Melflufen or pomalidomide plus dexamethasone for patients with multiple myeloma refractory to lenalidomide (OCEAN): a randomised, head-to-head, open-label, phase 3 study
Mené sur 246 patients atteints d'un myélome multiple récidivant ou réfractaire au lénalidomide (âge médian : 68 ans), cet essai de phase III compare l'efficacité, du point de vue de la survie sans progression, et la toxicité du melflufen et du pomalidomide, en combinaison avec la dexaméthasone
Background : Melphalan flufenamide (melflufen), an alkylating peptide-drug conjugate, plus dexamethasoneshowed clinical activity and manageable safety in the phase 2 HORIZON study. We aimedto determine whether melflufen plus dexamethasone would provide a progression-freesurvival benefit compared with pomalidomide plus dexamethasone in patients with previouslytreated multiple myeloma.
Methods : In this randomised, open-label, head-to-head, phase 3 study (OCEAN), adult patients(aged ≥18 years) were recruited from 108 university hospitals, specialist hospitals,and community-based centres in 21 countries across Europe, North America, and Asia.Eligible patients had an ECOG performance status of 0–2; must have had relapsed orrefractory multiple myeloma, refractory to lenalidomide (within 18 months of randomisation)and to the last line of therapy; and have received two to four previous lines of therapy(including lenalidomide and a proteasome inhibitor). Patients were randomly assigned(1:1), stratified by age, number of previous lines of therapy, and International StagingSystem score, to either 28-day cycles of melflufen and dexamethasone (melflufen group)or pomalidomide and dexamethasone (pomalidomide group). All patients received dexamethasone40 mg orally on days 1, 8, 15, and 22 of each cycle. In the melflufen group, patientsreceived melflufen 40 mg intravenously over 30 min on day 1 of each cycle and in thepomalidomide group, patients received pomalidomide 4 mg orally daily on days 1 to21 of each cycle. The primary endpoint was progression-free survival assessed by anindependent review committee in the intention-to-treat (ITT) population. Safety wasassessed in patients who received at least one dose of study medication. This studyis registered with ClinicalTrials.gov, NCT03151811, and is ongoing.
Findings : Between June 12, 2017, and Sept 3, 2020, 246 patients were randomly assigned to themelflufen group (median age 68 years [IQR 60–72]; 107 [43%] were female) and 249 tot he pomalidomide group (median age 68 years [IQR 61–72]; 109 [44%] were female). 474patients received at least one dose of study drug (melflufen group n=228; pomalidomidegroup n=246; safety population). Data cutoff was Feb 3, 2021. Median progression-freesurvival was 6·8 months (95% CI 5·0–8·5; 165 [67%] of 246 patients had an event) inthe melflufen group and 4·9 months (4·2–5·7; 190 [76%] of 249 patients had an event)in the pomalidomide group (hazard ratio [HR] 0·79, [95% CI 0·64–0·98]; p=0·032), ata median follow-up of 15·5 months (IQR 9·4–22·8) in the melflufen group and 16·3 months(10·1–23·2) in the pomalidomide group. Median overall survival was 19·8 months (95%CI 15·1–25·6) at a median follow-up of 19·8 months (IQR 12·0–25·0) in the melflufengroup and 25·0 months (95% CI 18·1–31·9) in the pomalidomide group at a median follow-upof 18·6 months (IQR 11·8–23·7; HR 1·10 [95% CI 0·85–1·44]; p=0·47). The most commongrade 3 or 4 treatment-emergent adverse events were thrombocytopenia (143 [63%] of228 in the melflufen group vs 26 [11%] of 246 in the pomalidomide group), neutropenia (123 [54%] vs 102 [41%]), and anaemia (97 [43%] vs 44 [18%]). Serious treatment-emergent adverse events occurred in 95 (42%) patientsin the melflufen group and 113 (46%) in the pomalidomide group, the most common ofwhich were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]). 27 [12%] patients in the melflufen group and 32 [13%] in the pomalidomidegroup had fatal treatment-emergent adverse events. Fatal treatment-emergent adverseevents were considered possibly treatment related in two patients in the melflufengroup (one with acute myeloid leukaemia, one with pancytopenia and acute cardiac failure)and four patients in the pomalidomide group (two patients with pneumonia, one withmyelodysplastic syndromes, one with COVID-19 pneumonia).
Interpretation : Melflufen plus dexamethasone showed superior progression-free survival than pomalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma.
The Lancet Haematology , résumé, 2021