News release

From: South Australian Health and Medical Research Institute (SAHMRI)

New research has uncovered why one of the most widely used treatments for multiple myeloma can cause debilitating nerve and gastrointestinal side effects, marking a significant step towards preventing them.

A unique collaboration between four research groups based at the South Australian Health and Medical Research Institute (SAHMRI) – the Myeloma Research Laboratory, Supportive Oncology Research Group, Visceral Pain Research Group and Systems Immunology Group – has investigated how the gut microbiome influences the side effects of bortezomib, a cornerstone treatment for the disease.

While bortezomib is a highly effective therapy for multiple myeloma, it’s known to cause painful nerve damage, known as peripheral neuropathy, and gastrointestinal issues that reduce quality of life.

This can profoundly disrupt daily living and make it very difficult for people to stay on therapy. Despite their debilitating impact on patients, the biological mechanisms driving these side effects have remained poorly understood, meaning there are no effective solutions.

Funded by The Hospital Research Foundation Group and recently published in the Journal of Neuroinflammation, the study aimed to fill this knowledge gap, with researchers developing a preclinical model to comprehensively investigate both the neurological and gastrointestinal effects of bortezomib.

Using a combination of highly specialised tools to map neural and gut function and dysfunction, the team identified that the treatment triggers changes in nerve-immune signalling linked to both peripheral neuropathy and gastrointestinal complications.

Lead researchers, Dr Jacqui Scott and Associate Professor Hannah Wardill say the development of these tools is a major achievement that’s advanced our understanding of what causes these side effects.

“We have known for a long time that bortezomib damages nerves, but this understanding has been almost exclusively focused on peripheral nerves, like those in the hands and feet,” Dr Scott said.

“Using this model, we were able to show that similar mechanisms occur in the gut, providing the first evidence to help us explain why bortezomib causes debilitating gut problems.”

A/Prof Hannah Wardill says the team took this work a step further to understand how the gut microbiome influences these processes.

“The gut microbiome is a key player in how someone responds to cancer therapy. We were able to extend these findings in special mice without a microbiome and found that the side effects of bortezomib almost entirely disappeared,” A/Prof Wardill said

“What makes our findings unique is that when we restore the microbiome, the side effects do not return. We’re now trying to identify why that is and whether we can translate this to patients,” Dr Scott said.

Senior author, Dr Krzysztof Mrozik, Hospital Research Foundation Myeloma Fellow at Adelaide University and SAHMRI says the collaborative approach enabled the team to explore the problem from multiple perspectives and answer questions that no group could’ve answered alone.

"By bringing together expertise from supportive oncology, pain research, microbiome science, immunology and myeloma research, we've been able to gain a completely new perspective on how these side effects develop and have identified new opportunities that could reduce their impact on patients,” Dr Mrozik said.

"Ultimately we want to find ways to help patients stay on highly effective treatments for longer. The results of this study provide a foundation for future research into microbiome-based strategies that may prove key to achieving this goal.”

“We are so appreciative of the Hospital Research Foundation Group for funding this work, and to our collaborators, who were instrumental in helping us achieve this outcome. These experiments are extremely laborious to conduct and require specialist skills. I’d like to thank Dr Miriam Lynn from the Systems Immunology Group for her important role in helping us take such an important step forward in myeloma care.”