Old drugs, new tricks: Thalidomide’s journey back from the wilderness

Thalidomide was one of the biggest disasters in the modern age of drug discovery. But research into the controversial drug is now leading to new medical applications, including as a way of managing a type of cancer called myeloma. We highlight one example this week.

But then, it’s easy to forget that when thalidomide was first sold in the 1950s, it was seen as something of a wonder drug. It was used as a sedative and a tranquiliser, it was safe enough to be given to children, and soon pregnant women were taking it to prevent morning sickness. It was only then that it became clear that the drug had major side-effects in pregnant women, resulting in thousands of babies born with severe birth-defects.

The drug was withdrawn early in the 1960s and new regulations were introduced that led to tougher testing and drug approval procedures around the world.

For years it seemed that thalidomide would be consigned to history’s dustbin - a cautionary tale for drug manufacturers - but now thalidomide is offering hope to patients with cancer.

Multiple myeloma is a cancer that affects blood plasma cells, causing them to grow uncontrollably in the bone marrow and become stuck there, disrupting normal blood cell production. While there have been improvements in myeloma care over the years, the disease remains difficult to treat. Standard myeloma treatments have failed to greatly extend patients’ survival time and many relapse after treatment, eventually succumbing to their illness. Thalidomide could help these patients to manage their disease.

Thalidomide’s potential as an innovative treatment was first investigated for a painful skin condition linked to leprosy, called erythema nodosum leprosum. Despite the drug still being banned, scientists found that thalidomide could effectively treat the condition by inhibiting a chemical messenger that regulates the inflammatory process, called tumour necrosis factor alpha (TNF-α).

This success encouraged further interest in the drug and soon researchers were testing its potential for other conditions. Scientists found that people with HIV/AIDS had elevated levels of TNF-α and they saw that thalidomide alleviated complications from their disease such as HIV wasting syndrome and nausea. When they found that thalidomide could also starve cancer cells, it was tested for use in treating myeloma.

While doctors didn’t know exactly how the drug worked, they found that thalidomide could stop tumours from growing their own blood vessels, making it effective as both the first line of attack in myeloma and as maintenance therapy to prevent or delay relapse after other treatments have been used.

Thalidomide is now an established myeloma treatment and many studies have demonstrated the drug’s benefit to patients, including the Myeloma IX Trial, run in part by Professor Gareth Morgan, Professor of Haematology at The Institute of Cancer Research, London, and Head of the Myeloma Unit at The Royal Marsden NHS Foundation Trust.

Follow-up research from the Myeloma IX Trial is identifying the long-term effects of thalidomide on myeloma patients, but a study carried out by the ICR has helped researchers understand better which patients benefit from the drug. When patients were given thalidomide as part of first-line induction therapy, the researchers saw that the drug improved their overall response to treatment compared with standard induction therapy, but they found that thalidomide seemed to benefit some patients more than others.

Other trials had seen similar results, suggesting that a cancer’s genetic make-up plays a part in determining how they will respond to thalidomide.

More research needs to be carried out to clarify which patients will benefit most from thalidomide treatments, but it shows the importance of studying the long-term effects of treatments and better understanding the different needs of patients.

Research by ICR scientists and many others has been vital for finding opportunities where old treatments could be effective in new types of cancers. Thalidomide’s history shows that a drug can be written off as useless, dangerous, or both, but continued research can help it find success years later.

It’s because of this dogged persistence that thalidomide has made the remarkable transition from nightmare drug to promising treatment for illnesses like HIV, leprosy and myeloma.