Combining daratumumab with bortezomib, cyclophosphamide, and dexamethasone (CyBorD) resulted in higher rates of hematologic response as well as improved survival free from hematologic progression and major organ deterioration in patients with newly diagnosed light-chain (AL) amyloidosis. This is according to results from the phase III ANDROMEDA trial published in the New England Journal of Medicine.
Study author Giampaolo Merlini, MD, of the University of Pavia in Italy, called these findings a breakthrough in the care of amyloidosis caused by monoclonal light chains. “These results led to approval by the U. S. Food and Drug Administration of the combination of daratumumab with CyBorD as the first-ever treatment for newly diagnosed patients with AL amyloidosis,” he said. “As such, this study has already changed our practice because the combination of daratumumab and CyBorD is now considered the standard of care in newly diagnosed patients.”
In the study, patients with newly diagnosed AL amyloidosis were randomly assigned in a 1:1 ratio to receive:
- CyBorD alone (n=193)
- CyBorD plus subcutaneous daratumumab (n=195)
Randomization was based on cardiac stage, transplant availability, and renal function. Neither treatment arm was blinded.
Patients in the daratumumab combination arm who continued six cycles of treatment sub-sequently received single agent daratumumab every four weeks for a maximum of 24 cycles from the start of the study until disease progression, initiation of subsequent therapy, or death.
At baseline, the median age of the population was 64 years. The median time between diagnosis and study entry was 43 days. Approximately 65.5% of patients had two or more involved organs, with 71.4% having heart involvement and 59.0% having kidney involvement. Most patients (76.8%) had cardiac stage 2 or higher, as classified by the European modification of the Mayo Clinic Cardiac Staging System.
Over the median follow-up period of 11.4 months, a significantly higher proportion of patients in the daratumumab combination group had a complete hematologic response compared with the control arm (53.3% vs. 18.1%, respectively; relative risk ratio, 2.9; 95% CI 2.1-4.1; p<0.001). Additionally, survival free from hematologic progression or major organ deterioration was significantly higher in the daratumumab group (hazard ratio = 0.58; 95% CI 0.36-0.93; p=0.02).
At the six-month follow-up, more patients in the daratumumab arm experienced cardiac responses (41.5% vs. 22.2%) and renal responses (53.0% vs. 23.9%). Six-month rates of cardiac progression were 2.5% in the daratumumab group and 7.7% in the control arm. In addition, rates of renal progression were 4.3% in the daratumumab group and 11.5% in the control arm at six months.
The most frequently reported grade 3 or 4 adverse events were lymphopenia (13.0% for daratumumab vs. 10.1% for control), pneumonia (7.8% vs. 4.3%), cardiac failure (6.2% vs. 4.8%), and diarrhea (5.7% vs. 3.7%). Up to 7.3% of patients experienced systemic administration-related reactions to daratumumab. A total of 56 patients died, including 27 patients in the daratumumab arm and 29 patients in the control group. The majority of deaths were attributed to amyloidosis-related cardiomyopathy.
“Due to the direct cardiotoxicity of the native immunoglobulin light chain, rapid reduction of light chains is an important goal of therapy, but the extent of the benefit of early response is unknown,” explained Dr. Merlini. “These findings validate the therapeutic goal of early and deep hematologic response in newly diagnosed patients with AL amyloidosis and further establish the daratumumab and CyBorD combination as the new standard of care in this disease.”
While the rapid activity of daratumumab and CyBorD appear to be an ideal therapy for patients with advanced cardiac involvement, Dr. Merlini suggests additional “controlled studies are needed to answer the question of the possibility to improve cardiac function in the presence of advanced myocardial damage, such as Mayo stage 3B disease.”
Now that an effective therapy has been ap-proved for patients with AL amyloidosis, improving diagnostics remains of paramount importance for early disease detection, particularly before severe cardiac damage occurs, Dr. Merlini added. “Early diagnosis is vital,” he said, “because if we start therapy in the early phase of the disease, we have now a real chance for curing this once-considered inevitably fatal disease.”
The authors report conflicts of interest with Janssen, which funded the study.
Kastritis E, Palladini G, Minnema MC, et al. Daratumumab-based treatment for immunoglobulin light-chain amyloidosis. N Engl J Med. 2021;385(1):46-58.