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Pushing the boundaries of drug discovery for myeloma patients

Consultant Haematologist Dr Rakesh Popat reviews 30 years’ progress in treating myeloma and sees a promising future

We have made huge progress in finding and delivering treatments for multiple myeloma – a blood cancer generated by faulty plasma cells in bone marrow – and a disease with a very poor prognosis has become a manageable, chronic condition.

It is still incurable, but the average patient can now expect survival of around ten years compared to three years thanks to effective treatments. Our continuing challenge is to find better therapies for a condition which, although classed as a rare cancer, affects around 17,500 people in the UK.

Myeloma is a relapsing and remitting condition that causes renal failure, anaemia, fatigue, hypercalcaemia and destructive bone lesions. It is different for each patient, making diagnosis difficult, and therapy regimes need to be tuned to keeping the disease at bay and providing good quality of life for patients.

Treatment has evolved from a single chemotherapy drug with poor outcomes and high toxicity through the use of the drug thalidomide around 15 years ago, which was the first of a new class of immunomodulatory drugs (IMiDs). We now have two more in that class and proteasome inhibitors, which came along more than ten years ago, help us better manage patients and improve survival.

These drugs are well tolerated and many patients enjoy a good quality of life, rarely being admitted to hospital. More than 60 percent of younger patients have a ten-year survival profile, but older patients can be more frail at diagnosis and we need to understand how best to treat them.

The medical and scientific community has made significant advances in decoding myeloma and laboratory tests have allowed us to identify the genetic markers in the myeloma cells so we can choose the appropriate treatment in each case. We expect to derive even further understanding from gene-expression profiling and next-generation sequencing platforms.

But, unlike with many solid tumours, we have been unable to find a specific driver or mutation which we can then hit. For instance, in lung cancer you can identify a mutation and use an inhibitor which works very effectively, but this simply doesn’t exist in myeloma.

It is a complex condition, but there is much hope in a series of clinical trials being undertaken globally and at University College Hospital, London. It has been discovered that the drug Venetoclax, which is funded and licensed for chronic lymphocytic leukaemia, is effective on a sub-group of myeloma patients and we are currently engaged in a clinical trial on its use.

We also have two brand-new IMiDs designed to improve on current therapies, which are looking promising in phase-1 trials and we would hope they could come through for patients next year.

The big challenge we face is that myeloma causes profound immune deregulation, which confers resistance on these myeloma cells. They are able to mutate and modify and, despite using established drugs, resistant clones keep appearing. So we are coming to the view that the only way to achieve long-term control is to invoke the body’s own immune system because it is the only element that has the ability to adapt and change to cure the cancer.

There is promise for myeloma patients, but this is a complex condition and our efforts must not, and will not, relax

At a recent conference, someone framed the difficulty succinctly by stating that plasma cells are designed to stay in your body for 80 years producing antibodies, so it is not surprising it is difficult to kill them. Other cancer cells have a quicker turnover and die, but there are a multitude of ways myeloma manages to survive from genetic abnormalities to interactions within the bone marrow micro-environment.

Huge promise is coming from the rapidly emerging approach of engineering a patient’s immune cells to attack the cancer, known as CAR T-cell therapy. It has worked well in leukaemia and lymphoma, but the story doesn’t seem to be as exciting in myeloma as with other cancers, which is disappointing. But there is a lot to learn and over the next five years we will be using a combination of CAR T-cells and drugs we know to leverage long-lasting impacts.

Worryingly, the incidence of myeloma is climbing. It has doubled to 2 percent of all cancers recently and, although better diagnosis is a factor, we are not completely sure why. This makes our research and quest for better therapies, and ultimately a cure, all the more critical.

We know the causes of myeloma are a combination of genetic and environmental influences. Population research shows a clustering of myeloma in families, while an interesting piece of data has emerged recently that the firefighters who attended the 9/11 World Trade Center disaster in New York have a higher risk of developing the pre-cancerous condition known as MGUS, which shows there is an environmental element.

In the near future, our aim is to continue to develop immunotherapies to see the next step change in survival for our patients who can look forward to new agents coming from clinical trials over the next few years.

Our aim is to provide a good quality of life with well-tolerated drugs, so people can continue working or, if they are retired, have the freedom to travel and not be stuck in hospital.

Myeloma is classified as a rare cancer and, consequently, does not get the profile of some more emotive cancers. But, even though incidence is low, survival has improved, so the number of people living with myeloma on treatment is equally as high as the more common cancers.

Patients are still primarily diagnosed when they attend A&E units and it can take months for a patient to see a haematologist. Therefore, we need to energise education as well as having more investment into research so the UK can lead the way to bring new treatments to patients.

There is promise for myeloma patients, but this is a complex condition and our efforts must not, and will not, relax.

Dr Popat is a Consultant Haematologist at University College Hospital, London and HCA Healthcare UK. He is Honorary Clinical Senior Lecturer at the UCL Cancer Institute, a member of the National Cancer Research Institute myeloma sub-group and North Thames Clinical Research Network Speciality Lead for haematology in the cancer division.

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