Melflufen plus dexamethasone for relapsed/refractory multiple myeloma — results from a phase I/II study

Melphalan flufenamide (melflufen) is a first-in-class, peptide–drug conjugate that induces irreversible DNA damage in multiple myeloma (MM) cells.^1,2 The alkylating activity of melflufen is initiated by aminopeptidases, which are often overexpressed by MM cells. Melflufen demonstrates favorable selectivity and is highly penetrative of MM cells as a result of its high lipophilicity.³

Promising early efficacy has been reported in a number of ongoing clinical trials investigating melflufen for the treatment of relapsed and/or refractory MM (RRMM).³ The MM Hub previously covered the results from the phase II HORIZON (OP-106) trial (NCT02963493), which explored the safety and efficacy of melflufen in combination with dexamethasone (dex) in patients with RRMM. The results from the primary analysis of an open-label, multicentre, international, phase I–II study (O-12-M1; NCT01897714), investigating melflufen both with or without dex for the treatment of patients with RRMM, have since been published by Paul Richardson and colleagues — below is a summary.³

Study design

Patient eligibility

• Adult patients with RRMM (N = 75) following treatment with ≥ 2 lines of prior therapy, including an immunomodulatory drug (lenalidomide) and a proteasome inhibitor (bortezomib), were enrolled
• Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, adequate organ function, progression to most recent anti-myeloma therapy, and measurable disease defined as ≥ 1 of
  • serum monoclonal protein ≥ 0.5 g/dL
  • urine monoclonal protein ≥ 200 mg/24 hours
  • serum immunoglobulin free light chain (FLC) ≥ 10 mg/dL and abnormal kappa/lambda FLC ratio
• Eligible patients were assigned to the phase I (n = 23) and/or phase II (n = 58) portion of the study and received treatment with melflufen ± dex in 21-day cycles* as per the dosing schedules illustrated in Table 1
  • Melflufen was administered as an intravenous infusion for 30 minutes on Day 1 of each cycle
    • Dose reductions were permitted after Cycle 1 in phase I and in any cycle of phase II, to a minimum of 15 mg
  • Dex (40 mg) was given orally, weekly
    • Patients unable to tolerate dex discontinued dex and could remain on single-agent melflufen at the discretion of the investigator
  • Patients were treated at three sites in the United States of America and one site in each of Italy, Denmark, Sweden, and the Netherlands

*On May 28, 2015, the cycle length in phase II was increased to 28 days

Phase I

• Primary objective: establish the maximum tolerated dose (MTD) of melflufen when combined with dex
• Secondary objective: define any dose-limiting toxicities (DLT)

 Phase II

• Primary objective: evaluate the overall response rate (ORR) and clinical benefit rate (CBR) to melflufen ± dex at the MTD determined in phase I
• Secondary objectives:
  • determine complete response (CR), stringent CR (sCR), partial response (PR), very good PR (VGPR), time to progression, duration of response, progression-free survival (PFS) and overall survival (OS)
  • assess the safety and tolerability of melflufen ± dex at the MTD
• This primary analysis was conducted in
  • all-treated patients
  • efficacy evaluable population (patients who received ≥ 2 doses of melflufen with a response assessment at baseline)

Results

Patient characteristics

• Data collection cutoff: November 9, 2017
• Baseline patient characteristics according to melflufen dosing schedules across the phase I and phase II studies are presented in Table 1

Table 1. Patient characteristics by treatment regimen³

Phase I

• MTD: 40 mg melflufen on Day 1 plus 40 mg oral dex weekly
• DLTs
• No DLTs were recorded in the 15 mg, 25 mg, or 40 mg melflufen cohorts
• Four patients in the 55 mg cohort experienced DLTs in their first treatment cycle; Grade 4 neutropenia occurred in in all four patients, with Grade 4 thrombocytopenia also reported in three of these patients
• Due to the DLTs reported at 55 mg, the planned dose of 70 mg was not tested
• Twenty-one patients discontinued, predominantly due to disease progression (52%) and adverse events (35%)
• All patients experienced AEs and ≥ 50% of patients in each cohort developed Grade ≥ 3 AEs (Table 2)
• A proportion of patients discontinued treatment due to treatment-emergent AEs (TEAEs), and serious TEAEs were observed in both treatment cohorts (Table 2)
• One death, due to fatal bacteremia (Cycle 2, Day 28), that occurred in a patient in the 25 mg cohort was considered to be related to study treatment

Table 2. Grade ≥ 3 AEs and TEAEs by treatment regimen³

Phase II

• Patient responses to melflufen ± dex are presented in Table 3
  • Six of the 45 patients receiving melflufen + dex were from the phase I portion
  • In the combination arm, 62% started the treatment with 21-day cycles
• The majority of patients in the combination (n = 34; 76%) and single (n = 11; 85%) cohorts received ≥ 2 doses of melflufen, constituting the efficacy evaluable population
  • ORR: 41% (14/34)
  • CBR: 65% (22/34)
• Patient responses in the efficacy evaluable combination cohort were superior to those in the all-treated population (Table 3)
• The most common reasons for treatment discontinuation in single vs combination cohorts were AEs (40% vs 23%) and disease progression (29% vs 31%)
• Enrollment in the single agent cohort was stopped early, with patients in this cohort allowed to receive 40 mg of dex at the discretion of the investigator

 Table 3. Patient responses to melflufen ± dex and treatment cohort characteristics³

 Adverse events

• Twenty-four serious TEAEs were reported in 38% of patients in the combination cohort (Table 4)
• Out of four deaths occurring in the combination cohort, two were considered to be melflufen-related and occurred after the first dose:
  • one due to neutropenic sepsis and one due to Escherichia coli sepsis
  • both occurred in the setting of disease progression
• Treatment cycle length influenced the establishment of Grade 4 thrombocytopenia
  • ≥ 1 event occurred in 32% of patients on a 21-day schedule vs none in the patients on a 28-day schedule

 Table 4. Grade ≥ 3 AEs and TEAEs by treatment regimen³

 Conclusion

• The study identified a melflufen treatment regimen that was well tolerated in patients with RRMM: 40 mg melflufen on Day 1 of a 28-day cycle plus 40 mg oral dex weekly
• The study suggests that clinical improvement and long-term benefit is achievable with melflufen plus weekly dex for patients with RRMM
• The safety profile of melflufen was consistent with previous studies and no additional toxicities were reported
  • The most commonly observed toxicities were reversible and clinically manageable thrombocytopenia and neutropenia
• Melflufen plus dex may be a viable approach for patients with RRMM who do not have alternative treatment options