The impact of intra‐clonal heterogeneity on the treatment of multiple myeloma

• Published in: British journal of haematology Vol. 165; no. 4; pp. 441 - 454
• Main Authors: Brioli, Annamaria, Melchor, Lorenzo, Cavo, Michele, Morgan, Gareth J.
• Format: Journal Article
• Language: English
• Published: Oxford Blackwell 01-05-2014
• Subjects: Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Cell Lineage; clonal heterogeneity; Clone Cells - drug effects; Clone Cells - pathology; Consolidation Chemotherapy; Disease Management; Disease Progression; Disease-Free Survival; DNA, Neoplasm - genetics; Drug Resistance, Neoplasm - genetics; Evolution, Molecular; genetics; Hematologic and hematopoietic diseases; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Maintenance Chemotherapy; Medical sciences; Models, Biological; multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - genetics; Multiple Myeloma - pathology; Mutation; Neoplasm Metastasis; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - pathology; Plasmacytoma - drug therapy; Plasmacytoma - pathology; Remission Induction; Selection, Genetic; sequential treatment; therapy; Treatment Outcome; Tumors; sequential treatment; Immunopathology; multiple myeloma; Hematology; clonal heterogeneity; therapy; Malignant hemopathy; Myeloma; Heterogeneity; Cancerology; Treatment; Immunoglobulinopathy; Sequential; Lymphoproliferative syndrome; Genetics; Cancer; genetics
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/bjh.12805

Summary
It is clear that cancers comprise a mixture of clones, a feature termed intra‐clonal heterogeneity, that compete for spatial and nutritional resources in a fashion that leads to disease progression and therapy resistance. This process of competition resembles the schema proposed by Darwin to explain the origin of the species, and applying these evolutionary biology concepts to cancer has the potential to improve our treatment strategies. Multiple myeloma (MM) has a unique set of characteristics that makes it a perfect model in which to study the presence of intra‐clonal heterogeneity and its impact on therapy. Novel therapies have improved the outcome of MM patients, increasing both progression‐free and overall survival. Current therapy comprises an induction, consolidation and maintenance phases and it is important to consider how these components of MM therapy are affected by the presence of intra‐clonal heterogeneity. In this evolutionary context therapy can be considered as a selective pressure differentially acting on the myeloma clones and impacting on their chances of survival. In this review current knowledge of intra‐clonal heterogeneity, as well as its impact on the different components of MM treatment is discussed.