Genomics, functional consequences, and potential therapeutic vulnerabilities of chromosome 13 deletion in multiple myeloma

Multiple myeloma is the second most common form of blood cancer and is a cancer of plasma cells, a type of white blood cell, which normally help to fight infections through the production of antibodies. Patients with multiple myeloma develop complications including low blood counts (anaemia), kidney damage, and bone damage including fractures which can cause significant symptoms.

Multiple myeloma progresses from asymptomatic precursor conditions, but most patients are diagnosed at the active, symptomatic stage. There are treatments for multiple myeloma, but it remains almost always incurable, and most patients will die because of their myeloma.

In multiple myeloma there are changes in the genes of the cancerous cells which can give rise to different behaviours and outcomes with treatment. These genetic changes can include gains or losses of whole or parts of chromosomes (copy number abnormalities), movement of genes between chromosomes (translocations), and changes in the sequence of genes (mutations). We know that some of these genetic changes are linked with worse outcomes despite treatment (termed high-risk genetics).

Chromosome 13 is often lost in multiple myeloma and is one of the most common genetic changes, seen in about half of patients at diagnosis. The presence of chromosome 13 loss is associated with progression from the asymptomatic precursor conditions into symptomatic disease. Whether chromosome 13 loss itself is linked with worse outcomes in multiple myeloma is not entirely clear but it is seen more commonly with other high-risk genetic features and due to this, overall patients who have this abnormality have inferior outcomes despite current treatments.

However, the impact of these changes on the myeloma cells remains largely unknown and we need a better understanding as it could make an ideal candidate for targeted treatments. This project has two linked aims: 1. To characterise the effect of chromosome 13 loss in myeloma genetically

I will perform gene sequencing in samples from patients with newly diagnosed multiple myeloma enrolled into a clinical trial, including those with and without loss of chromosome 13 to assess the impact of this abnormality on other chromosomes and genes as well as on RNA (the intermediate step between DNA and proteins within the cell). With this information, I aim to improve understanding of:

1.What happens to other genes and why this might happen 2.Why some genetic events are seen more commonly with one another 3.How chromosome 13 loss may impact on proteins (which are the drivers of behaviour) in myeloma cells 2. To characterise the effect of chromosome 13 loss in myeloma functionally

In myeloma cells which grow in the laboratory (myeloma cell lines), which have the normal two copies of the chromosome, I will use a recently described gene editing technique to create cells which have lost one of these copies mimicking what we see in some patient samples with myeloma. This will enable these cells to be grown and compared with those cells with the normal two copies in functional experiments.

The advantage of this approach is that this will be the only significant difference between these cells and therefore the specific effects of this abnormality can be studied. These functional studies will aim to understand the impact on: 1.How these cells grow 2.How these cells respond to current myeloma treatments

3.How this change specifically impacts proteins in myeloma cells 4.Whether any of these changes can be targeted with new treatments

The overall aim therefore is to improve the outcomes of patients with multiple myeloma who have loss of chromosome 13 through improving understanding of this genetic event on their cancer and how we may be able to treat this in a targeted manner.