AL Amyloidosis
Conditions
Brief summary
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.
Interventions
None listed
Sponsors
Fondazione IRCCS Policlinico San Matteo di Pavia
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* Biopsy-proven systemic AL amyloidosis * No IgM clone * No history of anti-plasma cell therapy * Diagnostic bone marrow aspiration at ARTC * Age \> 18 years * Willingness to allow use of clinical data and diagnostic leftovers of clinical specimens for research purposes through signing a written informed consent.
Exclusion criteria
* Non-AL amyloidosis * IgM clone * Previous anti-plasma cell therapy * Age \<18 years * Failure to show willingness to allow use of clinical data and diagnostic leftovers of clinical specimens for research purposes.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Identification of predictive biomarkers of response to proteasome inhibitor-based first-line therapy in AL amyloidosis | From baseline (diagnosis) to 6 months after initiation of first-line therapy | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Molecular characterization of mechanisms of resistance to proteasome inhibitors | From baseline (diagnosis) to MRD assessment after achievement of complete hematologic response (approximately up to 12-24 months) | 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. |
| Evaluation of the therapeutic potential of deubiquitinating enzyme (DUB) inhibitors | At baseline (sample collection at diagnosis) and during ex vivo experimental analyses | 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. |
| Role of mesenchymal stromal cells in modulating drug response | At baseline (sample collection at diagnosis) and during ex vivo experimental analyses | 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. |
Countries
Italy
Outcome results
None listed