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Aminopeptidase Expression in Multiple Myeloma Associates with Disease Progression and Sensitivity to Melflufen.

ABSTRACT: Multiple myeloma (MM) is characterized by extensive immunoglobulin production leading to an excessive load on protein homeostasis in tumor cells. Aminopeptidases contribute to proteolysis by catalyzing the hydrolysis of amino acids from proteins or peptides and function downstream of the ubiquitin-proteasome pathway. Notably, aminopeptidases can be utilized in the delivery of antibody and peptide-conjugated drugs, such as melflufen, currently in clinical trials. We analyzed the expression of 39 aminopeptidase genes in MM samples from 122 patients treated at Finnish cancer centers and 892 patients from the CoMMpass database. Based on ranked abundance, LAP3, ERAP2, METAP2, TTP2, and DPP7 were highly expressed in MM. ERAP2, XPNPEP1, DPP3, RNPEP, and CTSV were differentially expressed between relapsed/refractory and newly diagnosed MM samples (p < 0.05). Sensitivity to melflufen was detected ex vivo in 11/15 MM patient samples, and high sensitivity was observed, especially in relapsed/refractory samples. Survival analysis revealed that high expression of XPNPEP1, RNPEP, DPP3, and BLMH (p < 0.05) was associated with shorter overall survival. Hydrolysis analysis demonstrated that melflufen is a substrate for aminopeptidases LAP3, LTA4H, RNPEP, and ANPEP. The sensitivity of MM cell lines to melflufen was reduced by aminopeptidase inhibitors. These results indicate critical roles of aminopeptidases in disease progression and the activity of melflufen in MM.

SUBMITTER: Miettinen JJ

PROVIDER: S-EPMC8036322 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Aminopeptidase Expression in Multiple Myeloma Associates with Disease Progression and Sensitivity to Melflufen.

Miettinen Juho J JJ Kumari Romika R Traustadottir Gunnhildur Asta GA Huppunen Maiju-Emilia ME Sergeev Philipp P Majumder Muntasir M MM Schepsky Alexander A Gudjonsson Thorarinn T Lievonen Juha J Bazou Despina D Dowling Paul P O Gorman Peter P Slipicevic Ana A Anttila Pekka P Silvennoinen Raija R Nupponen Nina N NN Lehmann Fredrik F Heckman Caroline A CA

Cancers 20210326 7

Multiple myeloma (MM) is characterized by extensive immunoglobulin production leading to an excessive load on protein homeostasis in tumor cells. Aminopeptidases contribute to proteolysis by catalyzing the hydrolysis of amino acids from proteins or peptides and function downstream of the ubiquitin-proteasome pathway. Notably, aminopeptidases can be utilized in the delivery of antibody and peptide-conjugated drugs, such as melflufen, currently in clinical trials. We analyzed the expression of 39 ...[more]

PMID: 33810334

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Project description:Purpose of reviewMultiple myeloma (MM) is a hematologic malignancy of plasma cells that remains incurable with currently available therapies including proteosome inhibitors, immunomodulators, monoclonal antibodies, corticosteroids, and alkylators, in addition to autologous stem cell transplantation in patients who are eligible. Novel therapeutics are therefore required to improve patient outcomes. The goal of this paper is to review the role of three new agents in the MM treatment landscape: belantamab mafodotin, selinexor, and melflufen.Recent findingsAll three agents have demonstrated clinical activity in patients with MM. Belamaf is the first FDA-approved anti-BCMA targeted agent, showing single-agent response rates of 60% and higher response rates of 48-100% in combinations. The majority of patients treated with belamaf experience corneal toxicity which remains the main challenge with its use; however, fortunately, the vast majority of patients recover. Selinexor is also FDA approved for the treatment of relapsed MM, with single-agent response rates of 26% and combination rates of 48-65%. Gastrointestinal side effects are common with selinexor use, with roughly 65% of patients experiencing nausea, 50% anorexia, 35% vomiting, and 42% diarrhea, the majority of which are grades 1-2. Both agents have a plethora of ongoing clinical trials with data forthcoming on various combinations with standard backbone agents as well as additional novel treatments. While melflufen showed promising initial data showing single-agent response rates of about 30%, inferior survival outcomes in patients previously treated with ASCT in the phase 3 OCEAN study lead to early termination of the trial and subsequent removal from the US market. Belamaf, selinexor, and melflufen are active agents to treat myeloma. Belamaf and selinexor are current options for the treatment of relapsed multiple myeloma with improved response rates and durability when used in triplet combinations. The optimal timing of use and treatment combinations of both agents in the context of additional immunotherapeutics entering the MM landscape requires further study. Many prospective studies are in development and promise to afford further clarity in the near future.

Project description:PurposeMelphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need.Patients and methodsPatients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing.ResultsOf 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class-refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class-refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4.ConclusionMelflufen 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.

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Aminopeptidase Expression in Multiple Myeloma Associates with Disease Progression and Sensitivity to Melflufen.

Publications

Aminopeptidase Expression in Multiple Myeloma Associates with Disease Progression and Sensitivity to Melflufen.

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