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COMMENTARY
Year : 2014  |  Volume : 60  |  Issue : 2  |  Page : 159

Multiple myeloma pathogenesis: Blame it on the microenvironment


Department of Medical Oncology, Tata Memorial Centre, Mumbai, Maharashtra, India

Date of Web Publication13-May-2014

Correspondence Address:
Dr. M Sengar
Department of Medical Oncology, Tata Memorial Centre, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


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How to cite this article:
Sengar M, Jain H. Multiple myeloma pathogenesis: Blame it on the microenvironment. J Postgrad Med 2014;60:159

How to cite this URL:
Sengar M, Jain H. Multiple myeloma pathogenesis: Blame it on the microenvironment. J Postgrad Med [serial online] 2014 [cited 2019 Nov 17];60:159. Available from: http://www.jpgmonline.com/text.asp?2014/60/2/159/132326


Multiple myeloma (MM) is a postgerminal center B-cell neoplasm, characterized by the accumulation of clonal plasma cells in bone marrow and extramedullary sites along with a monoclonal protein in serum and/or urine. [1] All cases of MM evolve from a premalignant condition - monoclonal gammopathy of undetermined significance (MGUS). MGUS progresses to smouldering MM (SMM) and finally to symptomatic MM requiring therapy at the rate of 1% per year. [2] Given that not all patients with MGUS evolve to MM, it becomes relevant to identify patients who are at a risk of progression to MM. Studies examining neoplastic plasma cells from MM and MGUS, have not found significant differences in genetic abnormalities, suggesting that these genetic changes are early events in MM. [3] In some of the MGUS patients, the neoplastic cells re-program the microenvironment (bone marrow stromal cells, osteoclasts, osteoblasts, adhesion molecules, cytokines, growth factors, and extracellular matrix) to promote tumor progression and development of myeloma. Bone marrow stromal cells (BMSC) secrete several cytokines after paracrine stimulation or direct interaction with neoplastic cells via adhesion molecules. These cytokines in turn promote homing, migration, proliferation, drug resistance, and survival of malignant plasma cells, thus setting a vicious cycle with multiple feedback loops within and between compartments. [4] IL-6, IL-1β, TNF-α, SDF-α, BAFF, RANKL, and MIP-1α are some of the cytokines whose role in pathogenesis of MM, development of bone lesions, and drug resistance has been well studied. Given their key role in myeloma pathogenesis, cytokines seem to be attractive biomarkers in predicting risk of disease progression and response monitoring. [4] In addition, they can serve as relevant targets for drug development. However, till date most studies examining cytokine levels in plasma and marrow have shown discrepant results. Mehtap et al. evaluated IL-21, IL-6, IL-1β, and TNF-α in peripheral blood of patients with MM and healthy controls. [5] IL-21 is a growth-promoting and antiapoptotic factor as shown in an earlier study by Brenne et al. [6] Mehtap et al. did not find elevated serum levels of IL-21 in MM at diagnosis and levels did not correlate with the disease stage. Only levels of IL-1β and TNF-α were elevated in MM when compared with normal controls and higher levels correlated with advanced stage disease. IL-6 levels did not correlate with the stage of the disease but was found to be elevated in patients with three or more bony lesions. Considering the plethora of cytokines and growth factors involved in pathogenesis, it is unlikely to find a single biomarker to help diagnosis or prognostication. This explains the failure of reductionist approach in most studies, including the current study, evaluating levels of few cytokines. To address the complexity of interactions of various components of microenvironment, we need protein arrays to be constructed to measure multiple markers simultaneously. In addition, as acknowledged by authors, small sample size, use of serum instead of bone marrow, single time point estimation could also have contributed to negative results. Therefore, we need well-designed and adequately powered studies using high-throughput techniques to bring microenvironmental factors from laboratory to clinic as biomarkers.

 
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1.Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med 2004;351:1860-73.   Back to cited text no. 1
    
2.Landgren O, Kyle RA, Pfeiffer RM, Katzmann JA, Caporaso NE, Hayes RB, et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: A prospective study. Blood 2009;113:5412-7.  Back to cited text no. 2
    
3.Korde N, Kristinsson SY, Landgren O. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): Novel biological insights and development of early treatment strategies. Blood 2011;117:5573-81.  Back to cited text no. 3
    
4.Balakumaran A, Robey PG, Fedarko N, Landgren O. Bone marrow microenvironment in myelomagenesis: Its potential role in early diagnosis. Expert Rev Mol Diagn 2010;10:465-80.  Back to cited text no. 4
    
5.Mehtap O, Atesoglu EB, Tarkun P, Hacihanefioglu A, Dolasik I, Musul MM. IL-21 and other serum proinflammatory cytokine levels in patients with multiple myeloma at diagnosis. J Postgrad Med 2014;60:141-4.  Back to cited text no. 5
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6.Brenne AT, Ro TB, Waage A, Sundan A, Borset M, Hjorth-Hansen H. Interleukin-21 is a growth and survival factor for human myeloma cells. Blood 2002;99:3756-62.  Back to cited text no. 6
    




 

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2004 - Journal of Postgraduate Medicine
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