The combination of melflufen, daratumumab, and dexamethasone produces better outcomes than daratumumab alone in patients with relapsed or refractory multiple myeloma (MM), results from the LIGHTHOUSE trial suggest.1
In this phase 3 trial, melflufen plus daratumumab and dexamethasone improved the overall response rate (ORR) and prolonged progression-free survival (PFS) when compared to daratumumab alone. These findings were published in Haematologica.
The LIGHTHOUSE trial (ClinicalTrials.gov Identifier: NCT04649060) enrolled MM patients whose disease was refractory to an immunomodulatory agent (IMiD) and a proteasome inhibitor (PI) or who had received at least 3 prior lines of therapy, including an IMiD and a PI. Enrollment in this trial was stopped early after the US Food and Drug Administration (FDA) placed a partial clinical hold on all melflufen studies.2
The 54 patients who were enrolled were randomly assigned to receive melflufen, daratumumab, and dexamethasone (n=27) or daratumumab alone (n=27).1 The median age at baseline was 65 years (range, 43-80) in the melflufen arm and 68 years (range, 50-83) in the daratumumab arm. Patients in the melflufen arm had received a median of 3 prior lines of therapy (range, 1-9), and those in the daratumumab arm had received a median of 4 prior lines of therapy (range, 1-7).
In the intent-to-treat population, the median follow-up was 7.1 months in the melflufen arm and 6.6 months in the daratumumab arm.
The ORR was 59% in the melflufen arm and 30% in the daratumumab arm (P =.0300). The median PFS was not reached in the melflufen arm and was 4.9 months in the daratumumab arm (hazard ratio [HR], 0.18; 95% CI, 0.05-0.65; P =.0032).
Two patients in the daratumumab arm crossed over to the melflufen arm after disease progression. They were included in the daratumumab arm for the overall survival (OS) analysis and in the melflufen arm for the safety analysis.
OS data were immature, but 7% of patients in the melflufen arm died, as did 15% of those in the daratumumab arm (HR, 0.47; 95% CI, 0.09-2.57; P =.3721).
Treatment-emergent adverse events (TEAEs) were seen in 96% of patients in the melflufen arm and 85% of those in the daratumumab arm. Grade 3 or higher TEAEs occurred in 82% and 54%, respectively.
The most common grade 3 or higher hematologic TEAEs (in the melflufen and daratumumab arms, respectively) were neutropenia (50% and 12%), thrombocytopenia (50% and 8%), and anemia (32% and 19%). The most common non-hematologic grade 3 or higher TEAEs (in the melflufen and daratumumab arms, respectively) were pneumonia (9% and 8%) and femur fractures (0% and 8%).
Five patients died on study before crossover. The 3 deaths in the daratumumab arm were due to disease progression, unknown reasons, and COVID-19 pneumonia. The COVID-19 pneumonia occurred more than 30 days after the last dose of study treatment.
The 2 pre-crossover deaths in the melflufen arm were due to disease progression and unknown reasons. Both deaths occurred more than 30 days after the last dose of study treatment. An additional patient who crossed over to the melflufen arm died.
Melflufen received accelerated approval from the FDA in February 2021, but Oncopeptides AB (the company developing the drug) withdrew melflufen from the US market in October that same year.2,3 This move was based on results from the phase 3 OCEAN study, which showed worse OS with melflufen and dexamethasone than with pomalidomide and dexamethasone.
The FDA asked Oncopeptides to voluntarily withdraw the approval for melflufen, but Oncopeptides has argued that melflufen should remain approved in the US.4 The appeals process is still underway.
Disclosures: This research was supported by Oncopeptides AB. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
1. Pour L, Szarejko M, Bila J, et al. Efficacy and safety of melflufen plus daratumumab and dexamethasone in relapsed/refractory multiple myeloma: Results from the randomized, open-label, phase III LIGHTHOUSE study. Haematologica. Published online August 31, 2023. doi:10.3324/haematol.2023.283509
2. FDA alerts patients and health care professionals about clinical trial results showing an increased risk of death associated with Pepaxto (melphalan flufenamide). US Food and Drug Administration. Updated August 24, 2023. Accessed September 6, 2023.
3. Olivier T, Prasad V. The approval and withdrawal of melphalan flufenamide (melflufen): Implications for the state of the FDA. Transl Oncol. 2022;18:101374. doi:10.1016/j.tranon.2022.101374
4. Information regarding Oncopeptides’ appeal of U.S. withdrawal published. Oncopeptides. Published August 25, 2023. Accessed September 6, 2023.
This article originally appeared on Cancer Therapy Advisor