Neurobiology of multiple myeloma and its therapeutical use – results of the pilot study with a control arm

Czech version

Authors: P. Kotouček ¹; R. Enright ²; S. Gregor Sorgerová ³; Ľ. Hunáková ⁴; V. Chlebcová ³; D. Cholujová ⁵; J. Jakubíková ⁵; B. Mravec ^6,7; E. Naništová ³; Ľ. Paneková ³; J. Sedlák ^5,8
Authors‘ workplace: Haematology Department, Broomfield Hospital, MSE NHS FT, Chelmsford, UK ¹; Department of Educational Psychology, University Wisconsin-Madison, Madison, and International Forgiveness Institute, Madison, Wisconsin, USA ²; Ústav klinickej psychológie, Fakulta psychológie, Paneurópska vysoká škola, Bratislava, Slovenská republika ³; Imunologický ústav, Lekárska fakulta, Univerzita Komenského, Bratislava, Slovenská republika ⁴; Biomedicínske centrum, Ústav experimentálnej onkológie, Slovenská akadémia vied, v. v. i., Bratislava, Slovenská republika ⁵; Fyziologický ústav, Lekárska fakulta, Univerzita Komenského, Bratislava, Slovenská republika ⁶; Biomedicínske centrum, Ústav experimentálnej endokrinológie, Slovenská akadémia vied, v. v. i., Bratislava, Slovenská republika ⁷; Nadácia Výskum Rakoviny, Bratislava, Slovenská republika ⁸
Published in: Klin Onkol 2023; 37(4): 287-299
Category: Original Articles

Overview

Background: Myeloma cells, occupying a bone marrow niche, are influenced not only by neighbouring stroma cells but also by signals from the axons of sympathetic nervous system. The nervous system is directly involved in the process of myeloma progression. Among other cancers, patients with myeloma suffer the most difficult distress generating intensive adrenergic signals, causing its further progression. There is a question arising from these facts regarding whether psychological interventions, modulating a function of the nervous system, can further improve outcomes of myeloma treatments. We focus on interactions between myeloma cells and the nervous system.

Patients and methods: Twelve patients with monoclonal gamapathy of indetermined significance (MGUS) or myeloma have participated in this study; eight in the interventional arm with the intervention of forgiveness therapy and four in the control arm. The patients were in various phases of their treatment, from active observation to immuno-chemotherapy and autologous stem cell transplant. Two major types of parameters were measured during the intervention: parameters of the activity of the disease (MGUS or myeloma) and psycho-neuro-immunological parameters of the patient, such as psychological depression, anxiety, and anger by the validated test PROMIS), as well as activity of the autonomic nervous system by heart rate variability, and immune profile by flow cytometry of peripheral blood.

Results: Patients who completed the forgiveness intervention showed improvement of depression, anxiety, and anger measured by PROMIS above population average, significant expansion of physiological plasma cells CD138+38+ (P = 0.04), B memory lymphocytes CD27+ (P = 0.02), and dendritic plasmacytoid cells CD123+ (P = 0.03). Parameters of heart rate variability such as parasympatic nervous system (PNS) index, sympatic nervous system (SNS) index, stress index, standard deviation of NN intervals (SDNN) and root mean square of the successive differences (RMSSD) had improved in a majority of patients.

Conclusion: An intervention centered on forgiveness therapy was able to improve distress, reduce adrenergic signals in the autonomic nervous system, and restore parameters of the immune profile of patients with plasma cell dyscrasia who suffered from chronic stress caused by repressed anger and unforgiveness. Integrative treatment of myeloma can improve the quality of life of patients and thus affect the efficiency of immuno-chemotherapy. New randomised trials are warranted to test the integrative treatment of myeloma that might be able to improve overall survival.

Keywords:

Multiple myeloma – Sympathetic nervous system – neurobiology of cancer – forgiveness therapy

Sources

1. Sakalová A, Hrianka M, Kotouček P et al. Súčasná liečba mnohopočetného myelómu a jej perspektívy. Bratislava: A-medi management 2016.
2. Sung H, Ferlay J, Siegel R et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71 (3): 209–249. doi: 10.3322/caac.21660.
3. Ondrušová M, Suchanský M. Vybrané epidemiologické aspekty mnohopočetného myelómu v SR. Pharm-In, spol. s r. o.: Bratislava 2018.
4. Safaei Diba S. Incidencia zhubných nádorov v Slovenskej republike 2012. Bratislava: Národné centrum zdravotníckych informácií 2021.
5. Silva AS, Gatenby RA. Adaptation to survival in germinal center is the initial step in onset of indolent stage of multiple myeloma. Mol Pharm 2011; 8 (6): 2012–2020. doi: 10.1021/mp200279p.
6. Mravec B. Neurobiology of cancer: definition, historical overview, and clinical implications. Cancer Med 2022; 11 (4): 903–921. doi: 10.1002/cam4.4488.
7. Mravec B, Blaško F. Neurobiology of cancer – the role of cancer tissue innervation. Klin Onkol 2022; 35 (3): 208–214. doi: 10.48095/ccko2022208.
8. Cheng Y, Sun F, D’Souza A et al. Autonomic nervous system control of multiple myeloma. Blood Rev 2021; 46: 100741. doi: 10.1016/j.blre.2020.100741.
9. Calvo W. The innervation of the bone marrow in laboratory animals. Am J Anat 1968; 123 (2): 315–328. doi: 10.1002/aja.1001230206.
10. Jung WC, Levesque JP, Ruitenberg MJ. It takes nerve to fight back: the significance of neural innervation of the bone marrow and spleen for immune functions. Semin Cell Dev Biol 2017; 61: 60–70. doi: 10.1016/j.semcdb.2016.08.010.
11. Maryanovich M, Takeishi S, Frenette PS. Neural regulation of bone and bone marrow. Cold Spring Harb Perspect Med 2018; 8 (9): a031344. doi: 10.1101/cshperspect.a031344.
12. Noll JE, Williams SA, Purton LE et al. Tug of war in the haematopoietic stem cell niche: do myeloma plasma cells compete for the HSC niche? Blood Cancer J 2012; 2 (9): e91. doi: 10.1038/bcj.2012.38.
13. Olechnowicz SWZ, Weivoda MM, Lwin ST et al. Multiple myeloma increases nerve growth factor and other pain-related markers through interactions with the bone microenvironment. Sci Rep 2019; 9 (1): 14189. doi: 10.1038/s41598-019-50591-5.
14. Alexandrakis MG, Sfiridaki A, Miyakis S et al. Relationship between serum levels of vascular endothelial growth factor, hepatocyte growth factor and matrix metalloproteinase-9 with biochemical markers of bone disease in multiple myeloma. Clin Chim Acta 2007; 379 (1–2): 31–35. doi: 10.1016/j.cca.2006.11.024.
15. Hu Y, Sun C, Wang H et al. Brain-derived neurotrophic factor promotes growth and migration of multiple myeloma cells. Cancer Genet Cytogenet 2006; 169 (1): 12–20. doi: 10.1016/j.cancergencyto.2006.02.018.
16. Pearse RN, Swendeman SL, Li Y et al. A neurotrophin axis in myeloma: TrkB and BDNF promote tumor-cell survival. Blood 2005; 105 (11): 4429–4436. doi: 10.1182/blood-2004-08-3096.
17. Mravec B, Tibensky M, Horvathova L. Stress and cancer. Part I: mechanisms mediating the effect of stressors on cancer. J Neuroimmunol 2020; 346: 577311. doi: 10.1016/j.jneuroim.2020.577311.
18. Yang EV, Donovan EL, Benson DM et al. VEGF is differentially regulated in multiple myeloma-derived cell lines by norepinephrine. Brain Behav Immun 2008; 22 (3): 318–323. doi: 10.1016/j.bbi.2007.09.010.
19. Ganellin R, Duncan W. Obituary: James Black (1924–2010). Nature 2010; 464 (7293): 1292. doi: 10.1038/ 4641292a.
20. Baker JG, Hill SJ, Summers RJ. Evolution of b-blockers: from anti-anginal drugs to ligand-directed signalling. Trends Pharmacol Sci 2011; 32 (4): 227–234. doi: 10.1016/j.tips.2011.02.010.
21. Hwa YL, Shi Q, Kumar SK et al. Beta-blockers improve survival outcomes in patients with multiple myeloma: a retrospective evaluation. Am J Hematol 2017; 92 (1): 50–55. doi: 10.1002/ajh.24582.
22. Hwa YL, Lacy MQ, Gertz MA et al. Use of beta blockers is associated with survival outcome of multiple myeloma patients treated with pomalidomide. Eur J Haematol 2021; 106 (3): 433–436. doi: 10.1111/ejh.13559.
23. Knight J, Rizzo JD, Hari P et al. Propranolol inhibits molecular risk markers in HCT recipients: a phase 2 randomized controlled biomarker trial. Blood Adv 2020; 4 (3): 467–476. doi: 10.1182/bloodadvances.2019000 765.
24. Joshy G, Thandrayen J, Koczwara B et al. Disability, psychological distress and quality of life in relation to cancer diagnosis and cancer type: population-based Australian study of 22,505 cancer survivors and 244,000 people without cancer. BMC Med 2020; 18 (1): 372. doi: 10.1186/s12916-020-01830-4.
25. Lamers J, Hartmann M, Goldschmidt H et al. Psychosocial support in patients with multiple myeloma at time of diagnosis: who wants what? Psychooncology 2013; 22 (10): 2313–2320. doi: 10.1002/pon.3284.
26. McLellan L, Pohlman B, Rybicki L et al. Distress screening scores of malignant and benign hematology patients: results of a pilot project. Blood 2012; 120 (21): 3173. doi: 10.1182/blood.V120.21.3173.3173.
27. Boleková V, Chlebcová V, Naništová E. Psychoonkológia: indikátory – merania – intervencie. Trnava: Veda 2021.
28. Kotoucek P, Enright R, Orfao A et al. Neuro-immune interactions in the oncogenesis of multiple myeloma and their therapeutical relevance. Trans Hematol Dnes 2021; 27 (4): 306–315. doi: 10.48095/cctahd2021306.
29. Waltman MA, Russell DC, Coyle CT et al. The effects of a forgiveness intervention on patients with coronary artery disease. Psychol Health 2009; 24 (1): 11–27. doi: 10.1080/08870440903126371.
30. Harrison P. Forgiveness can improve immune function. [online]. Available from: https: //www.medscape.com/viewarticle/742198.
31. Enright RD, Fitzgibbons RP. Forgiveness therapy. Washington: APA Books 2015.
32. Shapiro YN, Peppercorn JM, Yee AJ et al. Lifestyle considerations in multiple myeloma. Blood Cancer J 2021; 11 (10): 172. doi: 10.1038/s41408-021-00560-x.
33. Richter J, Sanchez L, Biran N et al. Prevalence and survival impact of self-reported symptom and psychological distress among patients with multiple myeloma. Clin Lymphoma Myeloma Leuk 2021; 21 (3): e284–e289. doi: 10.1016/j.clml.2020.11.021.
34. Islam S, Lee CD, Kim J et al. Marital status and survival in patients with multiple myeloma: the role of marriage in the management of multiple myeloma. Clin Lymphoma Myeloma Leukemia 2019; 2 (3): e259–e260. doi: 10.1016/ j.clml.2019.09.429.
35. Keilani M, Kainberger F, Crevenna R et al. Typical aspects in the rehabilitation of cancer patients suffering from metastatic bone disease or multiple myeloma. Wien Klin Wochenschr 2019; 131 (21–22): 567–575. doi: 10.1007/s00508-019-1524-3.
36. Kotoucek P, Hrianka M, Nanistova E et al. Finding the meaning of life of patients with multiple myeloma correlates with better control of their disease by chemotherapy. Clin Lymphoma Myeloma Leukemia 2015; 15 (3): e203–e204. doi: 10.1016/j.clml.2015.07.444.
37. Strasser-Weippl K, Ludwig H. Psychosocial QOL is an independent predictor of overall survival in newly diag- nosed patients with multiple myeloma. Eur J Haematol 2008; 81 (5): 374–379. doi: 10.1111/j.1600-0609.20 08.011 26.x.
38. Stanzer S, Andritsch E, Zloklikovits S et al. A pilot randomized trial assessing the effect of a psychoeducational intervention on psychoneuroimmunological parameters among patients with nonmetastatic breast cancer. Psychosom Med 2019; 81 (2): 165–175. doi: 10.1097/PSY.0000000000000656.
39. Hiam-Galvez KJ, Allen BM, Spitzer MH. Systemic immunity in cancer. Nat Rev Cancer 2021; 21 (6): 345–359. doi: 10.1038/s41568-021-00347-z.
40. Paiva B, Cedena MT, Puig N et al. Minimal resi- dual disease monitoring and immune profiling in multiple myeloma in elderly patients. Blood 2016; 127 (25): 3165–3174. doi: 10.1182/blood-2016-03-705 319.
41. Knight A, Rihova L, Kralova R et al. Plasmacytoid dendritic cells in patients with MGUS and multiple myeloma. J Clin Med 2021; 10 (16): 3717. doi: 10.3390/jcm10163 717.
42. Zaleta AK, Miller MF, Olson JS et al. Symptom burden, perceived control, and quality of life among patients living with multiple myeloma. J Natl Compr Canc Netw 2020; 18 (8): 1087–1095. doi: 10.6004/jnccn.2020.7 561.
43. Lawler KA, Younger JW, Piferi RL et al. A change of heart: cardiovascular correlates of forgiveness in response to interpersonal conflict. J Behav Med 2003; 26 (5): 373–393. doi: 10.1023/a: 1025771716686.
44. Whited MC, Wheat AL, Larkin KT. The influence of forgiveness and apology on cardiovascular reactivity and recovery in response to mental stress. J Behav Med 2010; 33 (4): 293–304. doi: 10.1007/s10865-010-9259-7.
45. Freedman SR, Enright RD. Forgiveness as an intervention goal with incest survivors. J Consult Clin Psychol 1996; 64 (5): 983–992. doi: 10.1037//0022-006x.64.5.983.
46. Hansen MJ, Enright RD, Baskin TW et al. A palliative care intervention in forgiveness therapy for elderly terminally ill cancer patients. J Palliat Care 2009; 25 (1): 51–60.
47. Enright RD. The forgiving life. Washington: APA Books 2012.