Melflufen Combo Demonstrates Activity in Patients With R/R Multiple Myeloma and Extramedullary Disease


The combination of melflufen and dexamethasone showed antitumor activity in patients with relapsed or refractory multiple myeloma, both in those with and those without extramedullary disease, according to data from the phase II HORIZON study presented at the 17th International Myeloma Workshop.

Paul G. Richardson, MD

Paul G. Richardson, MD

Paul G. Richardson, MD

The combination of melflufen and dexamethasone showed antitumor activity in patients with relapsed or refractory multiple myeloma (RRMM), both in those with and those without extramedullary disease (EMD), according to data from the phase II HORIZON study presented at the 17th International Myeloma Workshop (IMW). Response rates with the combination were higher than those observed in prior studies of other agents in this patient populaiton. 

Outcomes for patients with RRMM who have EMD remain very poor despite recent advances in therapy, and EMD incidence appears to be increasing. Only daratumumab (Darzalex) has shown significant single-agent activity against EMD, with an overall response rate (ORR) of 17% (3 of 18) reported in daratumumab-naïve patients.

Melflufen is a novel, lipophilic, peptide-conjugated alkylator that rapidly delivers a highly cytotoxic payload into myeloma cells in vitro, inducing irreversible DNA damage and apoptosis. Melflufen is 50-fold more potent than melphalan in MM cells in vitro due to increased intracellular alkylator activity.

When presenting at IMW, Paul G. Richardson, MD, of Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, described outcomes for patients with and without EMD in the HORIZON study, a single-arm, open label, multicenter phase II study investigating melflufen plus dexamethasone in patients with RRMM refractory to available therapies (NCT02963493).

Patients with RRMM (n = 136) received ≥2 prior lines of therapy, were exposed to immunomodulatory drug (IMiD) and proteasome inhibitor (PI)—based therapy and had disease that was refractory to pomalidomide (Pomalyst) and/or daratumumab. Patients received melflufen 40 mg intravenously (IV) on day 1 of each 28-day cycle and dexamethasone 40 mg weekly (20 mg for patients age ≥75 years) until progressive disease or unacceptable toxicity. Dexamethasone was also given on days 8, 16, and 22. Patients were followed for progression-free survival (PFS) and overall survival (OS) for up to 24 months after the end of treatment.

The primary endpoint of the trial is ORR [≥ partial response (PR)]. Secondary endpoints included PFS, duration of response (DOR), OS, clinical benefit rate (CBR), time to relapse, time to progression, and safety. EMD assessment at screening was required for patients with known or suspected soft tissue and/or bone-related extramedullary plasmacytomas.

Interim results were presented at the meeting both for patients with (n = 44) and without (n = 86) EMD. There were no major differences between the 2 groups for most baseline characteristics, other than anti-CD38 exposure. EMD incidence was associated with anti-CD38 exposure (P= .01); EMD occurred in 40% of patients who were exposed to anti-CD38 and in 11% of patients not exposed to anti-CD38.

EMD was assessed per investigator choice and included multiple imaging modalities (eg, PET/CT, MRI) and physical examination. Most patients with EMD had multiple lesions at baseline (29 of 44); 41% had only bone-related lesions, and 59% had soft-tissue lesions with or without additional bone-related lesions. Central nervous system (CNS) involvement occurred in 5 patients (11%).

ORR was 27% for patients without EMD and 23% with EMD; CBR was 45% and 30%, respectively. In patients with EMD, those with soft tissue involvement (n = 26) had an ORR of 19%; those with bone-related EMD (n = 18) had an ORR of 28%. There was no response seen in patients with CNS and EMD.

Median DOR for patients without EMD was 4.4 months (95% CI, 3.5-11.2). For patients with EMD, median DOR was 3.4 months (95% CI, 1.8-15.4).

Median PFS was 2.9 months (95% CI, 2.0-4.0) for patients with EMD and 4.6 months (95% CI, 4.0-5.6) for patients without EMD.

Median OS was 5.8 months (95% CI, 5.0-11.8) for patients with EMD and 11.6 months (95% CI, 10.0-17.6) for patients without EMD.

Median OS was 18.5 months versus 5.1 months, respectively, in patients with EMD that did and did not respond to melflufen plus dexamethasone. In patients without EMD, on the other hand, median OS was 17.2 months versus 8.5 months, respectively, for those with disease that did respond versus disease that did not. Of the intent-to-treat (ITT) population, 54% of patients received subsequent therapy in line with previously published data with no significant difference observed between patients with or without EMD.

Safety profiles for patients with and without EMD in the ITT population were similar and the treatment was generally well tolerated with manageable toxicity. Serious adverse events (AEs) were predominantly hematologic; the incidence of non-hematologic AEs, including infections, was low and there were no treatment-related deaths reported.

HORIZON enrolled one of largest cohorts of patients with RRMM and EMD in a prospective trial; enrollment is nearly complete (n = 156), with final analysis pending. Melflufen plus dexamethasone demonstrates encouraging activity in this patient population.

Richardson concluded that these results support continued investigation in ongoing and future clinical trials, including 4 ongoing phase II and III trials, of melflufen-based combination therapy for this population with an unmet medical need.


Richardson PG, Mateos M-V, Rodríguez-Otero P, et al. Activity of melflufen in RR MM patients with extramedullary disease in the phase 2 HORIZON Study (OP-106): promising results in a high-risk population. Presented at: 17th International Myeloma Workshop; September 12-15, 2019; Boston, MA. Abstract 904.

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