A Study of Melphalan Flufenamide (Melflufen) Plus Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma

A Single Arm, Open-Label, Phase 2 Study of Melflufen in Combination With Dexamethasone in Patients With Relapsed Refractory Multiple Myeloma Who Are Refractory to Pomalidomide and/or an Anti-CD38 Monoclonal Antibody

This study will evaluate melflufen in combination with dexamethasone in adult patients with relapsed or refractory multiple myeloma in whose disease is refractory to pomalidomide and/or an anti-CD38 monoclonal antibody. All patients in the study will be treated with melflufen on Day 1 and dexamethasone on Days 1, 8, 15 and 22 of each 28-day cycle.

Melphalan flufenamide (melflufen) is a peptide-drug conjugate that rapidly delivers an alkylating payload into tumor cells. Peptidases are expressed in several cancers, including solid tumors and hematologic malignancies. Melphalan flufenamide is rapidly taken up by myeloma cells due to its high lipophilicity. Once inside the myeloma cell, the activity of melphalan flufenamide is determined by its immediate cleavage by peptidases into hydrophilic alkylator payloads that are entrapped. Melphalan flufenamide is 50-fold more potent than melphalan in myeloma cells in vitro due to increased intracellular alkylator concentration. It rapidly induces irreversible DNA damage leading to apoptosis of myeloma cells. Melphalan flufenamide displays cytotoxic activity against myeloma cell lines resistant to other treatments, including alkylators, in vitro. Melphalan flufenamide also has demonstrated inhibition of angiogenesis and DNA damage with a lack of functional DNA repair in preclinical studies.

Inclusion Criteria:

• Male or female, age 18 years or older
• A prior diagnosis of multiple myeloma with documented disease progression
• Measurable disease based on either of a) serum monoclonal protein by protein electrophoresis (SPEP), b) monoclonal protein in the urine on 24-hour urine electrophoresis (UPEP), and/or c) serum immunoglobulin free light chain combined with abnormal serum immunoglobulin kappa to lambda free light chain ratio
• A minimum of 2 prior lines of therapy including an IMiD and a PI and is refractory to pomalidomide and/or daratumumab
• Life expectancy of ≥ 6 months
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Female of child bearing potential (FCBP) and non-vasectomized male agree to practice appropriate methods of birth control
• Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information
• 12-lead ECG with QTc interval within defined limit
• Acceptable laboratory results during screening and prior to first study drug administration of the following parameters: absolute neutrophil count (ANC), platelet count, hemoglobin, total bilirubin, aspartate transaminase (AST/SGOT) and alanine transaminase (ALT/SGPT), renal function based on estimated creatinine clearance
• Must have, or accept to have, an acceptable central catheter for infusion of melflufen

Exclusion Criteria:

• Evidence of mucosal or internal bleeding and/or is platelet transfusion refractory
• Any medical conditions that, in the Investigator's opinion, would impose excessive risk to the patient or would adversely affect his/her participating in this study
• Known active infection requiring parenteral or oral anti-infective treatment within defined period
• Primary refractory disease
• Other malignancy diagnosed or requiring treatment within the defined period with specific exceptions
• Pregnant or breast-feeding females
• Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance or follow-up evaluation
• Known HIV or active hepatitis B or C viral infection
• Concurrent symptomatic amyloidosis or plasma cell leukemia
• POEMS syndrome [plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M-protein) and skin changes]
• Previous cytotoxic therapies, including cytotoxic investigational agents, for multiple myeloma within defined values prior to start of study treatment
• Residual side effects to previous therapy over specific grade prior to initiation of therapy
• Prior autologous or allogeneic stem cell transplant within defined period of initiation of therapy
• Prior allogeneic stem cell transplant with active graft-versus-host- disease (GVHD).
• Prior major surgical procedure or radiation therapy within specified period of the first dose of study treatment (with defined exception).
• Known intolerance to steroid therapy