Only a small subset of patients with newly diagnosed multiple myeloma (MM) have activating mutations in the BRAF oncogene, part of the RAS/MAPK signaling pathway.1 This percentage is as high as 8% in patients with refractory disease, and such patients are at higher risk of poor outcomes. A phase II trial of relapsed patients whose disease had such mutations showed that treatment with a BRAF inhibitor combined with an MEK inhibitor yielded high rates of response. Study results were published in Blood.2
Marc S. Raab, MD, PhD, of the University of Heidelberg in Germany and one of the study’s lead authors, explained the researchers decided to study BRAF inhibition in combination with MEK inhibition because randomized studies in patients with BRAF-mutant melanoma have shown the combination is both more effective and better tolerated than BRAF inhibitors alone.
The 12 patients in the prospective, open-label, multicenter trial received 450 mg of the BRAF inhibitor encorafenib once daily and 45 mg of the MEK inhibitor binimetinib twice daily. All patients had evidence for an activating BRAFV600E mutation and had previously received at least two lines of therapy (median = 5), including an immunomodulatory drug and a proteasome inhibitor.
The safety of the regimen was consistent with what has previously been reported from other disease applications. The most common organ-related adverse events (AEs) were eye disorders, occurring in 15.3% of patients. Blurred vision, a known side effect of MEK inhibitors, was common, Dr. Raab said, but all cases resolved or were successfully managed with dose reduction.
“Overall, [AEs] appeared to be generally milder than what has been reported in melanoma,” he added.
The study met its primary efficacy endpoint with an overall response rate of 83.3%, making it the first prospective clinical trial to demonstrate the benefits of the combination therapy in patients with relapsed or refractory MM with BRAFV600E mutations. A very good partial response or better was observed in 75% of patients. Patients responded for a median duration of 4.8 months, and the median progression-free survival was 5.6 months. Median overall survival had not yet been reached.
Dr. Raab noted, “This response rate is exceptional and even on par with novel immunotherapies like CAR-T [chimeric antigen receptor T-cell] or bispecific antibodies.”
However, he added, those therapies lead to more durable responses, whereas only about a third of the patients in his study had a duration of response greater than one year.
The small patient size is an important limitation of the current study, although it somewhat reflects the relative rareness of the BRAF mutation in this population. Larger studies will be needed to compare survival rates of BRAF inhibitors used as a single agent compared to their use paired with MEK inhibition.
Although targeting BRAF mutations is unlikely to become a first-line strategy, Dr. Raab said, it can be an important option for personalized therapy approaches in refractory disease.
“BRAF testing should be considered in all [patients with refractory MM], so you have the information available if you need it,” Dr. Raab said. “You can achieve rapid and even deep responses in patients with very limited options. Ideally, you still have another highly effective treatment option available, like CAR-T, which works best after inducing a remission by BRAF/MEK inhibition.”
Any conflicts of interest declared by the authors can be found in the original article.
- Walker BA, Boyle EM, Wardell CP, et al. Mutational spectrum, copy number changes, and outcome: results of a sequencing study of patients with newly diagnosed myeloma. Jour Clin Onc. 2015;33(33):3911-3920.
- Giesen N, Chatterjee M, Scheid C, et al. A phase II clinical trial of combined BRAF/MEK inhibition for BRAFV600E-mutated multiple myeloma [published online ahead of print, 2023 Jan 6]. Blood. doi: 10.1182/blood.2022017789.