Alkylating agents have represented the first effective drug class in multiple myeloma (MM) but, since the introduction of novel effective drugs, their use has progressively decreased and is currently relegated to autologous stem cell transplant (ASCT) and few other settings. Nevertheless, the combination of melflufen (a peptide-drug conjugate pro-drug of melphalan) and dexamethasone was approved by the U.S. Food & Drug Administration (FDA) for triple-class refractory (TCR) patients after ≥ 4 prior lines of therapy (LOT) following results of HORIZON clinical trial (NCT02963493). This combination was subsequently withdrawn as it was not associated with improved overall survival (OS) as compared to pomalidomide-dexamethasone (OCEAN clinical trial, NCT03151811). However, since a post-hoc analysis showed a benefit in OS for patients without prior ASCT or with a time to progression (TTP) > 36 months after ASCT, the European Medicines Agency (EMA) has approved melflufen-dexamethasone for TCR patients after ≥ 3 LOT, including specification that TTP must be ≥ 3 years in patients with prior ASCT. In this paper, we report three cases of patients receiving the combination melflufen-dexamethasone in the aforementioned clinical trials in three hematologic centers across Europe and achieving exceptionally long responses as compared to the overall enrolled populations, with good tolerability. Further, we discuss the potential use of this chemotherapy-based regimen in the era of novel immunotherapies.

Charles University Hospital and Faculty of Medicine Hradec Kralove Czech Republic

Dipartimento di Scienze Mediche e Chirurgiche Università di Bologna Via Massarenti 9 40138 Bologna Italy

Hematology Clinic and BMT Unit Evangelismos Hospital Athens Greece

IRCCS Azienda Ospedaliero Universitaria di Bologna Istituto di Ematologia Seràgnoli Bologna Italy

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