Good News on the HORIZON: Melflufen Induces Response in Heavily Refractory Myeloma

One-third of patients with relapsed/refractory multiple myeloma (MM) that was refractory to pomalidomide and/or daratumumab responded to treatment with melflufen, according to interim data from the phase II HORIZON trial. Paul Richardson, MD, from the Dana-Farber Cancer Institute in Boston, presented the results at the 2018 ASH Annual meeting.

“Melflufen is a first-in-class drug that is activated by aminopeptidases, which are overexpressed in multiple cancers, including myeloma,” Dr. Richardson explained, adding that aminopeptidases play a key role in DNA repair, cell proliferation, programmed cell death, and tumor angiogenesis.

The new agent is designed to overcome resistance pathways of existing MM treatments, making it a promising therapy for patients with relapsed and refractory disease, the authors noted, citing earlier phase I/II results in which melflufen was associated with an overall response rate (ORR) of 31 percent and a progression-free survival (PFS) of 5.7 months.

In the present study, an open-label, phase II trial, researchers evaluated the safety and efficacy of melflufen in patients who had received at least two prior therapies, including an immunomodulatory agent (IMiD) and a proteasome inhibitor (PI), and their disease was refractory to pomalidomide and/or daratumumab.

Melflufen was administered with dexamethasone according to the following dosing schedule: melflufen 40 mg on day 1 and dexamethasone 40 mg on days 1, 8, 15, and 22. Patients received treatment until disease progression or unacceptable toxicity.

The primary endpoint was investigator-assessed ORR (defined as partial response [PR] or better), assessed by investigators per International Myeloma Working Group criteria.

(data cutoff; median follow-up not provided), 83 patients had received study treatment and 82 were evaluable for response. Their median age was 63 years (range = 35-86 years), and median time since diagnosis was 6.5 years (range = 1-25 years). During that time, patients received a median of five prior lines of therapy (range = 2-13). More than half of patients (60%) had disease that was refractory to both agents, and 86 percent had disease that was double-refractory to IMiDs and PIs. In addition, 55 percent had disease that was refractory to a prior alkylator therapy.

Thirty-six percent of patients had poor prognosis (defined as International Staging System [ISS] stage 3 disease), and 61 percent had high-risk cytogenetics at study entry (defined as del17p, t[4;14], t[14;16], t[14;20] or gain1q).

Nineteen patients (23%) were still receiving treatment at last follow-up, while 64 (77%) had discontinued treatment due to progressive disease (57%), adverse events (AEs; 13%), or other reasons (7%).

Sixty-two participants (75%) experienced grade 3/4 treatment-related AEs, the majority of which were hematologic, including:

  • neutropenia (61%)
  • thrombocytopenia (59%)
  • anemia (25%)

Treatment-related non-hematologic grade 3/4 events were rare, with infections in 7 percent of patients. However, 14 participants (16%) experienced melflufen-related serious AEs, the most frequent of which were febrile neutropenia (n=5), neutropenia (n=3), and thrombocytopenia (n=2). “Thrombocytopenia was generally manageable with supportive care and there was a very low incidence of bleeding,” he added, and no treatment-related deaths were reported.

Preliminary efficacy results showed that approximately one-third of patients responded to treatment, including:

  • complete response: 1% (n=1)
  • very good partial response: 11% (n=9)
  • partial response: 21% (n=17)

Overall, 84 percent of patients experienced stable disease or better.

Responses were observed across subgroups, including in patients with ISS stage 3 MM (ORR=24%) and those with high-risk cytogenetics (ORR=22%).

Although survival data were immature at the time of the presentation, Dr. Richardson noted that, “we were encouraged to see that the median PFS in this very sick population was approximately 4 months … and was 6.4 months among patients with a PR or better.”

The findings are limited by the lack of a comparator arm and the relatively small patient population, which limits the generalizability of the results.

The authors reported relationships with Oncopeptides, which supported the study.


Richardson P, Ocio E, Oriol A, et al. OP-106 Horizon – melflufen therapy for RRMM patients refractory to daratumumab and/or pomalidomide; updated results and first report on PFS. Abstract #600. Presented at the 2018 ASH Annual Meeting, December 3, 2018; San Diego, CA.