Melflufen (melphalan flufenamide)

P2, N=30, Not yet recruiting, Fondazione EMN Italy Onlus

P3, N=495, Terminated, Oncopeptides AB | Completed --> Terminated; Sponsor assessed all endpoints and collected Overall Survival data for another two years following the primary completion date of 03Feb2021.

Finally, we observed proliferation of CD34+CD38- progenitor cells, which might be relevant for lymphocyte proliferation and function, and additionally supporting potential modulating effect. Further analyses are being done to validate these findings.

We review common toxicities associated with agents approved for RRMM in the past 5 years, including the anti-CD38 monoclonal antibody isatuximab, the antibody-drug conjugate belantamab mafodotin, the bispecific antibody teclistamab, the chimeric antigen receptor (CAR) T cell products idecabtagene vicleucel and ciltacabtagene autoleucel, the selective inhibitor of nuclear export compound selinexor, and the drug-peptide conjugate melflufen, as well as toxicities associated with emerging agents for RRMM including additional bispecific antibodies, the BCL-2 inhibitor venetoclax, and the cereblon E3 ligase modulators iberdomide and mezigdomide. We searched the published literature using PubMed, plus congress abstracts, for the above list of drug names or classes and 'myeloma.' Optimal management of toxicities associated with these recently approved and emerging therapies will be critical in maximizing clinical benefit and aiding widespread adoption in routine clinical practice. We summarize current recommendations and guidelines and provide expert insights into supportive care requirements.

Clearance increased and C decreased with increasing body weight and eGFR. In conclusion, melflufen administration differs from melphalan administration by a more rapid distribution into cells which in conjunction with a rapid intracellular metabolism allows for higher peak concentrations of alkylating agents, and by a more extensive distribution of melphalan to peripheral tissues.

Notably, in the bortezomib arm, ORR was 78% and median PFS was 14.7 months. Considering the totality of the data, melflufen 30 mg was established as the recommended dose for use with dexamethasone and daratumumab or bortezomib for future studies in RRMM.

The most common grade ≥3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% versus 12%), thrombocytopenia (50% versus 8%), and anemia (32% versus 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies.

These analyses demonstrate a consistent benefit for melflufen and dexamethasone in patients with relapsed/refractory multiple myeloma who have not received an ASCT or progressed >36 months after receiving an ASCT (ClinicalTrials.gov identifier: NCT03151811).

P3, N=495, Completed, Oncopeptides AB | Active, not recruiting --> Completed | Trial completion date: Sep 2024 --> Feb 2023

From the 1960s to the early 2000s, alkylating agents (e.g., melphalan, cyclophosphamide, and bendamustine) remained a key component of standard therapy for newly-diagnosed or relapsed/refractory multiple myeloma (MM). Meanwhile, new alkylating agents (e.g., melflufen) and new applications of old alkylators (e.g., lymphodepletion before chimeric antigen receptor T-cell [CAR-T] therapy) have emerged in recent years. Given the expanding use of antigen-directed modalities (e.g., monoclonal antibodies, bispecific antibodies, and CAR-T therapy), this review explores the current and future role of alkylating agents in different treatment settings (e.g., induction, consolidation, stem cell mobilization, pre-transplant conditioning, salvage, bridging, and lymphodepleting chemotherapy) to ellucidate the role of alkylator-based regimens in modern-day MM management.

We demonstrate that meflufen is highly effective at inducing cell death of plasma cells ex vivo, particularly in samples from RRMM patients. Importantly, melflufen was active in samples from patients with high-risk features such as del17p, 1q gain and TP53 mutation. Associated with this was a decrease in the p53 pathway and increasein other DNA damage repair genes.

Melflufen plus Vd or Dd showed encouraging activity in RRMM with ≥2 prior LoTs. Combined safety and efficacy analyses determined that melflufen 30 mg should be the recommended dose in triplet regimens.

Our preclinical study showed that melflufen is a more potent anti-myeloma (MM) agent than melphalan, overcomes drug-resistance, and induces synergistic anti-MM activity in combination with bortezomib, lenalidomide, or dexamethasone (Chauhan et al, Clinical Cancer Res 2013;19:3019 )...Here, we utilized our coculture models of pDCs, T-, and NK cells with autologous patient MM cells to examine whether a combination of melflufen and immune checkpoint inhibitor anti-PD-L1 Ab, or daratumumab (anti-CD38 Ab), restores anti-MM immunity...Moreover, combined melflufen and anti-CD38 Abs modestly enhance pDC-induced NK cell-mediated MM-specific cytolytic activity. Our preclinical data suggest targeting PD-L1 in combination with melflufen as well as support an ongoing clinical trial of melflufen with anti-CD38 Abs to enhance anti-MM immunity.

The primary endpoint for Ph2 is the hematologic overall response rate after 4 cycles of treatment. Secondary endpoints include pharmacokinetics (Ph1), best hematologic response, organ system responses, duration of hematologic response and organ system responses, time to next AL amyloidosis treatment, and overall survival.

Melflufen, a substrate of aminopeptidase B, efficiently eliminates bortezomib-resistant myeloma cells in vitro and in vivo, and completely suppresses clonogenic myeloma growth in vitro at subphysiological concentrations. Thus, melflufen represents a novel treatment option that is able to eradicate drug-resistant myeloma clones characterized by elevated aminopeptidase B expression.

Conclusion In summary, melflufen demonstrates high efficacy in venetoclax and ara-C resistant AML models in vitro. In addition, abundant expression of aminopeptidases in the AML patient samples provides rational for further clinical evaluation of melflufen in the RR AML setting.

Melflufen is a novel alkylator based peptide-drug conjugate (PDC) with DNA damaging effect but has also been described to have anti-angiogenic properties...In summary, although agents exclusively targeting the microenvironment in MM have not been very successful to date in monotherapy, many of the novel anti-MM agents that are currently under evaluation play also a role on the MM microenvironment, which contributes to their efficacy. Finding the best combination of agents targeting the myeloma, stromal, immune and bone compartments is one of the challenges facing the treatment of heavily-pretreated patients.

Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class-refractory and extramedullary disease.

2019;102:389), and outcomes are considerably worse than those for pts without EMD; for example, a recent analysis of isatuximab + pomalidomide + dex showed a median progression free survival (PFS) of 4.6 mo vs 11.5 mo in the total population (Beksac et al...Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents into tumor cells...To date, this clinical study provides the largest cohort of pts with EMD demonstrating benefit in this population with a high unmet medical need. These data support further evaluation of melflufen + dex in RRMM with EMD.

Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents into tumor cells...Methods : Patients with RRMM had received ≥2 lines of prior therapy, including an IMiD and a proteasome inhibitor, and were refractory to pomalidomide and/or an anti-CD38 monoclonal antibody...The safety profile of melflufen plus dex in patients with HR cytogenetics was consistent with that of the overall population. Taken together, these data support further evaluation of melflufen plus dex in RRMM with HR cytogenetics.

Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents into tumor cells. The activity of melflufen plus dex was shown in heavily pretreated RRMM pts refractory to pomalidomide and/or anti-CD38 monoclonal antibody (mAb) therapy in the phase 2 HORIZON study (OP-106; overall response rate [ORR], 29%; median progression-free survival [PFS], 4.2 months; median overall survival, 11.6 months), with acceptable safety (Richardson et al... Melflufen plus dex as a triplet regimen with BTZ or dara has encouraging activity in heavily pretreated RRMM with poor prognostic factors and was well tolerated. Analysis of the dara arm in more pts with longer follow-up suggests consistent responses with continued therapy.

Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents into tumor cells...Methods : Pts with RRMM who had received ≥2 lines of prior therapy, including an IMiD and a proteasome inhibitor and were refractory to pomalidomide and/or an anti-CD38 monoclonal antibody were treated with melflufen and dex as described (Richardson et al... Within this heavily pretreated pt population, most TRAEs could be managed without the need for hospitalization. Hematologic AEs were common but led to few hospitalizations overall. Although 11 cases (78.6%) of TRAEs of pneumonia required hospitalization, these events represent only 0.41% of all TRAEs, and infections are normally expected in advanced RRMM (Blimark et al.

Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents into tumor cells...Methods : Patients with RRMM must have received ≥2 prior lines of therapy, including an IMiD and a proteasome inhibitor, and been refractory to pomalidomide and/or an anti-CD38 monoclonal antibody... Melflufen, once monthly infusion, plus weekly dex demonstrated clinically meaningful efficacy and a manageable safety profile in older patients with heavily pretreated RRMM. In patients aged ≥75 years, treatment resulted in durable responses, with a safety profile consistent with that in previous reports. Further study is warranted to confirm these results suggesting that melflufen may be an efficacious, convenient, and tolerable therapy for elderly patients with RRMM who have limited treatment options.

Background: Melflufen (melphalan flufenamide) is a first-in-class peptide-drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents into tumor cells. Also, elimination of immunosuppressive osteoclasts by melflufen may provide a synergistic effect between melflufen and immunotherapy while treating MM patients. This hypothesis is currently being tested in clinical trials.

A panel of myeloma drugs consisting of carfilzomib, bortezomib, melflufen (melphalan flufenamide), melphalan, bendamustine, pomalidomide, iberdomide, panobinostat, doxorubicin, daunorubicin, vincristine, and paclitaxel was investigated in cytotoxicity assays using ABCB1+ and ABCB1- isogenic sublines of carfilzomib-adapted derivative of AMO-1. Moreover, elevated ABCB1 mRNA expression was associated with shorter PFS and OS in patients with multiple myeloma. Thus, this study may propose a novel therapy strategy including a novel lipophilic peptide-drug conjugate melflufen for myeloma patients with elevated ABCB1 which may potentially develop in carfilzomib-relapsed/refractory setting or EMD.

Methods : Pts with RRMM had received ≥2 prior lines, including an IMiD and PI, and were refractory to pomalidomide and/or an anti-CD38 mAb. Melflufen has a distinct mechanism of action from that of melphalan and other alkylators and in combination with dex showed efficacy in pts with disease refractory to prior alkylator therapy with a manageable safety profile. These results are consistent with those of previous preclinical and clinical studies.

Results : Using the My-DST approach with 48 hour drug treatments, melflufen significantly decreased the viable MPC populations, whereas melphalan had little effect (Fig 1A)... Overall, these data support that the peptide-drug-conjugate melflufen shows a broad efficacy across samples from patients with plasma cell disorders. Patients facing poor prognoses, including those with PCL, high-risk cytogenetics and daratumumab-refractory disease, have a great need for new treatments. Thus, the encouraging ex vivo results with melflufen in samples from these aggressive subsets support further clinical exploration.

Melphalan flufenamide (hereinafter referred to as "melflufen") is a peptide-conjugated drug currently in phase 3 trials for the treatment of relapsed or refractory multiple myeloma...Compared to the commonly used anti-cancer drug doxorubicin, melflufen was significantly more effective in reducing cell viability in vitro while it showed comparable effects in vivo...Knockdown of LAP3 and DPP7 aminopeptidases led to similar efficacy reduction, suggesting that also other aminopeptidases may facilitate melflufen conversion. In summary, we have shown that melflufen is a highly efficient anti-neoplastic agent in breast cancer cell lines and its efficacy is facilitated by aminopeptidases.

Methods Efficacy of melflufen versus melphalan was tested in the AMO-1 cell line, which displays biallelic wildtype TP53 and retains aspects of a functional p53 system, and AMO-1 clones with either complete loss of p53 or expressing point-mutated p53 protein (R282W hotspot mutation), created using the CRISPR/Cas9 system and modified via Sleeping Beauty vectors. It demonstrates better ex vivo efficacy in MM patient derived plasma cells harboring del17p or TP53 mutations. Melflufen response rates in the del17p

Melflufen (melphalan flufenamide) is a novel peptide-drug conjugate that rapidly delivers an alkylating payload into tumor cells...2019;37(suppl, abstr):8043). Further trials for melflufen are ongoing, including the phase 3 OCEAN study (NCT03151811) of melflufen + dex (vs pomalidomide + dex) in patients with RRMM who are refractory to lenalidomide.

Methods Efficacy of melflufen versus melphalan was tested in the AMO-1 cell line, which displays biallelic wild-type TP53 and retains aspects of a functional p53 system, and AMO-1 clones with either complete loss of p53 or expressing point-mutated p53 protein (R282W hotspot mutation)...We also assessed response rates in a subpopulation of patients with confirmed del17p from OP-106 HORIZON, an ongoing phase 2 study evaluating the efficacy of melflufen plus dexamethasone in patients with RRMM (NCT02963493)...Melflufen response rates in the del17p patient subpopulation are comparable to the general patient population comprising RRMM exposed to IMiD- and proteasome inhibitors and resistant to daratumumab- and/or pomalidomide-based salvage therapies. Collectively, these data suggest that melflufen might provide a valuable therapeutic option for this difficult-to-treat patient group.

Pts with RRMM who had received ≥2 prior lines of therapy, including an IMiD and a proteasome inhibitor (PI), and were refractory to pomalidomide and/or an anti-CD38 monoclonal antibody (mAb), received melflufen 40 mg (IV on d1 of each 28-d cycle) + dex 40 mg/wk until disease progression or unacceptable toxicity... TTNT in HORIZON (median 5 prior lines) was consistent with previous reports of TTNT in pts with RRMM who received melflufen + dex or other therapies (median 2-4 prior lines) (Bringhen et al. J Clin Oncol. 2019.

Melflufen continues to show promising activity (ORR, 28%) in patients with late-stage RRMM refractory to dara and/or pom and was generally well tolerated, with infrequent nonhematologic AEs and, of the 121 patients treated, 14% discontinued due to AEs. Additionally, melflufen has comparable efficacy in subsets of patients with poor-risk features, including triple-class refractory and high-risk cytogenetics, relative to the overall HORIZON patient population. Melflufen plus dex is being further investigated vs pom plus dex in the OCEAN phase 3 study (OP-103; NCT03151811) in patients with RRMM refractory to lenalidomide.