Teclistamab and Daratumumab for the Treatment of Previously Untreated AL Amyloidosis, IMPACT-AL Trial

Inclusion Criteria

• Age > 18 years and able to sign informed consent form (ICF)
• Ability to comply with the study protocol, in the investigator's judgment
• Confirmed histopathological diagnosis of systemic AL amyloidosis by mass spectrometry or immunohistochemistry (IHC) or immunofluorescence (IF) on a tissue biopsy that is positive for congo red
• Patient must not have received any prior plasma cell clone-directed therapy
• Measurable hematologic disease, defined as one of the following: * Difference between involved and uninvolved serum free light chain (dFLC) ≥ 50 mg/L and/or 5 mg/dL * Serum monoclonal (M)-protein ≥ 0.5 g/dL on protein electrophoresis
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
• One or more organs involved by AL amyloidosis as per consensus guidelines * Kidney: 24-hour (h) urine protein > 0.5 g/d, predominantly albumin * Heart: Mean wall thickness > 12 mm on echocardiogram without an alternative cause or an elevated N-terminal fragment of prohormone brain natriuretic protein (NT-proBNP) (> 332 ng/L) in the absence of renal failure or atrial fibrillation * Liver: Total liver span > 15 cm in the absence of heart failure or alkaline phosphatase > 1.5 times institutional upper limit of normal * Nerve: ** Peripheral: clinical; symmetric lower extremity sensorimotor peripheral neuropathy ** Autonomic: Gastric-emptying disorder; pseudo-obstruction; voiding dysfunction not related to direct organ infiltration * Gastrointestinal tract: Direct biopsy verification when gastrointestinal (GI) tract specific symptoms are present * Lung: Direct biopsy verification when lung specific symptoms are present; Interstitial radiographic pattern * Soft tissue: ** Tongue enlargement, clinical ** Arthropathy ** Claudication, presumed vascular amyloid ** Skin ** Myopathy by biopsy or pseudo-hypertrophy ** Lymph node (may be localized) ** Carpal tunnel syndrome
• Absolute neutrophil count ≥ 0.75 x 10^9/L
• Hemoglobin level ≥ 8.0 g/dL; red blood cell transfusion allowed until 7 days before cycle 1 day 0 (C1D0)
• Platelet count ≥ 50 x 10^9/L; Platelet transfusions are acceptable without restriction during the screening period
• Alanine aminotransferase level (ALT) ≤ 2.5 times the upper limit of normal (ULN)
• Aspartate aminotransferase (AST) ≤ 2.5 times the ULN
• Total bilirubin level ≤ 1.5 x ULN except for subjects with Gilbert syndrome, in which case direct bilirubin ≤ 2 x ULN
• Estimated glomerular filtration rate (eGFR) ≥ 20 mL/min/1.73 m^2, measured by using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception and agreement to refrain from donating eggs as defined: * Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and within 90 days after the last dose of study drug. Women must refrain from donating eggs during this same period. A woman is considered to be of childbearing potential if she is post-menarche, has not reached a postmenopausal state (> 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations * Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. Hormonal contraceptive methods must be supplemented by a barrier method * The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception. If required per local guidelines or regulations, locally recognized acceptable methods of contraception and information about the reliability of abstinence will be described in the local informed consent form
• For men: Agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined: * With a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 90 days after the final dose of study drug to avoid exposing the embryo. Men must refrain from donating sperm during this same period. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of preventing drug exposure. If required per local guidelines or regulations, information about the reliability of abstinence will be described in the local informed consent form

Exclusion Criteria

• Prior therapy for AL amyloidosis or multiple myeloma with the exception of 160 mg dexamethasone (or equivalent corticosteroid) maximum exposure prior to C1D0
• Patients meeting criteria for symptomatic multiple myeloma by any one of the following: * Lytic lesions on imaging (skeletal survey, whole body CT or MRI, or PET/CT) * Plasmacytoma * Hypercalcemia without any alternate etiology * Bone marrow plasma cell infiltrate of greater than 60% * Patients with involved/uninvolved serum free light chain (FLC) ratio > 100 as the sole myeloma-defining event will be allowed
• Evidence of significant cardiovascular conditions as specified below: * NT-Pro BNP > 8500 pg/mL, and/or * New York Heart Association (NYHA) class IIIb or IV functional class
• History of other malignancy that could affect compliance with the protocol or interpretation of results * Patients with a history of curatively treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix, breast cancer, or Hodgkin’s lymphoma are generally eligible. Patients with a malignancy that has been treated, but not with curative intent, will be excluded, unless the malignancy has been in remission without treatment for ≥ 2 years prior to enrollment
• Evidence of other clinically significant uncontrolled condition(s) including, but not limited to, uncontrolled systemic infection (viral, bacterial, or fungal)
• Patients on renal replacement therapy
• Patients with HIV who are not on highly active antiretroviral therapy (HAART) or those with active hepatitis A, B, or C infection
• Planned stem cell transplant during the first 6 cycles of protocol therapy are excluded. Stem cell collection during the first 6 cycles of protocol therapy is permitted, as per investigators’ discretion
• Known hypersensitivity to any of the agents
• Patients who are receiving any other investigational agent concurrently