BCMA/GPRC5D Trispecific Antibody Treatment for Newly Diagnosed Amyloidosis (AL-004)

Systemic light-chain (AL) amyloidosis is a rare plasma cell disorder caused by the production of monoclonal immunoglobulin light chains that misfold and deposit in vital organs, resulting in progressive organ dysfunction and poor survival. Rapid suppression of pathogenic plasma cells and achievement of deep hematologic responses are strongly associated with improved organ recovery and survival.

Current first-line treatment based on daratumumab plus cyclophosphamide, bortezomib, and dexamethasone has significantly improved clinical outcomes; however, approximately 40% of patients do not achieve complete hematologic remission, and early mortality remains substantial. Therefore, more effective frontline therapies are needed.

QLS4131 is a novel GPRC5D/BCMA/CD3 trispecific antibody that simultaneously targets two plasma-cell antigens (BCMA and GPRC5D) while redirecting CD3-positive T cells to eliminate malignant plasma cells. Dual-antigen targeting may improve tumor recognition, reduce antigen escape, and enhance antitumor activity without substantially increasing toxicity.

This prospective, single-arm, single-center study will enroll approximately 20 adult patients with newly diagnosed systemic AL amyloidosis. Participants will receive subcutaneous QLS4131 using a step-up dosing schedule followed by maintenance dosing for 6 to 8 treatment cycles.

Inclusion criteria

• Voluntarily provide written informed consent (ICF) prior to any study-specific procedures.
• Age ≥18 years, regardless of sex.
• Newly diagnosed primary systemic light-chain (AL) amyloidosis.
• Measurable disease at screening, defined as:

• Difference between involved and uninvolved serum free light chains (dFLC) ≥20 mg/L; and
• Abnormal serum free light chain (FLC) ratio or other confirmed evidence of monoclonal light chain production.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
• Adequate organ function within 3 days before the first administration of the investigational product:

i. Absolute neutrophil count (ANC) ≥1.0 × 10⁹/L, without treatment with granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) within 7 days, and without pegylated G-CSF within 14 days before dosing.

ii. Hemoglobin ≥75 g/L without whole blood or red blood cell transfusion within 7 days before dosing.

iii. Platelet count ≥70 × 10⁹/L without platelet transfusion, whole blood transfusion, or thrombopoietin receptor agonists within 7 days before dosing.

iv. Hepatic function:

• ALT ≤3 × upper limit of normal (ULN);
• AST ≤3 × ULN;
• Total bilirubin ≤2 × ULN. Participants with Gilbert syndrome may be enrolled if direct bilirubin is ≤2 × ULN.

v. Coagulation function:

• International normalized ratio (INR) or activated partial thromboplastin time (aPTT) ≤1.5 × ULN.

vi. Renal function:

• Estimated glomerular filtration rate (eGFR) ≥20 mL/min/1.73 m², calculated using the CKD-EPI equation.
• Male participants, women of childbearing potential, and their partners must agree to use effective contraception during study treatment and for at least 3 months after the last dose.
• Male participants must agree not to donate sperm from screening until 90 days after the last dose of study drug.
• Willing and able to comply with all study procedures and follow-up assessments.
• Women of childbearing potential must have a negative serum or urine β-human chorionic gonadotropin (β-hCG) pregnancy test at screening.

Exclusion criteria

• Non-AL amyloidosis, including hereditary amyloidosis or any other non-AL subtype.
• Symptomatic multiple myeloma.
• Grade >2 peripheral neuropathy or Grade ≥2 painful peripheral neuropathy at screening, regardless of current treatment.
• History of another malignancy within 5 years before enrollment, except AL amyloidosis.
• Prior anti-plasma cell therapy, including:

• Melphalan
• Cyclophosphamide
• Proteasome inhibitors
• Immunomodulatory drugs (IMiDs)
• Monoclonal antibodies
• Bispecific antibodies
• Trispecific antibodies
• Autologous stem cell transplantation
• Chimeric antigen receptor (CAR)-T cell therapy

Exceptions include:

• Therapy for myeloproliferative neoplasms (e.g., hydroxyurea).
• Chronic corticosteroid therapy (prednisone equivalent ≤20 mg/day) used for conditions such as adrenal insufficiency or rheumatoid arthritis.
• Known hypersensitivity, intolerance, or contraindication to the investigational BCMA/GPRC5D trispecific antibody.
• Unstable or active cardiovascular or cerebrovascular disease, including:

• Unstable angina, symptomatic myocardial ischemia, myocardial infarction, coronary revascularization, transient ischemic attack, subarachnoid hemorrhage, central nervous system hemorrhage, severe brain injury, stroke, seizure, deep vein thrombosis, or pulmonary embolism within 180 days before first dosing.
• Hospitalization for cardiovascular disease within 4 weeks before enrollment in participants with congestive heart failure.
• Heart failure primarily caused by ischemic heart disease or uncorrected valvular disease rather than AL cardiac amyloidosis.
• New York Heart Association (NYHA) Class IV heart failure.
• History of sustained ventricular tachycardia or ventricular fibrillation, or atrioventricular (AV) node or sinoatrial (SA) node dysfunction requiring but not receiving a pacemaker or implantable cardioverter-defibrillator (ICD). Participants with implanted pacemakers or ICDs are eligible.
• Corrected QT interval (QTcF) >500 ms (participants with implanted pacemakers are exempt).
• Supine systolic blood pressure <90 mmHg.
• Any other cardiovascular or cerebrovascular condition considered by the investigator to make study participation inappropriate.
• Symptomatic interstitial lung disease or noninfectious pneumonitis (e.g., pneumoconiosis, radiation pneumonitis, or drug-induced pneumonitis), or pulmonary impairment requiring supplemental oxygen.
• Requirement for oral anti-infective therapy within 2 weeks before first dose or intravenous systemic anti-infective therapy within 4 weeks before first dose.
• Active infection, including:

• Active hepatitis B infection (HBV DNA positive);
• Active hepatitis C infection (HCV RNA positive in participants with positive anti-HCV antibody);
• Human immunodeficiency virus (HIV) infection;
• Active or latent syphilis (positive Treponema pallidum antibody);
• Active pulmonary tuberculosis identified within 3 months before first dose or during screening.
• Pregnant or breastfeeding women.
• Any condition that may interfere with compliance with the study protocol (e.g., substance abuse, dementia, altered mental status), interfere with study procedures or interpretation of results, or pose unacceptable risk according to investigator judgment.
• Active gastrointestinal disorders that impair swallowing or are likely to interfere with study drug absorption.
• Major surgery within 2 weeks before enrollment, incomplete recovery from surgery, or planned major surgery during study participation. Kyphoplasty and vertebroplasty are not considered major surgery. Procedures under local anesthesia are permitted.
• Receipt of a live attenuated vaccine within 4 weeks before the first study drug administration.
• Contraindication to any required concomitant medication or supportive therapy.
• Any disease or medical condition that may interfere with study procedures.
• Unwillingness or inability to comply with the study protocol.
• Any other condition that, in the investigator's judgment, makes the participant unsuitable for study participation.