TY - JOUR
TI - Melflufen or pomalidomide plus dexamethasone for patients with multiple
myeloma refractory to lenalidomide (OCEAN): a randomised, head-to-head,
open-label, phase 3 study
AU - Schjesvold, Fredrik H.
AU - Dimopoulos, Meletios-Athanasios and
AU - Delimpasi, Sosana
AU - Robak, Pawel
AU - Coriu, Daniel
AU - Legiec,
AU - Wojciech
AU - Pour, Ludek
AU - Spicka, Ivan
AU - Masszi, Tamas
AU - Doronin,
AU - Vadim
AU - Minarik, Jiri
AU - Salogub, Galina
AU - Alekseeva, Yulia and
AU - Lazzaro, Antonio
AU - Maisnar, Vladimir
AU - Mikala, Gabor
AU - Rosinol,
AU - Laura
AU - Liberati, Anna Marina
AU - Symeonidis, Argiris
AU - Moody,
AU - Victoria
AU - Thuresson, Marcus
AU - Byrne, Catriona
AU - Harmenberg, Johan
AU - and Bakker, Nicolaas A.
AU - Hajek, Roman
AU - Mateos, Maria-Victoria and
AU - Richardson, Paul G.
AU - Sonneveld, Pieter
AU - OCEAN OP-103 Investigators
JO - The Lancet Haematology
PY - 2022
VL - 9
TODO - 2
SP - E98-E110
PB - Elsevier Sci Ltd, Exeter, United Kingdom
SN - 2352-3026
TODO - 10.1016/S2352-3026(21)00381-1
TODO - Published Online; See Comment page e82; Malignancies; University of;
Department of Hematology
TODO - Background Melphalan flufenamide (melflufen), an alkylating peptide-drug
conjugate, plus dexamethasone showed clinical activity and manageable
safety in the phase 2 HORIZON study. We aimed to determine whether
melflufen plus dexamethasone would provide a progression-free survival
benefit compared with pomalidomide plus dexamethasone in patients with
previously treated 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 or refractory 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 Staging System score, to either
28-day cycles of melflufen and dexamethasone (melflufen group) or
pomalidomide and dexamethasone (pomalidomide group). All patients
received dexamethasone 40 mg orally on days 1, 8, 15, and 22 of each
cycle. In the melflufen group, patients received melflufen 40 mg
intravenously over 30 min on day 1 of each cycle and in the pomalidomide
group, patients received pomalidomide 4 mg orally daily on days 1 to 21
of each cycle. The primary endpoint was progression-free survival
assessed by an independent review committee in the intention-to-treat
(ITT) population. Safety was assessed in patients who received at least
one dose of study medication. This study is registered with
ClinicalTrials.gov, NCT03151811, and is ongoing. Findings Between June
12, 2017, and Sept 3, 2020, 246 patients were randomly assigned to the
melflufen group (median age 68 years [IQR 60-72]; 107 [43%] were
female) and 249 to the pomalidomide group (median age 68 years [IQR
61-72]; 109 [44%] were female). 474 patients received at least one
dose of study drug (melflufen group n=228; pomalidomide group n=246;
safety population). Data cutoff was Feb 3, 2021. Median progression-free
survival was 6middot8 months (95% CI 5middot0-8middot5; 165 [67%] of
246 patients had an event) in the melflufen group and 4middot9 months
(4middot2-5middot7; 190 [76%] of 249 patients had an event) in the
pomalidomide group (hazard ratio [HR] 0middot79, [95% CI
0middot64-0middot98]; p=0middot032), at a median follow-up of 15middot5
months (IQR 9middot4-22middot8) in the melflufen group and 16middot3
months (10middot1-23middot2) in the pomalidomide group. Median overall
survival was 19middot8 months (95% CI 15middot1-25middot6) at a median
follow-up of 19middot8 months (IQR 12middot0-25middot0) in the melflufen
group and 25middot0 months (95% CI 18middot1-31middot9) in the
pomalidomide group at a median follow-up of 18middot6 months (IQR
11middot8-23middot7; HR 1middot10 [95% CI 0middot85-1middot44];
p=0middot47). The most common grade 3 or 4 treatment-emergent adverse
events were thrombocytopenia (143 [63%] of 228 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%) patients
in the melflufen group and 113 (46%) in the pomalidomide group, the
most common of which 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 pomalidomide group had fatal treatment-emergent
adverse events. Fatal treatment-emergent adverse events were considered
possibly treatment related in two patients in the melflufen group (one
with acute myeloid leukaemia, one with pancytopenia and acute cardiac
failure) and four patients in the pomalidomide group (two patients with
pneumonia, one with myelodysplastic 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. Funding
Oncopeptides AB Copyright (c) 2022 Elsevier Ltd. All rights reserved.
ER -