Sonrotoclax Plus Dexamethasone With or Without Daratumumab Regimen in Patients With t(11;14) Primary AL Amyloidosis

An Optimized Treatment for Patients With Primary Systemic Light Chain Amyloidosis

The goal of this study is to evaluate the efficacy and safety of Sonrotoclax combined Regimen in patients with t(11;14) AL amyloidosis. Participants will receive the Sonrotoclax Plus Dexamethasone regimen with or without Daratumumab for 12 cycles. The Hematologic Response, Organ Response, Survival, and Safety will be evaluated.

Treatment options for AL amyloidosis are limited. Before the approval of daratumumab, newly diagnosed light-chain amyloidosis was often managed with anti-myeloma regimens such as bortezomib. For patients with relapsed/refractory (R/R) disease, there is currently a lack of standard treatment options both domestically and internationally. Guidelines recommend enrollment in clinical trials or the use of regimens containing previously unexposed agents, such as bortezomib or daratumumab.

Based on preliminary data of BCL-2 inhibitors in t(11;14) amyloidosis, this study aims to explore the efficacy and safety of sonrotoclax and dexamethasone with or without Daratumumab. Newly diagnosed patients with t（11;14）will receive the combination of sonrotoclax, daratumumab, and dexamethasone. t(11;14) Patients with relapsed/refractory AL amyloidosis (RRAL) will be treated with sonrotoclax plus dexamethasone. For transplant-eligible patients, stem cell collection is permitted during the induction phase of therapy. The timing of ASCT may be assessed after the primary endpoint evaluation (completion of 4 treatment cycles) and determined by the investigator.

Inclusion Criteria:

1. Patients who meet the diagnostic criteria for Primary Systemic Light Chain Amyloidosis (according to the Systemic Light Chain Amyloidosis Diagnosis and Treatment Guidelines (2021 Revision)).

2. Age ≥ 18 years.

3. Confirmed FISH test result of t(11;14) positive by each center or a third-party laboratory, or a prior FISH test report indicating t(11;14) positivity

4. ECOG Performance Status score of 0-2.

5. Presence of measurable disease, defined by at least one of the following criteria:

   1. Serum M-protein ≥ 0.5 g/dL
   2. Serum free light chain (FLC) level ≥ 40 mg/L with an abnormal kappa/lambda ratio.

6. Adequate organ function, defined as:

   1. Hemoglobin (HGB) > 80 g/L
   2. Platelet count > 50 × 10⁹/L
   3. Absolute neutrophil count (ANC) > 1.0 × 10⁹/L
   4. Total bilirubin ≤ 2.0 × ULN; AST and ALT ≤ 3.0 × ULN
   5. Creatinine clearance (CrCl) ≥ 30 mL/min
   6. Oxygen saturation ≥ 90%

7. Life expectancy greater than 6 months.

8. Patient understands and voluntarily signs an informed consent form (ICF).

9. Cohort Assignment:

   • Cohort A: Includes patients who are newly diagnosed or have not been previously exposed to anti-CD38 monoclonal antibody therapy.
   • Cohort B: Includes patients who are insensitive to or have relapsed after anti-CD38 monoclonal antibody therapy.Insensitivity to anti-CD38 monoclonal antibody therapy is defined as failure to achieve at least a Partial Response (PR) after 1 cycle, or failure to achieve at least a Very Good Partial Response (VGPR) after 3 cycles of an anti-CD38-containing regimen.

Exclusion Criteria:

1. Meets the diagnostic criteria for active multiple myeloma or active lymphoplasmacytic lymphoma

2. Presence of other malignancies at an advanced stage with systemic metastases.

3. IgM-type AL amyloidosis.

4. Prior treatment with a BCL-2 inhibitor (BCL-2i).

5. Presence of any of the following severe cardiovascular diseases

   1. Mayo 2004 stage IIIb: NT-proBNP >8500 ng/L.
   2. NYHA class IIIb-IV
   3. Left ventricular ejection fraction (LVEF) <40%.
   4. QT interval corrected by Fridericia's formula (QTcF) >480 ms
   5. Investigator assessment that heart failure is due to ischemic heart disease (e.g., prior history of myocardial infarction with elevated cardiac enzymes and ECG changes) or uncorrected valvular disease, rather than primarily caused by AL amyloidosis.
   6. Hospitalization for unstable angina or myocardial infarction within 6 months prior to the first dose, or cardiac interventional therapy or coronary artery bypass grafting within 6 months.
   7. For patients with congestive heart failure, hospitalization for cardiovascular disease within 4 weeks prior to Cycle 1 Day 1.
   8. History of sustained ventricular tachycardia or aborted ventricular fibrillation, or history of atrioventricular node or sinus node dysfunction requiring a pacemaker/implantable cardioverter-defibrillator (ICD) but not implanted.

6. Severe or persistent infection that is not effectively controlled. (Acute infection requiring antibacterial, antifungal, or antiviral therapy that has not resolved within 14 days prior to dosing).

7. Positive status for human immunodeficiency virus (HIV) antibody (HIVAb).

8. Serological status reflecting active viral hepatitis B (HBV) or hepatitis C (HCV) infection, as follows:

   1. Positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients who are positive for HBcAb but negative for HBsAg are eligible if HBV DNA is undetectable and they are willing to undergo monthly monitoring for HBV reactivation.
   2. Positive for hepatitis C virus (HCV) antibody. Patients who are positive for HCV antibody are eligible if HCV RNA is undetectable.

9. Patients receiving renal replacement therapy.

10. Patients with known hypersensitivity to any component of the investigational regimen.

11. Any condition that, in the investigator's judgment, would increase the risk to the subject or affect the study results.

12. Patients with AL amyloidosis currently participating in other investigational drug clinical studies.

13. Patients who are pregnant, breastfeeding, or planning to become pregnant during the study participation.

14. Patients who are receiving any moderate or strong CYP3A4 inhibitors (within ≤7 days or 5 half-lives, whichever is shorter) or strong CYP3A4 inducers (within ≤14 days or 5 half-lives, whichever is shorter) prior to the first dose of the study drug; or patients who require continuous treatment with moderate or strong CYP3A inhibitors or strong CYP3A inducers