Global Expert Perspectives: Relapsed/Refractory Multiple Myeloma - Episode 1

Pathogenesis of Multiple Myeloma

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There has long been evidence based on clinical observations that there are multiple clones involved in multiple myeloma and that the disease changes from diagnosis to the time of progression, explains Andrew Spencer, MD. Through the use of next-generation sequencing, it is evident that multiple myeloma is highly complex and may have multiple subclones. As a result of these subclones activating different pathways, it is unlikely for a single therapy to cover all of the abnormalities in one patient, leading to the success of combination regimens, Spencer suggests.

At this current time, the understanding of epigenetic changes in multiple myeloma is relatively shallow, states Spencer. In the transition from monoclonal gammopathy of undetermined significance to multiple myeloma there is a pronounced degree of hypomethylation. However, with disease progression, there is hypermethylation of certain genes, which provides an opportunity for the use of hypomethylating agents, explains Spencer.

Epigenetic modifications are relevant in multiple myeloma, and deacetylase is a key element in the survival of the myeloma cells and tumor escape, states Maria-Victoria Mateos, MD, PhD. If deacetylase is overexpressed in patients with myeloma, histone deacetylase (HDAC) inhibitors may be used to try to block this activity. HDAC inhibitors may work to control the proliferation of the disease and induce apoptosis, adds Mateos. This concept was shown effective, with the FDA approval of the HDAC inhibitor panobinostat in February 2015.

Plasma cells are also important in the pathogenesis of multiple myeloma. It is important to consider the interaction that the plasma cells have with the bone marrow microenvironment and the bone marrow stroma cells. This complexity makes it difficult to use just one targeted therapy, and has resulted in the use combination therapies to attack different pathways involved in the disease, Mateos notes.