A five-drug combination therapy using existing drugs, combined with a stem cell transplant, has proven effective at extending the life of patients with an ultra-high risk form of multiple myeloma than those who received standard of care.

The new research from investigators at the Institute of Cancer Research, London, and the Clinical Trials Research Unit at the University of Leeds was presented at the American Society of Hematology (ASH) Annual Meeting Sunday.

Part of the ‘MUK Nine OPTIMUM’ trial, the researchers used a highly innovative methodology to open the door to the first tailored approach for people with the highest risk forms of the bone marrow cancer myeloma – whose outcomes from treatment are currently poor. The team said it adopted a 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.

“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, said leader of the study Martin Kaiser, team leader in myeloma molecular therapy at The Institute of Cancer Research, London, and consultant hematologist at The Royal Marsden NHS Foundation.

“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.”

The five drugs in the combination: bortezomib, lenalidomide, daratumumab, dexamethasone, and cyclophosphamide chemotherapy are all individually licensed and in clinical use. The investigators hope this will allow the five-drug combination to receive streamlined approval for use in the U.K. and become available to patients relatively quickly.

“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,” Kaiser added. “I hope the NHS will consider our data as soon as possible.”

When possessing specific genetic changes, multiple myeloma, a form of bone cancer, has been shown to be more aggressive, make patients less likely to respond to treatments, and more susceptible to relapse. Patients with ultra-high risk molecular markers are more likely to relapse within the first two years after diagnosis, suggest two previous studies. Patients not in the ultra-high risk group typically stay in remission for five years of longer.

There are no current treatments tailored for the ultra-high risk groups and their prognosis is poor.

The OPTIMUM trial enrolled 107 patients with ultra-high-risk myeloma between 2017 and 2019. The results presented at ASH 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. It showed that patients from the OPTIMUM trials were more likely than the MyXI patients to live longer, both during and after treatment before disease progression.

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.

“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,” noted Sarah Brown, director of early phase clinical trials at the Clinical Trials Research Unit, University of Leeds. “The study and the methodology used really has the potential to impact research widely.”