First Patient Dosed in Phase 3 Trial Testing Melflufen Triple Combo

The first participant has been dosed in a Phase 3 trial investigating a triple combination of melflufen (melphalan flufenamide) plus dexamethasone and under-the-skin Darzalex (daratumumab) in people with heavily treated multiple myeloma.

The trial, dubbed LIGHTHOUSE (NCT04649060), had been delayed by the COVID-19 pandemic but is now recruiting an estimated 240 participants, ages 18 and older, at two locations in the Czech Republic.

“There is an imminent need for additional therapeutic options as myeloma patients become multi-resistant earlier in their treatment journey,” Klaas Bakker, MD, PhD, chief medical officer of Oncopeptides, the maker of melflufen, said in a press release.

“A positive outcome may potentially support the use of melflufen as combination therapy with daratumumab in earlier stages of multiple myeloma,” Bakker said.

Melflufen is a peptide-drug conjugate designed to kill cancer cells by exploiting their surplus of enzymes, which are called aminopeptidases. The experimental treatment’s key component is a cancer-killing agent called an alkylating peptide, which is easily absorbed into cells, where aminopeptidases break it down and activate its toxic payload.

Because tumor cells — and advanced tumors in particular — make excess aminopeptidases, melflufen is meant to preferentially target cancer cells, while sparing healthy ones.

A combination of melflufen plus dexamethasone is under priority review by the U.S. Food and Drug Administration (FDA) for myeloma patients with triple-refractory disease — those who failed to respond to at least one immunomodulatory agent (IMiD), one proteasome inhibitor, and one CD38 inhibitor.

But recent data from the ANCHOR Phase 1/2 trial (NCT03481556) suggests that responses to treatment may be even better when this combination is added to agents, such as Darzalex, with a distinct mechanism of action.

Darzalex is an antibody designed to inhibit the activity of CD38, a protein found on the surface of myeloma cells, to prevent their growth and eliminate them. The treatment was initially developed as an intravenous (into-the-vein) injection, but an under-the-skin (subcutaneous) formulation was recently approved in the U.S. and Europe.

LIGHTHOUSE, sponsored by Oncopeptides, is an open-label study designed to confirm ANCHOR data.

It is enrolling people with relapsed or refractory myeloma who either failed to respond to an IMiD and a proteasome inhibitor — regardless of how many prior lines of therapy they have received — or who have had at least three prior lines of therapy, including those treatments.

Participants will be randomly assigned to receive either the triple combination of melflufen plus dexamethasone and Darzalex, or Darzalex alone, until their disease progresses, they experience unacceptable toxicity, or by the decision of the patient and/or attending physician.

Should disease progression be confirmed, patients receiving Darzalex alone will have the option to switch to the triple therapy.

The trial’s main goal is to measure the time patients live without experiencing disease progression. Other goals include the proportion of patients who respond to treatment, the duration of response, and the frequency and severity of any side effects.

Oncopeptides expects to complete the LIGHTHOUSE study in late 2025.

“Following the encouraging results of our ANCHOR study this is an important study to further evaluate the potential role of melflufen in triplet regimens,” Bakker said.