Study Rationale:

hATTR-PN is an inherited, progressive, fatal disease caused by misfolded transthyretin (TTR) proteins that accumulate as amyloid fibrils predominantly in the peripheral nerves, heart, gastrointestinal tract, and other organs. hATTR-PN is a rare disease and there are no large epidemiological studies that reliably provide an indication of its prevalence. The worldwide distribution is unequal, with higher rates in Portugal, Japan, Brazil, Northern Sweden, and the US. Current estimates suggest there may be 10,000 afflicted patients worldwide.

This is a prospective, non-interventional, Long-term, multinational cohort safety study of patients with Hereditary Transthyretin Amyloidosis with Polyneuropathy (hATTR-PN). The overarching goal of this study is to further characterize the long-term safety of TEGSEDI (inotersen) in patients with hATTR-PN under real-world conditions.

PRIMARY OBJECTIVES:

1. Test the safety and feasibility of isatuximab-based drug treatment.
2. Evaluate the preliminary efficacy of a slow-go approach in high risk AL amyloid patients.

STUDY TREATMENT

Each patient starts by receiving increasing intensity of treatment for AL Amyloidosis up to maximum tolerance, and then maintenance Isatuximab thereafter for a specified period.

This phase I trial studies the side effects of isatuximab and to see how well it works in treating patients with high risk immunoglobulin light chain amyloidosis (AL amyloidosis). Isatuximab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread.

Primary light chain amyloidosis (AL) is the most common systemic amyloidosis, resulting from a plasma cell dyscrasia, a hematological malignancy. It causes a restrictive cardiomyopathy (AL-CMP) in over 70% of individuals. AL-CMP is as lethal as stage 4 lung cancer and more lethal than any other form of restrictive heart disease; if untreated, the mortality rate is 50% within 18 months.

Cardiac amyloidosis is a major cause of early treatment-related death and poor overall survival in individuals with systemic light chain amyloidosis. This project will develop a novel approach to visualize cardiac amyloid deposits using advanced imaging methods. The long-term goal of this work is to identify the mechanisms of cardiac dysfunction, in order to guide the development of novel life-saving treatments.

Despite rapidly advancing developments in targeted therapeutics and genetic sequencing, persistent limits in the accuracy and throughput of clinical phenotyping has led to a widening gap between the potential and the actual benefits realized by precision medicine. This conundrum is exemplified by current approaches to assessing morphologic alterations of the heart. If reliably identified, certain cardiac diseases (e.g. cardiac amyloidosis and hypertrophic cardiomyopathy) could avoid misdiagnosis and receive efficient treatment initiation with specific targeted therapies.

Despite rapidly advancing developments in targeted therapeutics and genetic sequencing, persistent limits in the accuracy and throughput of clinical phenotyping has led to a widening gap between the potential and the actual benefits realized by precision medicine.

Recent advances in machine learning and image processing techniques have shown that machine learning models can identify features unrecognized by human experts and more precisely/accurately assess common measurements made in clinical practice.

Transthyretin cardiac amyloidosis (ATTR-CA) causes progressive heart disease that is often overlooked. It harms the heart muscle because the unstable, unfurled amyloid proteins fold up into large pieces that get caught in between layers of heart tissue, causing amyloid deposits. The earlier it is detected, the better for the patient.

This is a single center, prospective cohort study that is evaluating the ability of 124I-evuzamitide PET scanning to detect potential therapeutic changes in subjects under treatment for ATTR after one year has elapsed since their original 124I-evuzamitide PET scan.

Ten previously scanned subjects will re-consent to undergo another 124I-evuzamitide PET scan. Demographic, clinical and phenotypic data will be collected to characterize potential changes since their previous scans.

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of venetoclax, MLN9708 (ixazomib citrate), and dexamethasone when used in combination.

II. To determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of venetoclax, MLN9708 (ixazomib citrate), and dexamethasone when used in combination.

SECONDARY OBJECTIVES:

This phase I/Ia trial finds the best dose and side effects of venetoclax given in combination with ixazomib citrate and dexamethasone in treating patients with light chain amyloidosis that has come back (relapsed) or does not respond to treatment (refractory) and who have an abnormal genetic change \[translocation t(11;14)\]. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Ixazomib citrate is in a class of medications called proteasome inhibitors.

The goal of this clinical trial is to learn about malnutrition and weight loss in patients with Amyloidosis.

The main question it aims to answer is:

Is it feasible to use a low-cost nutrition-based application (apps) for use on a smartphone to obtain detailed information on caloric intake in Amyloidosis patients

Participants will be asked to:

This is a multicenter, prospective cohort study aimed at facilitating identification of individuals with ATTR-CA. Investigators will identify subjects with previous LSS surgery who have evidence of TTR amyloid deposits in spinal specimens. Subjects with localized TTR in spinal tissue will be invited to an on-site visit and be evaluated for the presence of clinical manifestations of ATTR cardiac amyloidosis (ATTR-CA).

Primary objective:

To identify older adults with transthyretin cardiac amyloidosis (ATTR-CA) early in the course of the illness, at a time when disease modifying therapies are most effective.

The specific aims of this epidemiologic investigation include:

1. To identify subjects with previous lumbar spinal stenosis (LSS) Surgery who have evidence of transthyretin (TTR) amyloid deposits in spinal specimens and could be at risk for ATTR cardiac amyloidosis.
2. To evaluate for ATTR-CA among those with localized TTR in the spinal tissue.

The main purpose of this study is to examine the outcome of a combined bone marrow and kidney transplant from a partially matched related (haploidentical or "haplo") donor. This is a pilot study, you are being asked to participate because you have a blood disorder and kidney disease. The aim of the combined transplant is to treat both your underlying blood disorder and kidney disease. We expect to have about 10 people participate in this study.

This study is composed of three dosing plan stages. The initial stage of this trial is the dose-escalation stage. A modified dose-escalation 3+3 design will be utilized to identify a safe maximum tolerated dose (MTD) of STI-6129 in patients with relapsed or refractory systemic AL amyloidosis.

The STI-6129-001 study is a three-stage, multicenter, open-label, dose-finding, phase 1b/2a trial. It is designed primarily to identify the recommended phase 2 dose (RP2D) of STI-6129 by assessing the safety, preliminary efficacy and pharmacokinetics of this anti-CD38-Duostatin 5.2 antibody-drug conjugate (ADC) for the treatment of relapsed or refractory systemic AL amyloidosis.

The patients that will be treated with STI-6129 in this trial are relapsed or refractory systemic AL amyloidosis patients who have received prior lines of treatment.