A combination of five existing drugs keeps cancer at bay for longer in patients with a highly aggressive type of bone marrow cancer, a major new trial reveals.

The five-drug cocktail, along with a stem cell transplant, allowed people with ultra-high risk multiple myeloma to live longer before their disease progressed than those who received the standard of care.    

The ‘MUK Nine OPTIMUM’ trial used a highly innovative methodology to open the door to the first tailored approach for people with the highest risk forms of myeloma – whose outcomes from treatment are currently poor.

It is also the latest study to demonstrate the benefit of combining drugs with different mechanisms of action to combat cancer’s ability to evolve and become resistant to treatment.

Five drugs individually licensed

A team at The Institute of Cancer Research, London, and the Clinical Trials Research Unit at the University of Leeds adopted a new high-speed trial methodology – testing the five-drug combination against the findings of an earlier study, rather than against a control group, to obtain the results faster for the eventual benefit for patients.

Their findings were presented at the American Society of Hematology (ASH) Annual Meeting on Sunday.

All five drugs in the combination – bortezomib, lenalidomide, daratumumab, dexamethasone and cyclophosphamide chemotherapy – are individually licensed and in clinical use. That means the combination has the potential to receive streamlined approval and become available to patients relatively quickly.               

Certain genetic changes can make multiple myeloma – a type of bone marrow cancer – more aggressive, less responsive to treatment and likely to relapse more quickly. So-called ultra-high-risk patients have particularly unfavourable genetic signatures and previous studies have suggested they are at very high risk of their disease relapsing within the first two years from diagnosis. In contrast, the majority of other patients now stay in remission for five years or longer.

Tailored treatment approaches urgently needed

Currently, there is no tailored treatment approach for these high-risk patients, and their outcomes remain poor.

The OPTIMUM trial involved 107 patients with ultra-high-risk myeloma recruited between 2017 and 2019. The results presented today compare survival outcomes from OPTIMUM patients, who received the new five-drug combination, with survival outcomes from patients in the Myeloma XI (MyXI) trial, who received carfilzomib, lenalidomide, cyclophosphamide and dexamethasone.

Patients from the OPTIMUM trial were more likely than MyXI patients to live for longer, during and after treatment, before seeing their disease progress and symptoms worsen. At 18 months, 82% of OPTIMUM patients had stable disease unlikely to progress in the immediate future, compared with 67% of MyXI patients.

The new findings represent a significant advance for patients with high-risk myeloma and highlight the need to tailor therapy to the genetic make-up of each patient’s cancer, which is currently not done routinely.         

The study is an independent academic trial, but received funding from the pharmaceutical companies that manufacture the drugs tested, Janssen and Bristol Myers Squibb, as well as support from the David Forbes-Nixon Foundation via Myeloma UK and from the NIHR Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the ICR.

A new trial framework to fast-track evidence

OPTIMUM is the first ‘digital comparator’ trial for multiple myeloma. Digital comparator trials do not use a traditional control arm, and instead model comparators using data collected from other sources – in this case, another trial known as MyXI.

This digital comparator trial provides a new framework to fast-track comparative evidence, helping scientists obtain answers faster for patients with high unmet clinical need.

OPTIMUM is therefore a successful proof of principle study, supporting the use of digital comparator arm trials for clinical development. Researchers now hope regulatory and health technology assessment bodies such as MHRA and NICE will consider and review the data so that this new framework can be used more widely.

'A new and better treatment option'

Study leader Dr. Martin Kaiser, Team Leader in Myeloma Molecular Therapy at The Institute of Cancer Research, London, and Consultant Haematologist at The Royal Marsden NHS Foundation Trust, said:

“We know that patients with multiple myeloma who have ‘ultra-high risk’ genetic signatures have particularly aggressive cancers that fail to respond to standard treatment. In this study, we have identified a new five-drug combination that can keep myeloma at bay for longer in these patients. Our study shows the benefit of genetic testing in patients with myeloma to identify those at highest risk, since we now have a new and better treatment option for these people.

“All these drugs are already individually licensed and available so we know they are safe, and that means the new combination could potentially be made available for patients quickly. I hope the NHS will consider our data as soon as possible.”

Getting new therapies to the clinic faster

Professor Kristian Helin, Chief Executive of The Institute of Cancer Research, London, said:

“Until now, patients with the highest risk forms of multiple myeloma have had no tailored treatment options, even though we know that they are likely to relapse on existing therapies. This study represents an important step forward, moving to more effective treatment of these patients.”

“This exciting trial is also a first of its kind – using sophisticated statistical analysis to compare results with those from an earlier study rather than a control group. The new trial methodology has great potential to get much-needed new therapies to the clinic faster and it also lowers trial costs.”

Dr. Sarah Brown, Director of Early Phase Clinical Trials at the Clinical Trials Research Unit, University of Leeds, said:

“We are really excited to see the positive results of this trial, and to be able to demonstrate how application of novel statistical methods can result in efficient trial design, conduct and dissemination. The study and the methodology used really has the potential to impact research widely.”