Extended Treatment With CAEL-101 Plus SOC Therapy Proves Safe in Light-Chain Amyloidosis


The addition of the chimeric monoclonal antibody CAEL-101 to standard therapy with cyclophosphamide, bortezomib, and dexamethasone with or without daratumumab demonstrated a manageable toxicity profile with prolonged clinical benefit in patients with amyloid light-chain amyloidosis.

Michaela Liedtke, MD

Michaela Liedtke, MD

The addition of the chimeric monoclonal antibody CAEL-101 to standard therapy with cyclophosphamide, bortezomib (Velcade), and dexamethasone with or without daratumumab (Darzalex) demonstrated a manageable toxicity profile with prolonged clinical benefit in patients with amyloid light-chain amyloidosis, according to findings from a phase 2 trial (NCT04304144) that were presented at the 2023 EHA Congress.

Results indicated improved or stabilized cardiac function based on the evaluation of serum NT-proBNP levels over time. The number of responders appeared to grow over time, with 4, 5, 6, 9, 6, and 5 responders at 14, 26, 38, 50, 62, and 74 weeks, respectively. The number of patients who experienced stable cardiac function was 12, 11, 10, 5, 10, and 11 over the prespecified time points, respectively. Remaining responses were indicative of progression or missing data at 14 (n = 2 vs 4), 26 (n = 1 vs 5), 38 (n = 2 vs 4), 50 (n = 3 vs 5), 62 (n = 2 vs 4), and 74 (n = 1 vs 5) weeks, respectively.

Responders were defined as having at least 30% reduction from baseline and decrease of NT-proBNP above 300 ng/L in patients with a baseline NT-proBNP of at least 650 ng/L. Stable disease was defined as neither response nor progression, the latter of which was defined as having at least 30% increase from baseline and at least 300 ng/L of NT-proBNP without decline in eGFR at least 25% from baseline.

“Among patients with AL amyloidosis treated with CAEL-101 for 18 months, CAEL-101 was generally well tolerated without evidence of toxicity in patients with AL amyloidosis. Most treatment-emergent adverse effects were mild to moderate, and cardiac response persisted even after cessation of anti–plasma cell dyscrasia treatment,” lead study author Michaela Liedtke, MD, associate professor of medicine (hematology) at Stanford Medicine in California, said in a presentation of the data.

AL amyloidosis is a rare, severe, progressive, systemic disease caused by free light chain misfolds due to plasma cell dyscrasia into amyloid fibrils. Amyloid fibrils deposit into organs, leading to severe damage and dysfunction and death.

Anti-plasma cell dyscrasia, which suppresses plasma cell growth, is a standard-of-care (SOC) treatment. However, there are no FDA-approved treatments that target fibrils that have already been deposited in organs.

CAEL-101 is a chimeric monoclonal antibody designed to bind a cryptic epitope on misfolded kappa and gamma light chains and resulting amyloid fibrils, leading to their removal from organs and tissues.

To be eligible for enrollment in the multicenter, open-label trial, adult patients had to have received a diagnosis of confirmed, Mayo Stage I to IIIA AL amyloidosis; have a life expectancy of at least 6 months; measurable hematologic disease; and planned or continuing treatment with SOC. Exclusion criteria included other forms of amyloidosis, multiple myeloma, supine systolic blood pressure below 90 mm Hg, or symptomatic orthostatic hypotension.

“The patient population was heterogenous with respect to disease stage at diagnosis, time since diagnosis, and number of prior treatments,” Liedtke said. Mean age was 65.2 years (range, 48-80), most patients were male (72%) and White (92%) and had cardiac involvement (88%) and prior anti–plasma cell dyscrasia treatment (80%). The Mayo Stage at screening was primarily stage II (76%), followed by stage IIIA (16%), and I (8%).

All patients received treatment until death, unacceptable toxicity, symptomatic deterioration, investigator decision, or sponsor decision to terminate the study. Plasma cell dyscrasia therapy was continued per the investigator. Following weekly administration of CAEL-101 for 4 cycles in parts A and B for dose-limiting toxicity and safety observation, respectively, patients continued to receive no more than 1000 mg/m2 of CAEL-101 every other week.

The primary end point of the study was the evaluation of long-term safety and tolerability of CAEL-101 in combination with SOC therapy. Secondary end points included long-term efficacy in cardiac-evaluable patients.

Regarding safety, common adverse effects (AEs) observed in patients who received the combination (n = 25) included nausea (40%), constipation (36%), fatigue (36%), diarrhea (32%), insomnia (32%), anemia (28%), dizziness (28%), and rash (28%).

All patients experienced at least 1 treatment-emergent AE (TEAE); 8% were treatment related and 24% were deemed possibly related to treatment. Grade 3 or greater TEAEs occurred in 60% of patients, 52% of which were deemed serious. No treatment-related discontinuations occurred, although discontinuations due to an AE (4%), septic pneumonia (4%), heart transplant (8%), heart and kidney transplant (4%), physician decision (8%), and consent withdrawal (8%), did occur.

Disclosures: Dr Liedtke reported trial support from Alexion and AstraZeneca Rare Disease, Inc.; and advisory board honoraria from Adaptive, Alexion, AstraZeneca Rare Disease, Inc., Celgene, GSK, Janssen, Jazz Pharmaceuticals, and Pfizer.


Valent J, Liedtke M, Zonder J, et al. Safety and tolerability of CAEL-101, an anti-amyloid monoclonal antibody, combined with anti-plasma cell dyscrasia therapy in patients with light-chain amyloidosis: 18-month results of a phase 2 study. Presented at: 2023 EHA Congress; June 8-15, 2023; Frankfurt, Germany. Abstract S204.

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