Understanding the Molecular Biology of Myeloma and Its Therapeutic Implications

Kevin D Boyd; Charlotte Pawlyn; Gareth J Morgan; Faith E Davies


Expert Rev Hematol. 2012;5(6):603-617. 

In This Article


Myeloma therapy is currently based on empirical studies that largely predate the molecular classification of the disease. There was, therefore, little biological basis for myeloma therapy. The genetic landscape of myeloma is now better understood, and primary events such as IGH@ translocations can be used as disease classifiers that have clinical significance. In this way, biological disease groups have been described and have been shown to have distinct clinical behavior. The first way that this can be achieved is to incorporate a risk-adapted therapy into the myeloma clinic. There is recognition that certain groups identified by chromosomal abnormalities are associated with a poor clinical outcome, and it is relatively easy to identify these groups with a combination of biochemical and genetic markers. Properly structured clinical trials are the only way to guide improvements in therapy for the high-risk patient group, and robust prognostic data exist in order to implement this strategy now. Ideally, all clinical trials should now have genetic analysis performed on tumor samples, with a predetermined plan for subgroup analyses of high-risk groups. Alternatively, there could be a move away from large, Phase III trials towards smaller trials of defined biological groups such as high-risk patients.

Moving beyond risk-adapted therapy is targeted therapy, with treatment that is tailored to the individual. With the cost of whole genome and exome sequencing rapidly falling, the future of myeloma therapy will involve genotyping of individual patient tumors, and designing therapy based on the results. Therapy will become bespoke, targeting the multiple deregulated pathways of a specific tumor. While this approach is in its infancy, we have given examples of drugs that are in development that may benefit specific patient groups defined by genetic biomarkers. The future of myeloma therapy is likely to evolve in this way with therapy not only having a biological basis for the disease, but a biological basis for the affected individual.