Melflufen or pomalidomide plus dexamethasone for patients with multiple myeloma refractory to lenalidomide (OCEAN): a randomised, head-to-head, open-label, phase 3 study

Abstract

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. MethodsIn 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 6•8 months (95% CI 5•0-8•5; 165 [67%] of 246 patients had an event) in the 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), at a 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 melflufen group and 25•0 months (95% CI 18•1-31•9) in the pomalidomide group at a median follow-up of 18•6 months (IQR 11•8-23•7; HR 1•10 [95% CI 0•85-1•44]; p=0•47). The most common grade 3 or 4 treatment-emergent adverse events were thrombocytopenia (143 [63%] of 228 in the melflufen group vs...

How I treat triple‐class refractory multiple myeloma

“…A single‐arm phase II trial 50 demonstrated an ORR of 26% in patients with TCR MM treated with melflufen plus dexamethasone, but with a short PFS and substantial haematological toxicity. Melflufen was transiently available in the USA after receiving accelerated approval but has since been voluntarily withdrawn from the market given the higher number of deaths than in the control arm in a confirmatory phase III trial 51 …”

“…Melflufen was transiently available in the USA after receiving accelerated approval but has since been voluntarily withdrawn from the market given the higher number of deaths than in the control arm in a confirmatory phase III trial. 51 In essence, alkylator-based regimens are often deployed in patients with TCR MM particularly in those with rapidly progressing disease. They offer a reasonable chance of short-term disease control, yet with substantial toxicity.…”

Treatment horizon in multiple myeloma

“…Although meflufen was initially granted accelerated FDA approval based on the HORIZON phase 2 study (NCT02963493), 85,86 FDA has since suspended enrollment to meflufen clinical trial based on the OCEAN phase 3 study, which evaluated the efficacy and safety of melfufen‐dexamethasone versus pomalidomide‐dexamethasone, as the study reported increased risk of death in the meflufan arm, and the study was terminated early. The investigators speculated that the poor OS in the melflufen group, among those with previous exposure to high‐dose melphalan (i.e., the autologous hematopoietic stem cell transplant subgroup), probably resulted from resistance to high‐dose alkylator therapy and an already compromised marrow reserve at study entry, making melflufen, with its attendant severe hematological toxicities, less tolerable 87,88 …”

The Role of Belantamab Mafodotin, Selinexor, and Melflufen in Multiple Myeloma

“…: Md ( n = 157) 5 (r. 2–12) 64, 97, 80 13% ref. to melphalan 14 29%, 1% 4.2 (95% CI 3.4–4.9) Median time to ≥ PR: 1.9 (r. 1–7.4) OCEAN [ 2 ] Prior exposure: I: Md ( n = 249) C: Pd ( n = 249) I: 3 (IQR 2–3) C: 3 (IQR 2–3) I: 66, 100, 20 C: 65, 100, 16 I: 19.8 C: 18.6 I: 33%, 3% C: 27%, 1% I: 6.8 (95% CI 5.0–8.5) C: 4.9 (95% CI 4.2–5.7) I: 2.1 (IQR 1.1–3.7) C: 2.0 (IQR 1.1–2.9) Selinexor STORM [ 3 ] Sd ( n = 122) 7 (range 3–18) Prior ref. : 100, 100, 100 - 26%, 2% 3.7 (95% CU 3–5.3) - STOMP [ 4 ] SVd ( n = 42) 3 (range 1–11) PI ref.…”