Patients with light-chain amyloidosis may soon have a new standard of care, according to data presented during the 25th European Hematology Association (EHA25) Virtual Annual Congress.1
Results of the phase III ANDROMEDA study have shown that adding subcutaneous daratumumab to the triplet combination of cyclophosphamide, bortezomib, and dexamethasone (CyBorD) significantly improved the hematologic complete response rate compared with CyBorD alone in patients with newly diagnosed light-chain (AL) amyloidosis (53% vs 18%). The 6-month organ response rate was nearly doubled for patients treated with daratumumab in combination therapy for both cardiac and renal responses.
The daratumumab/CyBorD combination also had an acceptable safety profile, consistent with what has been previously observed for either treatment alone, authors of the study reported.
“The addition of subcutaneous daratumumab to CyBorD resulted in deeper and more rapid hematologic responses than CyBorD alone,” said Efstathios Kastritis, MD, Associate Professor of Clinical Therapeutics/Medical Oncology at the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens, School of Medicine. “This combination will likely become the first approved therapy for light-chain amyloidosis and the global standard of care for the treatment of these patients.”
Efstathios Kastritis, MD
As Dr. Kastritis explained, light-chain amyloidosis is a rare disease characterized by insoluble amyloid fibril deposits in tissues and organs. The prognosis is poor due to advanced multiorgan involvement. Approximately 30% of patients die within the first year of diagnosis, and there are no approved therapies for this disease.
“Outcomes have improved due to the use of novel multiple myeloma drugs, in particular bortezomib-based therapies such as CyBorD, but more effective therapies are still needed,” said Dr. Kastritis. “Rapid, deep, and sustained hematologic responses are required in light-chain amyloidosis to reverse amyloid-mediated organ dysfunction and improve overall survival.”
Daratumumab has demonstrated promising single-agent activity in relapsed or refractory light-chain amyloidosis. The efficacy and safety profile of daratumumab are well characterized as monotherapy and in combination therapies in multiple myeloma.
Deeper, More Rapid Hematologic Response
In the phase III ANDROMEDA study, patients with newly diagnosed light-chain amyloidosis were randomly assigned to receive either subcutaneous daratumumab plus CyBorD or standard CyBorD alone. Patients enrolled in the study had typical disease characteristics, according to Dr. Kastritis, with at least one-third suffering from severe cardiac dysfunction related to the disease. The study’s primary endpoint was the rate of overall hematologic complete response.
Results of the study showed a substantial increase in the rate of complete hematologic response, which corresponded to elimination of toxic free light chains in patients treated with daratumumab plus CyBorD, Dr. Kastritis reported. More specifically, the complete hematologic response rate was 53% with the daratumumab combination vs 18% with CyBorD alone, and the median time to complete response was 60 days with daratumumab vs 85 days with CyBorD alone.
KEY POINTS
- In the first phase III study of daratumumab outside of multiple myeloma, the rate of hematologic complete response in patients with newly diagnosed light-chain amyloidosis was 53% with subcutaneous daratumumab in combination with CyBorD compared with 18% with CyBorD alone.
- The 6-month organ response rate was nearly doubled for patients treated with the daratumumab combination vs CyBorD alone, for both cardiac (42% vs 22%) and renal (54% vs 27%) responses.
“Complete hematologic responses remained high and were consistent in every subgroup evaluated, including patients with more severe cardiac amyloidosis and those with genetic abnormalities,” commented Dr. Kastritis. “This high rate of complete hematologic responses translated to significant improvement in the time to major organ deterioration, hematologic disease progression, or death and nearly doubled the rate of organ responses vs CyBorD alone.”
Safety Profile
The safety profile of the combination was also consistent with the known safety profile of subcutaneous daratumumab or CyBorD alone. Infections were reported in 12% of patients randomly assigned to daratumumab vs 9% of patients receiving standard CyBorD alone. Serious treatment-emergent adverse events occurred in 43% of patients on the daratumumab arm vs 36% of patients receiving CyBorD alone. The most common serious treatment-emergent adverse event was pneumonia, said Dr. Kastritis, and 4% of patients in either arm discontinued therapy due to treatment-emergent adverse events.
Subcutaneous daratumumab also was associated with a low rate of administration-related reactions, with most occurring during initial administration. Systemic administration-related reactions occurred in 14 patients (7%) in the combination arm, and all were grade 1 or 2.
DISCLOSURE: Dr. Kastritis has received honoraria from and served as a consultant or advisor to Amgen, Genesis Pharma, Janssen Oncology, Takeda, Pfizer, and Prothena; has received institutional research funding from Amgen and Janssen; and has been reimbursed for travel, accommodations, or other expenses by Genesis Pharma, Janssen Oncology, Pfizer, and Takeda.
REFERENCE
1. Kastritis E, Palladini G, Minnema MC, et al: Subcutaneous daratumumab + cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in patients with newly diagnosed light chain amyloidosis. EHA25 Virtual Congress. Abstract LB2604.
