Melflufen Shows Positive Response in Triple-refractory Multiple Myeloma Trial

Topline results show a 26% response rate in a Phase 2 clinical trial evaluating melflufen (melphalan flufenamide) in patients with triple-refractory multiple myeloma, a difficult-to-treat form of this disease, the therapy’s developer, Oncopeptides, announced.

These data will support a request for accelerated approval for melflufen to treat people with triple-refractory multiple myeloma in the U.S., the company said in a press release. The application is expected to be filed by midyear.

Melflufen belongs to a class of agents called peptidase-enhanced compounds, which work through a new mechanism of action. Once inside a cell, melflufen rapidly releases a toxic agent — an alkylating peptide — only when in contact with aminopeptidases, specific enzymes that are produced in excessive amounts by malignant cells, including those in multiple myeloma.

In this way, melflufen is designed preferentially targets and kills cancer cells containing large amounts of these enzymes, while leaving healthy cells unharmed.

The therapy, administered intravenously (into the vein), is intended for patients with triple-refractory multiple myeloma who failed to respond to treatment with at least one immunomodulatory drug (IMiD), one proteasome inhibitor, and one anti-CD38 monoclonal antibody.

The open-label Phase 2 HORIZON trial (NCT02963493) evaluated the safety and effectiveness of melflufen in combination with dexamethasone in 157 multiple myeloma patients, including 119 with triple-refractory disease. They had been given at least two prior therapies (including an IMiD and a proteasome inhibitor), and failed to respond to treatment with Darzalex (daratumumab) and/or Pomalyst (pomalidomide, also sold as Imnovid in Europe by Celgene).

All  were given melflufen intravenously at a dose of 40 mg on the first day, and 40 mg of dexamethasone on days eight, 15, and 22 in 28-day cycles, until disease progression or unacceptable toxicity.

The trial’s primary goal was to assess the treatment’s overall response rate — the percentage of patients responding to treatment. Secondary goals included overall survival, progression-free survival (the period without disease progression), and duration of response.

An interim analysis in 113 patients with measurable treatment response showed that the combination therapy was safe and led to at least disease stabilization in most patients (86%), and to a more than 50% reduction in tumor burden in nearly one-third.

Now, final data collected through Jan. 14 showed an improvement in patients’ overall response rate compared to the previously reported interim data.

Overall, 29% of patients achieved either a partial or complete reduction in tumor burden after receiving melflufen.

Response rates were similar for patients with triple-refractory disease (26%), and for those with extramedullary disease (24%) — an aggressive form of multiple myeloma in which myeloma cells form tumors outside the bone marrow, behaving like a metastatic cancer with very poor prognosis.

Similar findings were reported by an independent review committee.

People with triple class relapsed-refractory multiple myeloma and extramedullary disease represent the largest group of myeloma patients with unmet medical needs today, the company reported in an in-house trial presentation.

The therapy’s safety profile was consistent with that shown in previous reports from the HORIZON study, with adverse events being mostly related to blood disorders (hematological).

“The presentation of final data from our pivotal HORIZON study, with competitive results in triple-class refractory myeloma patients, represents the most important milestone for Oncopeptides to date,” Jakob Lindberg, Oncopeptides’ CEO, said in the release.

“These data confirm that melflufen has a good efficacy and safety profile in triple-class refractory myeloma patients — a fast-growing patient population with significant unmet medical need and lack of approved treatments,” he added. “We firmly believe that melflufen has the potential to become an important treatment option for patients with relapsed refractory multiple myeloma.” 

Topline results from a Phase 3 study (NCT03151811), called OCEAN, in pre-treated relapsed-refractory myeloma patients is due by September.

Oncopeptides also plans to launch an early access program in the U.S. as soon as possible for relapsed-refractory multiple myeloma patients.

Full results from the HORIZON trial will be disclosed in a future peer-reviewed publication.

Oncopeptides also noted in its presentation that clinical trials of its investigative therapies outside of HORIZON and OCEAN are paused due to the ongoing COVID-19 outbreak.