Long-Term Outcomes from the Phase 3 OCEAN (OP-103) Study: Melflufen and Dexamethasone (Dex) Versus Pomalidomide (Pom) and Dex in Relapsed Refractory Multiple Myeloma (RRMM)
Authors: Schjesvold Fredrik , Dimopoulos Meletios A. , Delimpasi Sosana , Robak Pawel , Coriu Daniel , Legiec Wojciech Maciej , Pour Ludek , Spicka Ivan , Masszi Tamas , Doronin Vadim Anatolievich , Minarik Jiri , Salogub Galina , Alexeeva Yulia , Lazzaro Antonio , Maisnar Vladimir , Mikala Gabor , Norin Stefan , Thuresson Marcus , Bergan Anna , Obermüller Jakob , Hajek Roman , Mateos Maria-Victoria , Richardson Paul G. , Sonneveld Pieter 
Published: December 2023

Background/Introduction: Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases resulting in rapid release of alkylating agents inside tumor cells. Based on the phase 2 HORIZON study and supported by the phase 3, randomized, controlled OCEAN study, melflufen was approved in Europe for use in patients (pts) with triple-class refractory RRMM with ≥3 prior lines of therapy (LoTs) and without prior autologous stem cell transplantation (ASCT) or with a time to progression (TTP) &gt;36 mo after prior ASCT. In the OCEAN study (NCT03151811), melflufen + dex showed superior progression-free survival (PFS) compared with pom + dex (6.8 vs 4.9 mo; hazard ratio [HR]: 0.79; P=0.032); PFS benefit in the melflufen + dex group was mainly driven by pts who had not received prior ASCT. Overall survival (OS) trended in favor of melflufen + dex in pts without prior ASCT and favored pom + dex in pts with prior ASCT (Schjesvold et al. Lancet Haematol. 2022;9:e98). Post-hoc analyses of OCEAN and HORIZON demonstrated that a TTP &lt;36 mo after prior ASCT was a negative prognostic factor for OS with melflufen + dex (Sonneveld et al. Clin Lymphoma Myeloma Leuk. 2023;S2152). Here, we present long-term OS and safety data from the final analysis of the OCEAN study.

Methods: Pts with RRMM (2-4 prior LoTs including lenalidomide [len] and a proteasome inhibitor) refractory to len and last LoT were randomized 1:1 (stratified by age, no. of prior LoTs, and International Staging System score) to receive 28-day (d) cycles of melflufen 40 mg intravenously on d1 or pom 4 mg orally (PO) daily on d1 to 21. All pts received dex 40 mg (20 mg for pts ≥75 y) PO on d1, 8, 15, and 22. Pts received therapy until disease progression or unacceptable toxicity. The primary endpoint was PFS, as assessed by independent review committee per IMWG Uniform Response Criteria, and key secondary endpoints were overall response rate, OS, and safety.

Results: As of 3 Feb 2023, 495 pts were randomized (246 to melflufen; 249 to pom); median age was 68 y (range, 39-91) and median prior LoTs was 3. In the intent-to-treat (ITT) melflufen and pom populations, median OS was 20.2 mo vs 24.0 mo (HR, 1.09 [95% CI, 0.88-1.35]), at a median follow-up of 40.3 mo and 38.1 mo, respectively. In the target subgroup of the melflufen and pom groups (pts without a prior ASCT or TTP &gt;36 mo after an ASCT), median OS was 23.6 mo vs 19.1 mo (HR, 0.88 [95% CI, 0.67-1.16]); in the non-target population (pts with TTP &lt;36 mo after ASCT), median OS was 15.7 mo vs 27.5 mo (HR, 1.60 [95% CI, 1.15-2.21]), respectively.

While any grade hematologic toxicities were more common with melflufen, the occurrence of non-hematologic toxicities was similar in the 2 groups. Grade 3/4 (G3/4) treatment-emergent adverse events (TEAEs) in the safety population (melflufen [n=228] and pom [n=246]) occurred in 90% vs 76% of pts, respectively; most commonly thrombocytopenia (78% vs 13%; occurring with G3/4 hemorrhage in 1% vs 0%), neutropenia (64% vs 50%; occurring with G3/4 infections in 4% vs 7%), anemia (43% vs 19%), and infection and infestations (14% vs 24%). Serious AEs occurred in 43% vs 50% of pts (including pneumonia [6% vs 9%], COVID-19 pneumonia [5% vs 6%], and anemia [4% vs 2%]), and fatal AEs in 14% vs 15% (including COVID-19 pneumonia [4% vs 2%] and pneumonia [2% vs 2%]) in the melflufen and pom groups, respectively. With melflufen and pom, TEAEs led to dose reductions in 52% vs 28% of pts (most frequently thrombocytopenia [32% vs 2%] and neutropenia [12% vs 8%]), and discontinuations in 30% vs 24% of pts, respectively. Deaths occurred in 74% vs 68% of pts in the melflufen and pom groups, with AEs being the primary cause of death ≤30 d after last dose in 8% and 11%, respectively.

Conclusion: Long-term results were consistent with those of previous analyses (Schjesvold, et al. Lancet Haematol. 2022;9:e98-e110). While OS trended in favor of pom in the ITT population, OS outcomes continued to be more favorable with melflufen in pts with no prior ASCT or with TTP &gt;36 mo after ASCT. No new safety signals were reported, and AEs were manageable with dose modifications, consistent with previous reports. This long-term follow-up of OCEAN confirms the favorable safety and OS outcomes of melflufen + dex in the target population and supports its continued use as an alternative treatment choice for pts with RRMM who have received ≥2 prior LoT and who have not received ASCT.