Safety and tolerability data from the OCEAN (OP-103) study found that melflufen plus dexamethasone remained consistent with prior reports; these data were presented at the 63rd American Society of Hematology Annual Meeting.

“Melphalan flufenamide (melflufen)—a first-in-class alkylating peptide-drug conjugate targeting aminopeptidases—and dexamethasone received accelerated approval for use in [relapsed/refractory multiple myeloma] RRMM in the United States based on the phase 2 HORIZON study results (J Clin Oncol. 2021;39:757),” explained Paul G. Richardson, MD, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, and colleagues.

In phase 3 randomized OCEAN study, melflufen plus dexamethasone was superior to pomalidomide plus dexamethasone based on progression-free survival (PFS) but showed no overall survival (OS) benefit.

OCEAN included patients with RRMM who had 2-4 prior lines of therapy (including lenalidomide and a proteasome inhibitor) who were refractory to lenalidomide refractory and the last line of therapy. Patients were randomized 1:1 to receive 28-day cycles of melflufen 40mg intravenously (day 1) plus dexamethasone 40 mg (20mg for patients ≥75 years of age) orally on days 1, 8, 15, and 22; or 4mg of oral pomalidomide (days 1-21) plus dexamethasone (dosage same as melflufen arm)

The safety and tolerability were assessed by the incidence and severity of adverse events (AEs) and presented by MedDRA Preferred Terms (PTs); hematologic AEs, infections, hemorrhages were AEs of special interest. Furthermore, dose modifications of melflufen and pomalidomide were permitted to manage AEs.

As of February 2021, 228/246 (93%) in the melflufen arm and 246/249 (99%) patients in the pomalidomide arm received ≥1 dose of the study drug and were included in the safety analysis. The median duration of therapy was 5.8 months in the melflufen arm and 5.1 months in the pomalidomide arm. 

Treatment-emergent AEs (TEAEs) of grade 3.4 were experienced among 90% and 74% of patients in the melflufen and pomalidomide arm, respectively. The most common grade 3/4 hematologic AEs were: neutropenia (melflufen: 64% vs pom: 49%), anemia (43% vs 18%), and thrombocytopenia (76% vs 13%). With melflufen, hemorrhages (mostly grade 1/2) occurred in 16% of patients, compared to 7% in the pomalidomide arm; grade 3 hemorrhages with concurrent grade 3/4 thrombocytopenia occurred in 2 patients (1%) and 0 patients, respectively. Additionally, grade 3/4 infections occurred in 13% v.s. 22% of patients (concurrently with grade 3/4 neutropenia in 3% vs 7%), respectively.

Furthermore, dose reductions due to TEAEs occurred in 47% of melflufen patients and 15% of pomalidomide patients, with the most common being causes being thrombocytopenia (31% v.s 2%) and neutropenia (12% v.s 8%); 26% of melflufen patients and 22% of pomalidomide patients permanently discontinued treatment due to TEAEs.

The median time to dose reduction was 106 days (range:28-449) with melflufen and 50 days (29-144) with pomalidomide. The median time to onset of grade 3/4 thrombocytopenia and grade 3/4 neutropenia by lab values was 51 days (2-451) and 24 days (5-561) with melflufen compared to 16 (8-189) and 22 days (8-541) with pomalidomide. 

Younger patients receiving melflufen saw more dose reductions due to TEAEs than older patients, but among the pomalidomide group, dose reductions were more frequent in older patients. The proportion of dose modifications was higher with melflufen than pomalidomide in patients aged <65 years (79% v.s 55%) but was similar in both arms in patients aged ≥75 years (65% v.s 64%). Additionally, TEAEs which led to discontinuation were similar rates in patients ages <65 and ≥75 years taking melflufen (26% v.s 22%), but not with pomalidomide (20% v.s 36%).

In the melflufen arm, deaths occurred in 106 patients (46%), compared to 106 patients (43%) in the pomalidomide arm. Deaths ≤3 days after the last dose occurred in 23 (10%) and 33 (13%) patients in the melflufen and pomalidomide arms, respectively. 

“In the OCEAN study, safety and tolerability of melflufen [plus dexamethosone] was consistent with prior reports. Hematologic AEs were common but generally manageable with dose modifications. Despite a higher cytopenia frequency with melflufen, rates of concurrent grade 3/4 bleedings and infections were low and grade 3/4 infections were more common with pomalidomide,” concluded Dr Richardson et al.—Alexandra Graziano

Richardson P, Schjesvold F, Abdulhaq H, et al. OCEAN (OP-103): Melflufen/Dexamethasone (Dex) Compared with Pomalidomide (Pom)/Dex in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM) — Safety and Tolerability Analyses. Presented at: the 63rd ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 2732