;36(8):728–34

17. Siegel D, Martin T, Nooka A. Integrated safety profile of single- agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies. Hematologica. 2013; 98: 1753–61.

18. Atrash S, Tullos A, Panozzo S, Bhutani M, Van Rhee F, Barlogie B, et al. Cardiac complications in relapsed and refractory multiple myeloma patients treated with carfilzomib. Blood Cancer J. 2015;5: e272.

19. Cornell RF, et al. Prospective study of cardiac events during proteasome inhibitor therapy for relapsed multiple myeloma. J Clin Oncol. 2019:JCO.19.00231

20. Yamamoto S, Egashira N. Pathological Mechanisms of Bortezomib-Induced Peripheral Neuropathy. International Journal of Molecular Sciences. 2021; 22(2):888. https://doi.org/10.3390/ijms22020888

21. Cengiz Seval, Guldane; Beksac, Meral. The safety of bortezomib for the treatment of multiple myeloma. Expert Opinion on Drug Safety, (2018), 14740338.2018.1513487–.doi:10.1080/14740338.2018.1513487

22. Hanley MJ, Mould DR, Taylor TJ, Gupta N, Suryanarayan K, Neuwirth R, et al. Population pharmacokinetic analysis of bortezomib in pediatric leukemia patients: model-based support for body surface area-based dosing over the 2- to 16-year age range. J Clin Pharmacol. 2017;57(9):1183–93. https://doi.org/10. 1002/jcph.906.

23. Sachin Diwadkar, Aarti A. Patel and Michael G. Fradley. Bortezomib-Induced Complete Heart Block and Myocardial Scar: The Potential Role of Cardiac Biomarkers in Monitoring Cardiotoxicity. Case report in Cardiology. Vol.2016. DOI: 10.1155/2016/3456287

24. Yaman Alali, Muhamed Baljevic. Bortezomib-Induced Perimyocarditis in a Multiple Myeloma Patient: A Case Report. Case Rep Oncol. 2021 Dec 30;14(3):1853-1859. doi: 10.1159/000520382.

25. Scott K, Hayden PJ, Will A, Wheatley K, Coyne I. Bortezomib for the treatment of multiple myeloma. Cochrane Database Syst Rev. 2016;4:CD010816. https://doi.org/10.1002/14651858. cd010816.pub2.

26. Ashif Iqubal, Mohammad Kashif Iqubal, Sumit Sharma. Molecular mechanism involved in cyclophosphamide-induced cardiotoxicity: Old drug with a new vision. Life Sciences. Jule 2018. DOI:10.1016/j.lfs.2018.12.018 ]

27. Zamorano J.L., Lancellotti P., Muñoz D.R., Aboyans V., Asteggiano R., Galderisi M. et al. ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines. European Heart Journal. 2016 August 2016. 37(36):2768-2801. DOI:10.1093/eurheartj/ehw211.

28. Lorenzatti, Alberto J.; Servato, Maria Luz (2019). New evidence on the role of inflammation in CVD risk. Current Opinion in Cardiology, 34(4), 418–423. doi:10.1097/hco.0000000000000625

29. Brian B. Hasinoff et. all. Molecular Mechanisms of the Cardiotoxicity of the Proteasomal- Targeted Drugs Bortezomib and Carfilzomib. Cardiovasc Toxicol, 2016. DOI 10.1007/s12012-016-9378-7

30. Lyon A. et all. Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio-Oncology Society. European Journal of Heart Failure (2020) 22, 1945–1960, doi:10.1002/ejhf.1920

31. Budanova D.A. Assessment of the cardiotoxic effect of indolent type lymphomas by the dynamics of markers of early myocardial damage and indicators of endothelial dysfunction. 2021

32. Heckmann M.B. Cardiovascular adverse events in multiple myeloma patients. J Thorac Disease, 2018;10(Supl35):S4296-S4305

33. Vasyuk Yu.A., Gendlin G.E. et all. Сonsensus statement of Russian experts on the prevention, diagnosis and treatment of cardiotoxicity of anticancer therapy. Russian Journal of Cardiology. 2021; 26(9):4703. doi.org/10.15829/1560-4071-2021-4703

34. Ogura, M., Ayaori, M. et. all. Proteasomal Inhibition Promotes ATP-Binding Cassette Transporter A1 (ABCA1) and ABCG1 Expression and Cholesterol Efflux From Macrophages In Vitro and In Vivo. Arteriosclerosis, Thrombosis, and Vascular Biology, 31(9), 2011. doi:10.1161/ATVBAHA.111.228478

35. Abdulhamied A., Seth S.M. et all. Inflammation and cardiovascular disease: From mechanisms to therapeutics. Am J Prev Cardiol. 2020 Nov 21;4:100130. doi: 10.1016/j.ajpc.2020.100130.

36. Paolo R. et all. Role of inflammation in the pathogenesis of atherosclerosis and therapeutic interventions. Atherosclerosis. 2018 Sep;276:98-108. doi: 10.1016/j.atherosclerosis.2018.07.014.

37. Hussain A., Ballantyne C.M. New Approaches for the Prevention and Treatment of Cardiovascular Disease: Focus on Lipoproteins and Inflammation. Annu Rev Med. 2021 Jan 27; 72:431-446. doi: 10.1146/annurev-med-100119-013612.

38. Jong M.E. et all. The multiple myeloma microenvironment is defined by an inflammatory stromal cell landscape. Nat Immunol. 2021 Jun;22(6):769-780.doi: 10.1038/s41590-021-00931-3.

39. Konstantinos I.A. et all. Obesity and cancer risk: Emerging biological mechanisms and perspectives. Metabolism. 2019 Mar; 92:121-135. doi: 10.1016/j.metabol.2018.11.001.

40. Ptushkin V.V., Muller M. Analysis of the effectiveness of treatment of multiple myeloma based on the clinical experience of European countries. Terapevticheskii arkhiv; 2021, 93 (4):404–414.DOI:10.26442/00403660.2021.04.200682

41. MacLeod C. et. all. Glucocorticoids: Fuelling the Fire of Atherosclerosis or Therapeutic Extinguishers? Int. J. Mol. Sci. 2021, 22(14), 7622; https://doi.org/10.3390/ijms22147622