Melflufen Plus Dexamethasone Exhibits Clinically Meaningful Efficacy in Heavily Pretreated R/R Multiple Myeloma

Contemporary Concepts | <b>Contemporary Concepts in Hematologic Oncology</b>

The phase 2 HORIZON study indicated that melflufen plus dexamethasone (Ozurdex) demonstrated clinically meaningful efficacy as well as a manageable safety profile in patients with heavily pretreated relapsed/refractory multiple myeloma.

Results from the phase 2 HORIZON study published in the Journal of Clinical Oncology indicated that melflufen plus dexamethasone (Ozurdex) demonstrated clinically meaningful efficacy as well as a manageable safety profile in patients with heavily pretreated relapsed or refractory multiple myeloma, including those with triple-class refractory and extramedullary disease.1

Importantly, the phase 2 data are the basis for the ongoing priority review of the new drug application to the FDA for accelerated approval of melflufen in combination with dexamethasone in patients with triple-class refractory multiple myeloma who are refractory to at least 1 proteasome inhibitor, 1 immunomodulatory drug, and 1 anti-CD38 monoclonal antibody.2

“The results from the HORIZON study demonstrate that melflufen in combination with dexamethasone, has a potential to provide a therapeutic option for patients who are difficult to treat and have a poor prognosis, including patients with triple class refractory myeloma and patients with extramedullary disease,” Klaas Bakker, MD, PhD, chief medical officer at Oncopeptides AB, said in a press release. “These patients have limited, or no treatment options left. The introduction of a new treatment class may represent a potentially important alternative.”

The pivotal, single-arm, multicenter study enrolled patients with relapsed or refractory multiple myeloma who were refractory to pomalidomide (Pomalyst) and/or an anti-CD38 monoclonal antibody to receive melflufen at a 40 mg dose intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg or 20 mg for patients older than 75 years.

The primary end point of the study was overall response rate (ORR), defined as partial response or better, assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival (PFS), overall survival (OS), and safety. The primary analysis is complete, though long-term follow-up remains ongoing.

Among a total of 157 patients enrolled and treated, 119 patients (76%) had triple-class–refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy.

The ORR was 29% in the all-treated population, with 26% in the triple-class–refractory population. At a median follow-up of 14 months, median duration of response was 5.5 months, median PFS was 4.2 months, and median OS was 11.6 months in the all-treated population.

Regarding safety, grade 3 or higher treatment-emergent adverse events (AEs) occurred in 96% of patients. The most common grade 3 or higher AEs observed were neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3 or 4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4, but fully reversible) were reported concomitantly in 4 patients. GI events were reported in 97 patients (62%) and were predominantly grade 1 or 2 (93%); none were grade 4.

“These findings build substantially on previously reported results but in a population that is more aligned with current treatment practice in the relapsed and refractory as well as highly resistant disease setting (ie, patients refractory to an anti-CD38 monoclonal antibody and/or pomalidomide, as well as exposed and refractory to prior lenalidomide, dexamethasone, and proteasome inhibitors),” the study authors wrote.

Based on the results of the current study, the efficacy and safety of melflufen plus dexamethasone versus pomalidomide plus dexamethasone are being further evaluated in the multicenter, randomized, global, phase 3 OCEAN study (OP-103; NCT03151811) for patients in earlier relapse. Additionally, studies of melflufen plus dexamethasone in combination with bortezomib (Velcade) or daratumumab (Darzalex) are also ongoing, with promising results reported to date.


1. Richardson PG, Oriol A, Larocca A, et al. Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma. Journal of Clinical Oncology. doi: 10.1200/JCO.20.02259

2. Full data set of Oncopeptides phase 2 HORIZON study in multiple myeloma published in the Journal of Clinical Oncology [news release]. Stockholm. Published December 9, 2020. Accessed December 14, 2020.