Microenvironment Regulation and Targeted Therapy for Multiple Myeloma Bone Disease

Xinrong Li

doi:10.54097/kx84t858

Authors

Xinrong Li

DOI:

https://doi.org/10.54097/kx84t858

Keywords:

Myeloma, Myeloma-Related Bone Disease, Bone Marrow Microenvironment

Abstract

Multiple myeloma bone disease (MBD) is one of the most common clinical complications associated with multiple myeloma (MM). Skeletal-related events (SREs) caused by MBD significantly impair patients' quality of life and prognosis. Anti-bone resorption drugs are the main therapeutic approach and have been effective in controlling bone disease. However, these treatments are still limited by drug-related side effects and limited therapeutic efficacy. With the in-depth investigation into the pathogenesis of MBD, modulation of the bone marrow microenvironment has gradually emerged as a novel therapeutic direction for the treatment of multiple myeloma bone disease. This review aims to concisely describe the mechanisms by which the bone marrow microenvironment contributes to multiple myeloma bone disease and to discuss the targeted therapeutic strategies based on the modulation of the microenvironment.

Downloads

Download data is not yet available.

References

[1] Terpos E, Berenson J, Cook RJ, Lipton A, Coleman RE: Prognostic variables for survival and skeletal complications in patients with multiple myeloma osteolytic bone disease. Leukemia 2010, 24(5):1043-1049.

[2] Coleman RE, Croucher PI, Padhani AR, Clézardin P, Chow E, Fallon M, Guise T, Colangeli S, Capanna R, Costa L: Bone metastases. Nature Reviews Disease Primers 2020, 6(1):83.

[3] Ramsenthaler C, Osborne TR, Gao W, Siegert RJ, Edmonds PM, Schey SA, Higginson IJ: The impact of disease-related symptoms and palliative care concerns on health-related quality of life in multiple myeloma: a multi-centre study. Bmc Cancer 2016, 16:427.

[4] Terpos E, Zamagni E, Lentzsch S, Drake MT, García-Sanz R, Abildgaard N, Ntanasis-Stathopoulos I, Schjesvold F, de la Rubia J, Kyriakou C et al: Treatment of multiple myeloma-related bone disease: recommendations from the Bone Working Group of the International Myeloma Working Group. Lancet Oncology 2021, 22(3):E119-E130.

[5] Zhang C, Shen G, Li H, Xin Y, Shi M, Zheng Y, Wang M, Liu Z, Zhao Y, Zhao F et al: Incidence rate of osteonecrosis of jaw after cancer treated with bisphosphonates and denosumab: A systematic review and meta‑analysis. Special Care in Dentistry 2023, 44(2):530-541.

[6] Hoff AO, Toth BB, Altundag K, Johnson MM, Warneke CL, Hu MM, Nooka A, Sayegh G, Guarneri V, Desrouleaux K et al: Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. Journal of Bone and Mineral Research 2008, 23(6):826-836.

[7] Anastasilakis AD, Makras P, Yavropoulou MP, Tabacco G, Naciu AM, Palermo A: Denosumab Discontinuation and the Rebound Phenomenon: A Narrative Review. Journal of Clinical Medicine 2021, 10(1).

[8] Gau YC, Yeh TJ, Hsu CM, Hsiao SY, Hsiao HH: Pathogenesis and Treatment of Myeloma-Related Bone Disease. International Journal of Molecular Sciences 2022, 23(6).

[9] Terpos E, Ntanasis-Stathopoulos I, Dimopoulos MA: Myeloma bone disease: from biology findings to treatment approaches. Blood 2019, 133(14):1534-1539.

[10] Hofbauer LC, Bozec A, Rauner M, Jakob F, Perner S, Pantel K: Novel approaches to target the microenvironment of bone metastasis. Nature Reviews Clinical Oncology 2021, 18(8): 488-505.

[11] Tao H, Li W, Zhang W, Yang C, Zhang C, Liang X, Yin J, Bai J, Ge G, Zhang H et al: Urolithin A suppresses RANKL-induced osteoclastogenesis and postmenopausal osteoporosis by, suppresses inflammation and downstream NF-κB activated pyroptosis pathways. Pharmacological Research 2021, 174: 105967.

[12] Xu GS, Liu K, Anderson J, Patrene K, Lentzsch S, Roodman GD, Ouyang HJ: Expression of XBP1s in bone marrow stromal cells is critical for myeloma cell growth and osteoclast formation. Blood 2012, 119(18):4205-4214.

[13] Xu H, Wang WT, Liu X, Huang W, Zhu C, Xu YZ, Yang HL, Bai JX, Geng DC: Targeting strategies for bone diseases: signaling pathways and clinical studies. Signal Transduct Tar 2023, 8(1):202.

[14] Wang X, He Y, Tian S, Zhu F, Huang B, Zhang J, Chen Z, Wang H: Fluid Shear Stress Increases Osteocyte and Inhibits Osteoclasts via Downregulating Receptor-Activator of Nuclear Factor κB (RANK)/Osteoprotegerin Expression in Myeloma Microenvironment. Medical Science Monitor 2019, 25:5961-5968.

[15] Baron R, Kneissel M: WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nature Medicine 2013, 19(2):179-192.

[16] Spaan I, Raymakers RA, van de Stolpe A, Peperzak V: Wnt signaling in multiple myeloma: a central player in disease with therapeutic potential. Journal of Hematology & Oncology 2018, 11(1):67.

[17] Qiang YW, Chen Y, Stephens O, Brown N, Chen BZ, Epstein J, Barlogie B, Shaughnessy JD: Myeloma-derived Dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma. Blood 2008, 112(1):196-207.

[18] Zhang F, Zhuang J: Pathophysiology and therapeutic advances in myeloma bone disease. Chronic Diseases and Translational Medicine 2022, 8(4):264-270.

[19] Silbermann R, Bolzoni M, Storti P, Guasco D, Bonomini S, Zhou D, Wu J, Anderson JL, Windle JJ, Aversa F et al: Bone marrow monocyte-/macrophage-derived activin A mediates the osteoclastogenic effect of IL-3 in multiple myeloma. Leukemia 2014, 28(4):951-954.

[20] Tucci M, Stucci S, Strippoli S, Dammacco F, Silvestris F: Dendritic Cells and Malignant Plasma Cells: An Alliance in Multiple Myeloma Tumor Progression? The Oncologist 2011, 16(7):1040-1048.

[21] Alsamraae M, Cook LM: Emerging roles for myeloid immune cells in bone metastasis. Cancer Metast Rev 2021, 40(2):413-425.

[22] Vyzoukaki R, Tsirakis G, Pappa CA, Devetzoglou M, Tzardi M, Alexandrakis MG: The Impact of Mast Cell Density on the Progression of Bone Disease in Multiple Myeloma Patients. Int Arch Allergy Imm 2015, 168(4):263-268.

[23] Hao P, Zhang CL, Wang RF, Yan P, Peng RC: Expression and pathogenesis of VCAM-1 and VLA-4 cytokines in multiple myeloma. Saudi Journal of Biological Sciences 2020, 27(6): 1674-1678.

[24] Vallet S, Pozzi S, Patel K, Vaghela N, Fulciniti MT, Veiby P, Hideshima T, Santo L, Cirstea D, Scadden DT et al: A novel role for CCL3 (MIP-1α) in myeloma-induced bone disease via osteocalcin downregulation and inhibition of osteoblast function. Leukemia 2011, 25(7):1174-1181.

[25] Li X, Wang J, Zhu S, Zheng J, Xie Y, Jiang H, Guo J, Wang Y, Peng Z, Wang M et al: DKK1 activates noncanonical NF-κB signaling via IL-6–induced CKAP4 receptor in multiple myeloma. Blood Advances 2021, 5(18):3656-3667.

[26] Faraahi Z, Baud'huin M, Croucher PI, Eaton C, Lawson MA: Sostdc1: A soluble BMP and Wnt antagonist that is induced by the interaction between myeloma cells and osteoblast lineage cells. Bone 2019, 122:82-92.

[27] Cowan AJ, Green DJ, Kwok M, Lee S, Coffey DG, Holmberg LA, Tuazon S, Gopal AK, Libby EN: Diagnosis and Management of Multiple Myeloma A Review. Jama-J Am Med Assoc 2022, 327(5):464-477.

[28] Marino S, Petrusca DN, Roodman GD: Therapeutic targets in myeloma bone disease. British Journal of Pharmacology 2020, 178(9):1907-1922.

[29] Abdulkadyrov KM, Salogub GN, Khuazheva NK, Sherman ML, Laadem A, Barger R, Knight R, Srinivasan S, Terpos E: Sotatercept in patients with osteolytic lesions of multiple myeloma. Brit J Haematol 2014, 165(6):814-823.

[30] Pisklakova A, Grigson E, Ozerova M, Chen F, Sullivan DM, Nefedova Y: Anti-myeloma effect of pharmacological inhibition of Notch/gamma-secretase with RO4929097 is mediated by modulation of tumor microenvironment. Cancer Biology & Therapy 2016, 17(5):477-485.

[31] Iyer SP, Beck JT, Stewart AK, Shah J, Kelly KR, Isaacs R, Bilic S, Sen S, Munshi NC: A Phase IB multicentre dose-determination study of BHQ880 in combination with anti-myeloma therapy and zoledronic acid in patients with relapsed or refractory multiple myeloma and prior skeletal-related events. Brit J Haematol 2014, 167(3):366-375.

[32] Terpos E, Sezer O, Croucher P, Dimopoulos MA: Myeloma bone-disease and proteasome inhibition therapies. Blood 2007, 110(4):1098-1104.

[33] Terpos E, Kastritis E, Ntanasis-Stathopoulos I, Christoulas D, Papatheodorou A, Eleutherakis-Papaiakovou E, Kanellias N, Fotiou D, Ziogas DC, Migkou M et al: Consolidation therapy with the combination of bortezomib and lenalidomide (VR) without dexamethasone in multiple myeloma patients after transplant: Effects on survival and bone outcomes in the absence of bisphosphonates. American Journal of Hematology 2019, 94(4):400-407.

[34] Terpos E, Ntanasis-Stathopoulos I, Katodritou E, Kyrtsonis MC, Douka V, Spanoudakis E, Papatheodorou A, Eleutherakis-Papaiakovou E, Kanellias N, Gavriatopoulou M et al: Carfilzomib Improves Bone Metabolism in Patients with Advanced Relapsed/Refractory Multiple Myeloma: Results of the CarMMa Study. Cancers 2021, 13(6).

[35] Terpos E, Ntanasis-Stathopoulos I, Kastritis E, Hatjiharissi E, Katodritou E, Eleutherakis-Papaiakovou E, Verrou E, Gavriatopoulou M, Leonidakis A, Manousou K et al: Daratumumab Improves Bone Turnover in Relapsed/ Refractory Multiple Myeloma; Phase 2 Study "REBUILD". Cancers 2022, 14(11).

[36] Teramachi J, Miki H, Nakamura S, Hiasa M, Harada T, Abe M: Myeloma bone disease: pathogenesis and management in the era of new anti-myeloma agents. Journal of Bone and Mineral Metabolism 2023, 41(3):388-403.