Melflufen well tolerated with encouraging activity in heavily pretreated R/R MM

In heavily pretreated patients with relapsed/refractory multiple myeloma (R/R MM) who were refractory to an immunomodulatory drug and/or a proteasome inhibitor and had poor prognostic factors, melflufen plus dexamethasone as a triplet regimen with either daratumumab or bortezomib was well tolerated. Both combinations demonstrated encouraging activity [1].

Patients with R/R MM often develop resistance to standard treatments, underscoring the need for novel therapies with new mechanisms of action. Melphalan flufenamide (melflufen) is an investigational first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly releases alkylating agents into tumour cells. In the phase 2 HORIZON study (OP-106; NCT02963493), the activity of melflufen plus dexamethasone was demonstrated in heavily pretreated R/R MM patients refractory to pomalidomide and/or anti-CD38 monoclonal antibody (mAb) therapy, with acceptable safety [2,3].

The approved agents daratumumab and bortezomib have non-overlapping mechanisms of action to melflufen, supporting the rationale for combining these agents to overcome therapy resistance. The phase 1/2 ANCHOR study (OP-104; NCT03481556) evaluated melflufen plus dexamethasone in combination with either daratumumab or bortezomib in R/R MM patients. Dr Enrique Ocio (University Hospital Marqués de Valdecilla, Spain) presented updated efficacy and safety of this combination therapy [1].

The safety profile of the triplet combination was similar as when used as a doublet (melflufen plus dexamethasone) [1-3]. Grade 3/4 treatment-related AEs were mostly haematologic and clinically manageable with dose reductions. No dose-limiting toxicities were observed across both regimens and melflufen dose levels. ORR was 73% in combination with daratumumab and 62% in combination with bortezomib. Median PFS was 12.9 months in combination with daratumumab.

Based on the safety and efficacy analyses of the daratumumab arm, melflufen should be recommended at a dose of 30 mg in future studies evaluating the combination with daratumumab. The bortezomib arm of ANCHOR is still recruiting, and the recommended phase 2 dose is yet to be determined.

1. Ocio EM, et al. ANCHOR (OP-104): Melflufen Plus Dexamethasone (dex) and Daratumumab (dara) or Bortezomib (BTZ) in Relapsed/Refractory Multiple Myeloma (RRMM) Refractory to an IMiD and/or a Proteasome Inhibitor (PI) - Updated Efficacy and Safety. 62^nd ASH Annual Meeting, 5-8 December 2020. Abstract 417.
2. Richardson PG, et al. HORIZON (OP-106): Melflufen Plus Dexamethasone in Relapsed/Refractory Multiple Myeloma (RRMM) Refractory to Pomalidomide and/or an Anti-CD38 Monoclonal Antibody (mAb) – Primary and Subgroup Analysis. EHA 2020, 11-21 June. Poster EP945.
3. Richardson PG, et al. Lancet Haematol. 2020;7:e395-e407.

Posted on 18 February 20214 September 2023