Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Oncopeptides AB (publ), Luntmakargatan 46, 111 37 Stockholm, Sweden
Pharmacotherapeutic group: antineoplastic agents, nitrogen mustard analogues
ATC code: L01AA10
Melphalan flufenamide is a peptide conjugated alkylating drug. The drug is composed of a di-peptide and an alkylating moiety of the nitrogen mustard analogues group. The lipophilic intact peptide conjugate is rapidly distributed via passive transport into cells where it is bound to and catalysed by esterases and peptidases to the metabolite melphalan. Similar to other nitrogen mustard drugs, crosslinking of DNA is involved in the antitumor activity of melphalan flufenamide. In cellular assays, melphalan flufenamide inhibited proliferation and induced apoptosis of haematopoietic tumour cells. Retained cytotoxic activity was demonstrated in multiple myeloma cells with absent or impaired p53 functionality. Melphalan flufenamide showed synergistic cytotoxicity with dexamethasone in melphalan resistant and non-resistant multiple myeloma cell lines.
At the approved dose, melphalan flufenamide does not affect the ECG parameters PR interval, QRS interval, or QTc interval to any clinically relevant extent.
The efficacy and safety of melphalan flufenamide in combination with dexamethasone were evaluated in HORIZON, a multicentre, single-arm study in 157 patients with relapsed-refractory multiple myeloma (RRMM). A total of 157 patients received melphalan flufenamide 40 mg on Day 1 and dexamethasone 40 mg (20 mg for patients ≥ 75 years of age) on Day 1, 8, 15 and 22 of each 28 day cycle. Patients were treated until disease progression or unacceptable toxicity. 110 of the patients had multiple myeloma that was refractory to at least one proteasome inhibitor, at least one immunomodulatory agent and an anti-CD38 monoclonal antibody, i.e. were triple-class refractory (TCR) and had received at least 3 prior lines of therapies. Primary refractory patients were excluded from the study.
The median duration of melphalan flufenamide treatment in the TCR patient population (n=110) was 3.0 months (range 1.0 to 28.0 months).
Out of the 110 ≥3rd line TCR patients in the HORIZON study, 52 patients had no ASCT or progressed more than 36 months after an ASCT and 58 patients had progressed within 36 months from an ASCT. The disease characteristics and efficacy results in TCR patients who have received at least 3 prior lines of therapies and who had no ASCT or progressed more than 36 months after an ASCT are summarised in Table 4 and Table 5.
The major efficacy outcome measure was overall response rate (ORR) assessed according to the IMWG criteria by investigators.
Table 4. Disease characteristics in triple-class refractory patients who have received at least 3 prior lines of therapies and who had no ASCT or progressed more than 36 months after an ASCT in HORIZON study:
| Parameter | HORIZON study (n=52) |
|---|---|
| Median years from diagnosis to start of study treatment (range) | 7.4 (0.7-24.6) |
| Prior treatment regimens, median (range) | 5 (3-10) |
| Age, median (range) | 70 (42-86) |
| Patients ˂65 years of age, n (%) | 18 (35%) |
| Patients 65-74 years of age, n (%) | 18 (35%) |
| Patients ≥75 years of age, n (%) | 16 (31%) |
| Documented refractory status, n (%) | |
| Lenalidomide | 47 (90%) |
| Pomalidomide | 49 (94%) |
| Bortezomib | 37 (71%) |
| Carfilzomib | 26 (50%) |
| Daratumumab | 49 (94%) |
| Alkylator refractory | 32 (62%) |
| Melphalan exposed | 30 (58%) |
| Melphalan refractory | 11 (21%) |
| Previous stem cell transplant, n (%) | 19 (37%) |
| ECOG at baseline, n (%) | |
| 0/1 | 9 (17%)/34 (65%) |
| 2/3 | 8 (15%)/1 (2%) |
| International Staging System at Baseline, n (%) | |
| I | 15 (29%) |
| II | 15 (29%) |
| III | 19 (37%) |
| Missing/Unknown | 3 (6%) |
| High-risk cytogeneticsa, n (%) | 21 (40%) |
| Extramedullary disease (EMD), n (%) | 22 (42%) |
a del(17p), t(4;14), t(14;16), gain (1q) and t(14;20)
Table 5. Efficacy results for triple-class refractory patients who have received at least 3 prior lines of therapies and who had no ASCT or progressed more than 36 months after an ASCT in HORIZON study:
| HORIZON study, n=52 | |
|---|---|
| Response | Assessed by investigator |
| Overall response rate (ORR)a, 95% CI (%) | 28.8% (17.1%, 43.1%) |
| Stringent complete response (sCR) | 0 |
| Complete response (CR) | 0 |
| Very good partial response (VGPR) | 5 (9.6%) |
| Partial response (PR) | 10 (19.2%) |
| Duration of response (DOR) | |
| Median, 95% CI (months) | 7.6 (3.0-12.3) |
| Time to response, median range (months) | 2.3 (1.0-10.5) |
a Includes sCR + CR + VGPR + PR.
The European Medicines Agency has waived the obligation to submit the results of studies with Pepaxti in all subsets of the paediatric population in the treatment of multiple myeloma (see section 4.2 for information on paediatric use).
Following Pepaxti 40 mg, melphalan flufenamide peak plasma concentrations of an average 159 ng/mL (CV% 39) were reached during the 30-minute infusion. Peak plasma concentrations of the active metabolite melphalan were reached 4 to 15 minutes after the end of infusion of Pepaxti 40 mg. Following Pepaxti 40 mg, the mean (CV%) Cmax was 432 ng/mL (30%) and AUC0-INF was 873 ng/mL·hr (28%) for the metabolite melphalan after a single dose. The mean (CV%) Cmax was 419 ng/mL (33%) and AUC0-INF was 815 ng/mL·hr (29%) for the metabolite melphalan at steadystate. Comparison of PK parameters of the metabolite melphalan showed that the 90% CI for the adjusted geometric mean ratio for peripheral and central intravenous infusion was within 0.8 and 1.25 for Cmax, AUC(0-t), and AUC(0-∞), which concludes bioequivalence for peripheral and central venous infusion of melphalan flufenamide.
Melphalan flufenamide and the metabolite melphalan AUC increases in an approximately dose proportional manner over the dose range 25 to 130 mg.
In vivo the disappearance of melphalan flufenamide from plasma is rapid and is attributed to distribution to peripheral tissues.
The mean (CV%) volume of distribution was 35 L (71%) for melphalan flufenamide and the mean apparent volume of distribution is 76 L (32%) for the metabolite melphalan after a single dose of melphalan flufenamide.
Melphalan flufenamide is metabolised in tissues into the metabolite desethyl-melphalan flufenamide and into the metabolite melphalan. There is no appreciable metabolism of melphalan flufenamide to the metabolite melphalan in plasma. Melphalan is metabolised primarily by spontaneous hydrolysis to monohydroxy-melphalan and dihydroxy-melphalan.
After the end of infusion of Pepaxti 40 mg, the mean (CV%) elimination half-life of melphalan flufenamide is 2.1 minutes (34%). The mean (CV%) elimination half-life of the metabolite melphalan is 70 minutes (21%). The mean (CV%) clearance of melphalan flufenamide and the metabolite melphalan is 692 L/hr (49%) and 23 L/hr (23%), respectively, at the recommended dose of Pepaxti 40 mg.
Renal and hepatic excretion of unchanged melphalan flufenamide is assessed to be negligible as total plasma clearance of melphalan flufenamide greatly exceeds renal glomerular filtration rate (GFR) and hepatic blood flow.
Based on population PK analysis, no differences in the pharmacokinetics of the metabolite melphalan were observed based on age or gender.
The melphalan flufenamide metabolite melphalan is partially cleared through renal excretion. In melphalan flufenamide treated patients in study OP-103 58 patients had normal renal function, 103 patients had mild renal impairment and 117 patients had moderate renal impairment.
Based on population PK analysis melphalan AUC was on average 6% higher in mild impairment, 18% higher in patients with moderate renal impairment with eGFR 45-60 mL/min/1.73 m² and 32% higher in patients with moderate renal impairment with eGFR 30-45 mL/min/1.73 m² compared to patients with normal renal function. A larger effect of Pepaxti on thrombocyte levels was observed in patients with a lower eGFR. A Pepaxti dose of 30 mg is recommended in patients with eGFR 30-45 mL/min/1.73 m². There are insufficient data in patients with eGFR below 30 mL/min/1.73 m² to support a dose recommendation.
No differences in the PK of the metabolite melphalan were observed in patients with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to 1.5 × ULN and any AST). The effect of moderate to severe hepatic impairment (total bilirubin > 1.5 × ULN and any AST) on PK is not known.
Higher exposures of the metabolite melphalan were observed in patients with lower body weight. At a body weight of 60 kg Cmax was on average 36% higher and AUC on average 31% higher compared to a body weight of 95 kg. Higher incidence of thrombocytopenia and neutropenia was observed in patients with lower body weight. A Pepaxti dose of 30 mg is recommended in patients with a body weight of 60 kg or less
Pepaxti is genotoxic. Mechanistic in vitro studies showed that melphalan flufenamide caused irreversible DNA damage.
No carcinogenicity or mutagenicity studies have been conducted with melphalan flufenamide.
In repeated dose toxicology studies, melphalan flufenamide was administered intravenously to rats at 20, 40, or 55 mg/m², and to dogs at 0.45 or 0.90 mg/kg (9 or 18 mg/m²) every 21 days for two or three doses. Decreased testes weights and depletion of germ cells were observed in both species, and epididymal oligospermia was observed in dogs. Adverse effects on male reproductive organs were observed in dogs at exposures below the recommended clinical dose of 40 mg. The reversibility of adverse effects on male reproductive organs was not assessed.
Reproduction toxicity studies have not been conducted with melphalan flufenamide. The melphalan flufenamide metabolite melphalan was teratogenic in rats after single dose exposure. In repeated dose reproductive toxicity studies, melphalan exposure resulted in maternal toxicity and induced congenital malformations. In a study in mice, a reduction in number of pups per litter was observed.
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