PRIMARY OBJECTIVES:~I. To determine the maximum-tolerated dose (MTD)/ the recommended phase 2 dose (RP2D) of venetoclax (VEN) with or without daratumumab subcutaneous (DARA SC) and dexamethasone (DEX), in previously treated light chain (AL) amyloidosis (PTAL) patients with t(11;14). (Phase Ia).~II. To evaluate the safety and tolerability of VEN/DARA SC and DEX in the treatment of PTAL patients with t(11;14). (Phase Ib).~III. To evaluate the safety and efficacy of VEN/DARA SC and DEX in the treatment of PTAL patients with t(11;14). (Phase II).~SECONDARY OBJECTIVES:~I. To evaluate the safety and tolerability of VEN/DARA SC, and DEX in the treatment of PTAL patients with t(11;14). (Phase Ia).~II. To evaluate the preliminary efficacy of VEN/DARA SC and DEX in the treatment of PTAL patients with t(11;14) as measured by complete hematologic response (CHR) rate, overall hematologic response rate (ORR), progression-free survival (PFS), overall survival (OS), organ response rate (orRR), time to complete response (TTCR), time to next treatment (TTNT), and duration of response (DOR). (Phase Ib).~III. To evaluate the efficacy of VEN/DARA SC and DEX in the treatment of PTAL patients with t(11;14). (Phase II).~IV. To evaluate the death rate, therapy-related death rate, infection rate, and cardiac event rate, in the VEN/DARA SC and DEX arm and the DARA SC and DEX arm. (Phase II).~EXPLORATORY OBJECTIVE:~I. To evaluate the complete response (CR) rate, overall hematologic response rate (ORR), progression-free survival (PFS), major organ deterioration PFS (MOD-PFS), overall survival (OS), organ response rate (OrRR), time to complete response (TTCR), time to next treatment (TTNT) and duration of response (DOR) separated by patients who are minimal residual disease (MRD) negative versus positive by EXENT.~OUTLINE: This is a phase Ia, dose-escalation study of venetoclax followed by phase Ib, dose-expansion study and a phase II study.~PHASE I: All patients receive venetoclax orally (PO) once daily (QD) on days 1-28 of each cycle for levels 1-4. Depending on dose-level assignment, patients may also receive dexamethasone PO on days 1, 8, 15, and 22 of each cycle with or without daratumumab SC on days 1, 8, 15, and 22 of cycles 1-2, days 1 and 15 of cycles 3-6, then on day 1 of cycles thereafter. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.~PHASE II: Patients are randomized to 1 of 2 arms.~ARM A: Patients receive venetoclax PO QD on days 1-28 of each cycle, dexamethasone PO on days 1, 8, 15, and 22 of each cycle, and daratumumab SC on days 1, 8, 15, and 22 of cycles 1-2, days 1 and 15 of cycles 3-6, then on day 1 of cycles thereafter. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.~ARM B: Patients receive dexamethasone PO on days 1, 8, 15, and 22 of each cycle, and daratumumab SC on days 1, 8, 15, and 22 of cycles 1-2, days 1 and 15 of cycles 3-6, then on day 1 of cycles thereafter. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.~After completion of study treatment, patients are followed up at 30 days and then every 3 months until the last patient on the study completes 2 years of treatment.
This phase I/II trial tests the safety, side effects, and best dose of venetoclax, daratumumab, and dexamethasone for the treatment of systemic light-chain amyloidosis in patients with a deoxyribonucleic acid (DNA) abnormality called a translocation involving chromosomes 11 and 14, or t(11;14). Venetoclax works by attaching to a protein called Bcl-2, in order to kill cancer cells. Daratumumab works by binding to a target on the surface of cancer cells called CD38. When daratumumab binds to CD38, it enables the immune system to find the cancer cell and kill it. Dexamethasone is a type of drug called a corticosteroid. A corticosteroid is a drug made of artificial steroid hormones, that are used to treat symptoms such as inflammation (swelling and irritation to a part of the body). The combination of these medications may more effectively treat patients with systemic light-chain amyloidosis and t(11;14).