Cancer stem cells are the cause of drug resistance in multiple myeloma: fact or fiction?

Reinaldo Franqui-Machin, Erik B. Wendlandt, Siegfried Janz, Fenghuang Zhan and Guido Tricot _

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Oncotarget. 2015; 6:40496-40506. https://doi.org/10.18632/oncotarget.5800

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Reinaldo Franqui-Machin1,*, Erik B. Wendlandt2,*, Siegfried Janz3, Fenghuang Zhan1,2 and Guido Tricot2

1 Interdisciplinary Graduate Program in Molecular and Cellular Biology, The University of Iowa Carver College of Medicine, Iowa City, Iowa, USA

2 Department of Internal Medicine, The University of Iowa Carver College of Medicine, Iowa City, Iowa, USA

3 Department of Pathology, The University of Iowa Carver College of Medicine, Iowa City, Iowa, USA

* These authors have contributed equally to this work

Correspondence to:

Guido Tricot, email:

Fenghuang Zhan, email:

Keywords: drug resistance, neoplasia, myeloma and other plasma cell dyscrasias, signaling therapies

Received: June 30, 2015 Accepted: September 12, 2015 Published: September 22, 2015


Multiple myeloma (MM) remains a largely incurable, genetically heterogeneous plasma-cell malignancy that contains – just like many other cancers – a small fraction of clonogenic stem cell-like cells that exhibit pronounced self-renewal and differentiation capacities, but also pronounced drug resistance. These MM stem cells (MMSCs) are a controversial but highly significant issue in myeloma research because, in our opinion, they are at the root of the failure of anti-neoplastic chemotherapies to transform myeloma to a manageable chronic disease. Several markers including CD138, ALDH1+ and SP have been used to identify MMSCs; however, no single marker is reliable for the isolation of MMSC. Nonetheless, it is now known that MMSCs depend on self-renewal and pro-survival pathways, such as AKT, Wnt/β-catenin, Notch and Hedgehog, which can be targeted with novel drugs that have shown promise in pre-clinical and clinical trials. Here, we review the pathways of myeloma “stemness”, the interactions with the bone marrow microenvironment that promote drug resistance, and the obstacles that must be overcome to eradicate MMSCs and make myeloma a curable disease.

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