Treatment with melflufen in combination with dexamethasone demonstrated clinical efficacy and a manageable safety profile among patients with recurrent/refractory multiple myeloma (RRMM) who had already exhausted multiple lines of therapy, according to results from the phase 2 HORIZON trial presented at the Virtual Edition of the 25th European Hematology Association (EHA) Annual Congress.1

Based on these results, Oncopeptides AB has submitted its New Drug Application (NDA) to the FDA for accelerated approval of this new therapy for the treatment of adult patients with Triple-class–refractory multiple myeloma. Triple-class–refractory patients have already been treated with the 3 major classes of myeloma drugs: a proteasome inhibitor, an immunomodulatory drug, and a CD38 inhibitor.

“This is a population with a high unmet need, since there is no approved treatment in patients who have failed these 3 drug classes,” said Klaas Bakker, MD, PhD, chief medical officer of Oncopeptides. “The HORIZON population represents 1 of the largest sets of patients with this Triple-class–refractory disease, and with melflufen in this population we show a 26.1% overall response rate.”

The single-arm HORIZON trial enrolled 157 patients with a median of 5 prior lines of therapy. Seventy-six percent of participants were triple-class–refractory, and 59% were refractory to a previous alkylator. Thirty-eight percent of patients had high-risk cytogenetics and 35% had extramedullary disease. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression-free survival (PFS), overall survival, duration of response, and safety.


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“One of the important things is that they had 93 patients that had previous anti-CD38 antibody treatment,” said Nina Shah, MD, a hematologist-oncologist specializing in myeloma at the UCSF Helen Diller Family Comprehensive Cancer Center. “That category of patients is very difficult to treat.”

The ORR among all participants was 29%, and triple-refractory patients showed an ORR of 26%. The median duration of response among all patients was 5.5 months, and 4.4 months among triple-refractory patients.

“The median duration of 4.4 months is decent in this heavily pretreated patient population and in line with other new agents,” said Dr Bakker.  Closer scrutiny of individual patient data suggests the results may be even more promising than they first appear, he explained. The duration of response only counts the time after the cancer shows a partial response or better, but many patients had several months of stable disease before achieving partial response. 

“The responses deepen over time,” Dr Bakker said. “When we analyzed the PFS in responders, we ended up at 8.5 months of median progression-free survival, and that’s a significant number.”

Melflufen (melphalan flufenamide) is a peptide-drug conjugate that delivers an alkylating payload into tumor cells. Melphalan, the alkylating agent, has been used to treat myeloma for decades. It kills cancer cells by inhibiting DNA synthesis, but it is nonspecific, and can cause debilitating side effects.

“This is an important study because this is a new class of drug,” said Dr Shah. “It’s always a good thing to have a different class.”