AL Amyloidosis, MGUS, Monoclonal Gammopathies, Multiple Myeloma
Conditions
Brief summary
Immunoglobulin light chain (AL) amyloidosis is caused by a typically small, minimally proliferating bone marrow plasma cell clone secreting a patient-unique, unstable, aggregation-prone, toxic light chain (LC). The amyloidogenicity of LCs is encrypted in their sequence, yet molecular determinants of LC pathogenicity remain obscure. N-glycosylation has been long suspected to be a determinant of LC amyloidogenicity based on anecdotal reports of individual AL patients with a clonal LC displaying this post-translational modification. It is hypothesized that N-glycosylation fundamentally contributes to determining the amyloidogenicity of immunoglobulin LCs in a subset of patients with AL and might influence its clinical phenotype. It is further proposed that the synthesis and secretion of unstable LCs that also have to be N-glycosylated might reverberate on the biology of the plasma cell clone, possibly modulating the sensitivity toward different drugs and might represent itself a therapeutic target. The objective of our study is now to elucidate the molecular role of LC N-glycosylation in AL amyloidosis, exploit it for risk assessment, and define its potential impact on the biology of the underlying plasma cell clone and its drug sensitivity.
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
* Diagnosis of monoclonal gammopathy (e.g. AL amyloidosis, MGUS, MM, others) * Planned peripheral blood sampling +/- bone marrow aspiration * 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
* Lack of monoclonal gammopathy * Patients fulfilling the criteria for complete hematologic response after anti-clonal 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 |
|---|---|---|
| Dataset of full-length LC variable region sequences | two years | Generation of a clinically annotated dataset of full-length immunoglobulin light chain (LC) variable region sequences derived from the largest reported series of patients with AL and MGUS, including clonal characterization and clinical annotation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical correlates of LC N-glycosylation | two years | Identification of clinical features associated with LC N-glycosylation; evaluation of the impact of LC N-glycosylation on current assays for M-protein identification/quantification and amyloid typing; exploration of potential corrective measures if assay interference is demonstrated. |
| Refinement of sequence-based prediction of LC amyloidogenicity | two years | Validation of existing algorithms/scoring systems for predicting LC amyloidogenicity using newly generated sequences; development of an improved prediction algorithm incorporating sequence and structural/spatial features associated with LC N-glycosylation. |
| Biologic and pharmacologic correlates of LC N-glycosylation | two years | Comparative transcriptional profiling of plasma cell clones expressing unglycosylated versus N-glycosylated LCs; assessment of differential sensitivity to anti-plasma cell drugs and small-molecule inhibitors targeting N-glycosylation pathways. |
Countries
Italy
Outcome results
None listed