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 results 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 peptidase-potentiated alkylating peptide that delivers alkylating molecules to tumor cells, resulting in selective cytotoxicity. “Aminopeptidases are heavily over-expressed and are key for the transformation process in MM,” Dr. Richardson explained, and are “critically involved in tumor migration, cell proliferation, and angiogenesis.”

The new agent is designed to overcomes 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 with MM that was considered “highly refractory,” meaning they 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 in 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 overall response rate (defined as partial response [PR] or better), assessed by investigators per International Myeloma Working Group criteria.

As of October 22, 2018 (data cutoff), 83 patients had received study treatment and 82 were evaluable for response.

Their median age was 63 years (range = 35-86 years), and the 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 (60%) of patients 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 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 gain of 1q).

As of data cutoff, 23 percent of patients were still receiving melflufen. Treatment discontinuations were most often related to progressive disease (57%) and adverse events (13%), and 7 percent of patients discontinued for other reasons.

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

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

“Treatment-related non-hematologic grade 3/4 events were rare,” the authors noted, “with infections in only 7 percent of patients.” However, 14 participants (16%) experienced a melflufen-related serious AE, the most frequent of which were febrile neutropenia (n=5), neutropenia (n=3), and thrombocytopenia (n=2). No treatment-related deaths were reported.

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

  • complete response: 1.2%
  • very good partial response: 11%
  • partial response: 20.7%

Overall, 84.1 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=27%). “Melflufen has promising activity in patients with heavily pretreated and refractory late-stage relapsed/refractory MM – in whom the majority of available, approved, and experimental therapies have failed,” Dr. Richardson concluded.

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 financial relationships with Oncopeptides AB, 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.