PORT (OP-109): Phase 2, randomised, Pharmacokinetic (PK), cross-over study of peripheral vs central intravenous administration of Melflufen in patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Background Melphalan flufenamide (melflufen) is a peptide–drug conjugate with unique PK properties that rapidly penetrates cells, where it is metabolised to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. Melflufen has only been administered via central venous catheter (CVC); however, peripheral venous catheter (PVC) administration may be preferred by patients if safety and tolerability are acceptable. The ongoing PORT study aims to assess the PK, safety, tolerability and efficacy of melflufen CVC vs PVC administration in patients with RRMM (NCT04412707). Methods Patients (following ≥2 lines of prior therapy) were randomised (1:1) to melflufen 40 mg (with oral dexamethasone 40 mg [20 mg for patients aged ≥75 years] weekly on Days 1, 8, 15 and 22) either via PVC in cycle 1 then CVC in cycle 2 (Arm A) or via CVC in cycle 1 and then PVC in cycle 2 (Arm B). From cycle 2 (Arm A) or cycle 3 (Arm B) onwards, patients received melflufen via CVC. PK sampling was performed frequently during and after the 30-minute melflufen infusion. Primary endpoints were maximum observed concentration (Cmax), area under the concentration–time profile from start of infusion to both last measurable concentration (AUC0–t) and to infinity (AUC0–inf) for melphalan, and frequency and severity of PVC-related local infusion-site reactions. Secondary endpoints included PK variables for melflufen and desethyl-melflufen and general safety and tolerability. PK parameters after CVC and PVC administration were compared using bioequivalence methods. Results At data cutoff (2 June 2021), 27 patients had received melflufen (median age 67 years; 48.1% male), of whom 19 patients received at least two doses and were evaluable for PK analysis. Melphalan Cmax, AUC0–t, and AUC0–inf were all bioequivalent for CVC and PVC administration, as demonstrated by a 90% confidence interval (CI) for the ratio of means within 80–125%. For melflufen, the ratio of means was 107–117% for the PK parameters, with all upper 90% CIs above 125%. For desethyl-melflufen, AUC0–t and AUC0–inf were bioequivalent and the 90% CI for Cmax was marginally above the upper limit (127%). Melflufen disappeared rapidly from plasma after the end of infusion, with an average half-life of 5–7 minutes. Melphalan Cmax was observed on average 7–9 minutes after the end of melflufen infusion for both routes of administration, which reflects the delay in distribution of melphalan from tissues to plasma. No PVC-related local reactions were reported. The overall melflufen safety profile was in line with previous studies. Conclusion Systemic melphalan exposure is similar after melflufen PVC and CVC administration. Differences between PVC- and CVC-related PK parameters for melflufen and desethyl-melflufen are considered to have no clinical consequences as their plasma-exposure duration is short. There were no local reactions after melflufen PVC administration.