Melphalan Flufenamide Plus Daratumumab Elicits PFS Benefit in Relapsed/Refractory Myeloma

María-Victoria Mateos, MD, PhD

The combination of melphalan flufenamide (Pepaxto) and daratumumab plus hyaluronidase-fihj (Darzalex Faspro) and dexamethasone elicited an improvement in progression-free survival (PFS) compared with daratumumab and dexamethasone alone in patients with relapsed/refractory multiple myeloma who were refractory to at least an immunomodulatory drug (IMiD) and a proteasome inhibitor (PI) or received at least 3 prior lines of therapy including a PI and an IMiD.¹

Findings from the phase 3 LIGHTHOUSE trial (NCT04649060) showed that patients treated in the melphalan flufenamide arm (n = 27) achieved a superior PFS benefit vs patients treated in the control arm (n = 27; HR, 0.18; P = .0032). Additionally, melphalan flufenamide plus daratumumab and dexamethasone demonstrated superiority vs the control in overall response rate (P = 0.3) and overall survival (OS; HR, 0.47; P = .37)

In July 2021, the FDA requested a partial clinical hold for the LIGHTHOUSE trial after 54 patients were enrolled. In February 2022, the study was prematurely terminated after 27 patients had been randomly assigned to each treatment arm.

“Data from the phase 3 LIGHTHOUSE study are very encouraging and clearly indicate that the combination of melflufen and daratumumab has a clinical benefit in patients with relapsed/refractory multiple myeloma,” María-Victoria Mateos, MD, PhD, of the Department of Hematology at Salamanca’s University Hospital in Spain, and the lead investigator of the LIGHTHOUSE study, stated in a press release. “Multiple myeloma is still an incurable disease for most patients, and we welcome additional evidence on how to combine treatment options with different mode of actions in clinical practice.”

In September 2022, the FDA’s Oncologic Drugs Advisory Committee voted that the benefit-risk profile of melphalan flufenamide was not favorable for the approved indicated population of patients with relapsed/refractory multiple myeloma.²

In February 2022, the FDA approved melphalan flufenamide for use in combination with dexamethasone in adult patients with relapsed or refractory multiple myeloma, who have received at least four prior lines of therapy and whose disease is refractory to at least one PI, one IMiD, and one CD38-directed monoclonal antibody.³

The approval was based on findings from the phase 2 HORIZON trial (NCT02963493); however, the confirmatory phase 3 OCEAN study (NCT03151811) failed to meet the primary or secondary end points for PFS and overall survival (OS), respectively, for melphalan flufenamide plus dexamethasone compared with pomalidomide (Pomalyst) plus dexamethasone.

In October 2022, Oncopeptides AB (publ) withdrew the indication of melphalan flufenamide in combination with dexamethasone in select adult patients with relapsed or refractory multiple myeloma from the US market.⁴

In August 2022, the European Commission approved melphalan flufenamide plus dexamethasone for the treatment of adult patients with multiple myeloma who have received at least 3 prior therapies, whose disease is refractory to at least one PI, one IMiD, and one anti-CD38 monoclonal antibody, and who have demonstrated disease progression on or after the last therapy.⁵ Oncopeptides noted that among patients enrolled in LIGHTHOUSE who fit those criteria (n = 29), melphalan flufenamide demonstrated superior PFS (HR, 0.062; P = .0005), ORR (P = .0051), and OS (HR, 0.00; P = .037).

LIGHTHOUSE was a randomized, open-label trial, designed as a confirmatory study in addition to OCEAN. It planned to enroll 240 patients with relapsed/refractory multiple myeloma with documented disease progression after the last line of therapy who were double refractory to an IMiD and a PI, regardless of the number of prior lines of therapy, or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients were permitted to have prior treatment with daratumumab or another anti-CD38 antibody under certain circumstances.⁶

Key exclusion criteria included primary refractory disease, prior CD38-directed CAR T-cell therapy, prior CD38/CD3 bispecific antibodies, known or suspected amyloidosis, plasma cell leukemia or POEMS syndrome, known central nervous system or meningeal involvement of myeloma, or prior stem cell transplant within 6 months of initiation of therapy or prior allogeneic stem cell transplantation with active graft-vs-host disease.

Patients who were randomly assigned to the experimental arm received 30 mg of intravenous melphalan flufenamide on day 1 of each cycle, 40 mg of oral dexamethasone weekly, and 1800 mg of subcutaneous daratumumab on days 1, 8, 15, and 22 of cycles 1 and 2, on days 1 and 15 in cycles 3 to 6, and day 1 of cycle 7 and beyond. Notably, dexamethasone was given at 20 mg weekly for patients 75 years of age and older. Those in the control arm received the same dosing regimen of daratumumab alone.

PFS served as the primary end point. Secondary end points included ORR, duration of response, OS, clinical benefit rate, time to response, time to progression, time to next treatment, and safety.

Patient characteristics were balanced between the two study arms. Regarding safety, the profile of melphalan flufenamide plus daratumumab was in line with what was observed in the phase 1/2 ANCHOR study (NCT03481556), with predominantly clinically manageable cytopenias.

“LIGHTHOUSE is the second phase 3 study to confirm the clinical benefit of melphalan flufenamide in [patients with] multiple myeloma with a treatment history with no stem cell transplant or a successful prior stem cell transplant in line with the recent full European approval,” Jakob Lindberg, chief executive officer of Oncopeptides, said. “In addition, the LIGHTHOUSE data support the European Medicines Agency conclusion that there is no indication of absolute OS harm from treatment with melphalan flufenamide.”

References

1. Oncopeptides phase 3 LIGHTHOUSE study further confirms clinical benefit of melflufen. News release. Oncopeptides AB (publ). October 26, 2022. Accessed October 26, 2022. https://prn.to/3gKKo4A
2. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. September 22, 2022. Accessed September 22, 2022. https://www.youtube.com/watch?v=SON2biqVX_8
3. FDA approves Oncopeptides' PEPAXTO (melphalan flufenamide) for patients with relapsed or refractory multiple myeloma. News release. Oncopeptides AB (publ). February 26, 2021. Accessed October 26, 2022. http://cisn.co/3q2bZgq
4. Oncopeptides withdraws Pepaxto in US, scale down organization and focus on R&D. News release. Oncopeptides AB (publ). October 22, 2021. Accessed October 22, 2021. https://bit.ly/3vzvjGc
5. European Commission approves Oncopeptides' Pepaxti for the treatment of patients with relapsed refractory multiple myeloma. News release. Oncopeptides AB (publ). August 18, 2022. Accessed October 26, 2022. https://prn.to/3wdLjzt
6. Study of melphalan flufenamide (Melflufen) in combination with daratumumab in relapsed refractory multiple myeloma (LIGHTHOUSE). ClinicalTrials.gov. Updated March 4, 2022. Accessed October 26, 2022. https://clinicaltrials.gov/ct2/show/NCT04649060