Potential Multiple Myeloma Therapeutic Strategies through Targeting Macrophages and Mesenchymal Stromal Cells


  • William Hu Washington University of St. Louis




Multiple Myeloma, Tumor-associated Macrophages, Mesenchymal Stromal Cells, Bone Marrow, Clodronate Liposomes


Multiple Myeloma (MM), a bone marrow plasma cell hematopoietic cancer, remains a critical but incurable hematological malignancy, prone to deadly relapses even after existing treatment. In this review, I describe the origins of pro-tumor myeloma-associated macrophages. I specifically outline how classically activated anti-tumor macrophages that home to the cancerous bone marrow tumor microenvironment is polarized into pro-tumor macrophages. We then explain how these myeloma-associated macrophages play an important role in supporting multiple myeloma by enabling drug resistance, improved growth, angiogenesis, and protection. We also describe several treatments in development aimed to sever the supportive link between myeloma-associated macrophages and MM by blocking signaling pathways, destroying, or repolarizing macrophages and even preventing macrophage polarization in the first place. We conclude that careful study is needed to improve the reliability of targeting myeloma-associated macrophages to reduce MM relapse and comprehensively treat this cancer.


Download data is not yet available.


Metrics Loading ...

References or Bibliography

Siegel, R.L., Miller, K.D. and Jemal, A. (2016), Cancer statistics, 2016. CA: A Cancer Journal for Clinicians, 66: 7-30. https://doi.org/10.3322/caac.21332

Bristol Myers Squibb. (2020). Blood Cancers. [pdf]. https://www.bms.com/assets/bms/us/en us/pdf/Disease-State-Info/blood-cancers-at-a-glance.pdf

American Society of Clinical Oncology. (Feb 2022). Multiple Myeloma: Statistics. Cancer.Net.


Majithia, N., Rajkumar, S., Lacy, M. et al. Early relapse following initial therapy for multiple myeloma predicts poor outcomes in the era of novel agents. Leukemia 30, 2208–2213 (2016). https://doi.org/10.1038/leu.2016.147

Opperman, K.S., Vandyke, K., Psaltis, P.J. et al. Macrophages in multiple myeloma: key roles

and therapeutic strategies. Cancer Metastasis Rev 40, 273–284 (2021).


Mosser, D., Edwards, J. Exploring the full spectrum of macrophage activation. Nat Rev

Immunol 8, 958–969 (2008). https://doi.org/10.1038/nri2448

Werner, S. & Grose, R. (2003). Regulation of Wound Healing by Growth Factors and

Cytokines. Physiological Reviews 83: 835-870. https://doi.org/10.1152/physrev.2003.83.3.835

Roberts, D. B., Sporn, M. B., Assoian, R. K. et al. Transforming growth factor type beta: rapid

induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro.

Proceedings of the National Academy of Sciences 82 (12).


Vacca, A., Ribatti, D., Presta, M., Minischetti, M., Lurlaro, M., Ria, R., Albini, A., Bussolino, F.,

Dammacco, F.; Bone Marrow Neovascularization, Plasma Cell Angiogenic Potential, and Matrix

Metalloproteinase-2 Secretion Parallel Progression of Human Multiple Myeloma. Blood 1999;

(9): 3064–3073. doi: https://doi.org/10.1182/blood.V93.9.3064

Berardi, S., Ria, R., Reale, A., De Luisi, A., Catacchio, I., Moschetta, M., Vacca, A. "Multiple

Myeloma Macrophages: Pivotal Players in the Tumor Microenvironment", Journal of Oncology,

vol. 2013, Article ID 183602, 6 pages, 2013. https://doi.org/10.1155/2013/183602

Chen P, Cescon M, Bonaldo P. Autophagy-mediated regulation of macrophages and its

applications for cancer. Autophagy. 2014 Feb;10(2):192-200.


Martinez F. O. & Gordon S. (2014). The M1 and M2 paradigm of macrophage activation:

time for reassessment. Faculty Opinions. https://facultyopinions.com/prime/reports/b/6/13/

De Beule, N., De Veirman, K., Maes, K., De Bruyne, E., Menu, E., Breckpot, K., De Raeve, H.,

Van Rampelbergh, R., Van Ginderachter, J.A., Schots, R., Van Valckenborgh, E. and

Vanderkerken, K. (2017), Tumour-associated macrophage-mediated survival of myeloma cells

through STAT3 activation. J. Pathol, 241: 534-546. https://doi.org/10.1002/path.4860

Liposoma. (n.d.). Product Description. https://clodronateliposomes.com/about-clodronate


Opperman, K., Vandyke, K., Clark, K., Coulter, E., Hewett, D., Mrozik, K., Schwarz, N.,

Evdokiou, A., Croucher, P., Psaltis, P., Noll, J., Zannettino, A. Clodronate-Liposome Mediated

Macrophage Depletion Abrogates Multiple Myeloma Tumor Establishment In Vivo, Neoplasia,

Volume 21, Issue 8, 2019, Pages 777-787, ISSN 1476-5586,


Li Y., Zheng Y., Li T., Wang Q., Qian J., Lu Y., Zhang M., Bi E., Yang M., Reu F., Yi Q., Cai Z.

Chemokines CCL2, 3, 14 stimulate macrophage bone marrow homing, proliferation, and

polarization in multiple myeloma. Oncotarget. 2015; 6: 24218-24229.


Beider K, Bitner H, Leiba M, Gutwein O, Koren-Michowitz M, Ostrovsky O, Abraham M, Wald

H, Galun E, Peled A, Nagler A. Multiple myeloma cells recruit tumor-supportive macrophages

through the CXCR4/CXCL12 axis and promote their polarization toward the M2 phenotype.

Oncotarget. 2014 Nov 30;5(22):11283-96. doi: 10.18632/oncotarget.2207

Chen, J., He, D., Chen, Q. et al. BAFF is involved in macrophage-induced bortezomib

resistance in myeloma. Cell Death Dis 8, e3161 (2017). https://doi.org/10.1038/cddis.2017.533

Zheng, Y., Yang, J., Qian, J. et al. PSGL-1/selectin and ICAM-1/CD18 interactions are involved

in macrophage-induced drug resistance in myeloma. Leukemia 27, 702–710 (2013).


Catlett-Falcone, Robyn et al. Immunity, Volume 10, Issue 1, 105 – 115


Papadimitriou K, Tsakirakis N, Malandrakis P, Vitsos P, Mitousis A, Orologas-Stavrou N,

Ntanasis-Stathopoulos I, Kanellias N, Eleftherakis-Papaiakovou E, Pothos P, Fotiou D,

Gavriatopoulou M, Kastritis E, Dimopoulos M-A, Terpos E, Tsitsikronis OE, Kostopoulos IV. Deep

Phenotyping Reveals Distinct Immune Signatures Correlating with Prognostication, Treatment

Responses, and MRD Status in Multiple Myeloma. Cancers. 2020; 12(11):3245.


Andersen, M. N., Abildgaard, N., Maniecki, M. B., Moller, H. J., & Andersen, N. F. (2014).

Monocyte/macrophage-derived soluble CD163: A novel biomarker in multiple myeloma.

European Journal of Haematology, 93(1), 41–47. https://doi.org/10.1111/ejh.12296

Scavelli, C., Nico, B., Cirulli, T. et al. Vasculogenic mimicry by bone marrow macrophages in

patients with multiple myeloma. Oncogene 27, 663–674 (2008).


Kim, J., Denu, R.A., Dollar, B.A., Escalante, L.E., Kuether, J.P., Callander, N.S., Asimakopoulos,

F. and Hematti, P. (2012), Macrophages and mesenchymal stromal cells support survival and

proliferation of multiple myeloma cells. Br J Haematol, 158: 336-346.


Calcinotto, A., Ponzoni, M., Ria, R., Grioni, M., Cattaneo, E., Villa, I., Bertilaccio, M., Chesi, M.,

Rubinacci, A., Tonon, G., Bergsagel, P., Vacca, A. & Bellone, M. (2015) Modifications of the

mouse bone marrow microenvironment favor angiogenesis and correlate with disease

progression from asymptomatic to symptomatic multiple myeloma, OncoImmunology, 4:6.


Alexandrakis, M.G., Goulidaki, N., Pappa, C.A. et al. Interleukin-10 Induces Both Plasma Cell

Proliferation and Angiogenesis in Multiple Myeloma. Pathol. Oncol. Res. 21, 929–934 (2015).


Sun, M., Qiu, S., Xiao, Q. et al. Synergistic effects of multiple myeloma cells and tumor

associated macrophages on vascular endothelial cells in vitro. Med Oncol 37, 99 (2020).


Richer M.J., Nolz J.C., Harty J.T. Pathogen-specific inflammatory milieux tune the antigen

sensitivity of CD8(+) T cells by enhancing T cell receptor signaling. Immunity. 2013; 38: 140


Kim, D., Wang, J., Willingham, S. et al. Anti-CD47 antibodies promote phagocytosis and

inhibit the growth of human myeloma cells. Leukemia 26, 2538–2545 (2012).


Anton K, Banerjee D, Glod J (2012) Macrophage-Associated Mesenchymal Stem Cells

Assume an Activated, Migratory, Pro-Inflammatory Phenotype with Increased IL-6 and CXCL10

Secretion. PLoS ONE 7(4): e35036. https://doi.org/10.1371/journal.pone.0035036

Chen, H., Li, M., Wang, C., Sanchez, E., Soof, C., Udd, K., Director, C., Cao, J., Tang, G., &

Berenson, J. (2017). Increase in M2 macrophage polarization in multiple myeloma bone

marrow is inhibited with the JAK2 inhibitor ruxolitinib which shows anti-MM effects. Clinical Lymphoma, Myeloma & Leukemia, 17(1), e93. https://doi.org/10.1016/j.clml.2017.03.166.

Cannarile MA, Weisser M, Jacob W, et al Colony-stimulating factor 1 receptor (CSF1R)

inhibitors in cancer therapy Journal for ImmunoTherapy of Cancer 2017;5:53. doi:

1186/s40425-017-0257-y. https://doi.org/10.1186/s40425-017-0257-y

Wang, Q., Lu, Y., Li, R. et al. Therapeutic effects of CSF1R-blocking antibodies in multiple

myeloma. Leukemia 32, 176–183 (2018). https://doi.org/10.1038/leu.2017.193

Alexander M. Lesokhin, Susan Bal, Ashraf Z. Badros; Lessons Learned from Checkpoint

Blockade Targeting PD-1 in Multiple Myeloma. Cancer Immunol Res 1 August 2019; 7 (8):

–1229. https://doi.org/10.1158/2326-6066.CIR-19-0148

Advani, R., Flinn, I., Popplewell, L., Forero, A., Bartlett, N. L., Ghosh, N., Kline, J., Roschewski,

M., LaCasce, A., Collins, G. P., Tran, T., Lynn, J., Chen, J. Y., Volkmer, J. P., Agoram, B., Huang, J.,

Majeti, R., Weissman, I. L., Takimoto, C. H., Chao, M. P., & Smith, S. M. (2018). CD47 blockade by

Hu5F9-G4 and rituximab in non-Hodgkin’s lymphoma. The New England Journal of Medicine,

(18), 1711–1721. https://doi.org/10.1056/NEJMoa1807315

. Linderoth, E., Helke, S., Lee, V., Mutukura, T., Wong, M., Lin, G., Johnson, L., Pang, X., Winston, J., Petrova, P., Uger, R., Viller, N.; Abstract 2653: The anti-myeloma activity of TTI-621 (SIRPaFc), a CD47-blocking immunotherapeutic, is enhance when combined with a proteasome inhibitor. Cancer Res 1 July 2017; 77 (13_Supplement): 2653. https://doi.org/10.1158/1538-7445.AM2017-2653

Wilson, W., Richards, J., Puro, R., Andrejeva, G., Capoccia, B., Donio, M., Hiebsch, R., Chakraborty, P., Sung, V., Pereira, S.; AO-176, a Highly Differentiated Clinical Stage Anti-CD47 Antibody, Exerts Potent Anti-Tumor Activity in Preclinical Models of Multiple Myeloma As a Single Agent and in Combination with Approved Therapeutics. Blood 2020; 136 (Supplement 1): 3–4. doi: https://doi.org/10.1182/blood-2020-139655

Rastgoo, N., Wu, J., Liu, A., Pourabdollah, M., Atenafu, E., Reece, D., Chen, W., Chang, H. Targeting CD47/TNFAIP8 by miR-155 overcomes drug resistance and inhibits tumor growth through induction of phagocytosis and apoptosis in multiple myeloma. Haematologica 2019;105(12):2813-2823; https://doi.org/10.3324/haematol.2019.227579

Chen, H., Li, M., Sanchez, E., Soof, C.M., Bujarski, S., Ng, N., Cao, J., Hekmati, T., Zahab, B., Nosrati, J.D., Wen, M., Wang, C.S., Tang, G., Xu, N., Spektor, T.M. and Berenson, J.R. (2020), JAK1/2 pathway inhibition suppresses M2 polarization and overcomes resistance of myeloma to lenalidomide by reducing TRIB1, MUC1, CD44, CXCL12, and CXCR4 expression. Br J Haematol, 188: 283-294. https://doi.org/10.1111/bjh.16158

Jensen, J., Rakhmilevich, A., Heninger, E., Broman, A., Hope, C., Phan, F., Miyamoto, S., Maroulakou, I., Callander, N., Hematti, P., Chesi, M., Bergsagel, P., Sondel, P., Asimakopoulos, F.; Tumoricidal Effects of Macrophage-Activating Immunotherapy in a Murine Model of Relapsed/Refractory Multiple Myeloma. Cancer Immunol Res 1 August 2015; 3 (8): 881–890. https://doi.org/10.1158/2326-6066.CIR-15-0025-T

Gutiérrez-González, A., Martínez-Moreno, M., Samaniego, R., Arellano-Sánchez, N., Salinas-Muñoz, L., Relloso, M., Valeri, A., Martínez-López, J., Corbí, A., Hidalgo, A., García-Pardo, A., Teixidó, J., Sánchez-Mateos, P.; Evaluation of the potential therapeutic benefits of macrophage reprogramming in multiple myeloma. Blood 2016; 128 (18): 2241–2252. doi: https://doi.org/10.1182/blood-2016-01-695395

Gantke, T., Sriskantharajah, S & Ley, S. Regulation and function of TPL-2, an IkB kinase-regulated MAP kinase. Cell Res 21, 13-145 (2011). https://doi.org/10.1038/cr.2010.173

Zhang, D., Huang, J., Wang, F. et al. BMI1 regulates multiple myeloma-associated macrophage’s pro-myeloma functions. Cell Death Dis 12, 495 (2021). https://doi.org/10.1038/s41419-021-03748-y

Li X, Yao W, Yuan Y, et al. Targeting of tumor-infiltrating macrophages via CCL2/CCR2 signaling as a therapeutic strategy against hepatocellular carcinoma. Gut 2017;66:157-167. https://gut.bmj.com/content/66/1/157

Smith, L. K., Boukhaled, G.M., Condotta, S.A., Mazouz, S., Guthmiller, J.J., Vijay, R., Butler, N.S., Bruneau, J., Shoukry, N.H., Krawczyk, C.M., Richer, M.J. Interleukin-10 Directly Inhibits CD8+ T Cell Function by Enhancing N-Glycan Branching to Decrease Antigen Sensitivity. Immunity. 2018 Feb 20;48(2):299-312.e5. https://doi.org/10.1016/j.immuni.2018.01.006



How to Cite

Hu, W. (2023). Potential Multiple Myeloma Therapeutic Strategies through Targeting Macrophages and Mesenchymal Stromal Cells. Journal of Student Research, 12(1). https://doi.org/10.47611/jsr.v12i1.1870



Review Articles