Through an observational clinical study, partly prospective and partly retrospective, based on the collection of clinical data and on in vitro experimental analyses carried out on residual biological samples obtained during routine clinical procedures, it is proposed to identify predictive biomarkers of in vivo response to first-line therapies.
Study Type
OBSERVATIONAL
Enrollment
250
Fondazione IRCCS Policlinico San Matteo
Pavia, Lombardy, Italy
Identification of predictive biomarkers of response to proteasome inhibitor-based first-line therapy in AL amyloidosis
To identify and validate biological, genetic, and proteomic biomarkers predictive of in vivo response to proteasome inhibitor-based first-line therapies in patients with AL amyloidosis. This will be achieved through the integration of ex vivo drug sensitivity assays performed on patient-derived CD138+ plasma cells, characterization of plasma cell and mesenchymal stromal cell biological features, and retrospective and prospective molecular analyses. Biomarker profiles will be correlated with hematologic response at 6 months and used to develop a predictive statistical model of treatment response.
Time frame: From baseline (diagnosis) to 6 months after initiation of first-line therapy
Molecular characterization of mechanisms of resistance to proteasome inhibitors
To investigate the mutational, transcriptional, and proteomic profiles associated with in vivo resistance to proteasome inhibitors by comparing plasma cell clones at diagnosis and minimal residual disease (MRD). Analyses will include next-generation sequencing, targeted DNA sequencing of genes involved in proteostasis, and quantitative proteomics to identify molecular determinants of drug resistance.
Time frame: From baseline (diagnosis) to MRD assessment after achievement of complete hematologic response (approximately up to 12-24 months)
Evaluation of the therapeutic potential of deubiquitinating enzyme (DUB) inhibitors
To assess the ex vivo sensitivity of patient-derived amyloidogenic plasma cells to DUB inhibitors and to characterize the expression of DUB family members at RNA and protein level. The study will evaluate whether DUB inhibition can overcome resistance to proteasome inhibitors and identify candidate DUB inhibitors for therapeutic development.
Time frame: At baseline (sample collection at diagnosis) and during ex vivo experimental analyses
Role of mesenchymal stromal cells in modulating drug response
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To evaluate the contribution of patient-derived mesenchymal stromal cells to resistance against proteasome inhibitors by assessing their protective effect in co-culture systems with amyloidogenic plasma cells or cell lines.
Time frame: At baseline (sample collection at diagnosis) and during ex vivo experimental analyses