1. Daratumumab therapy addition to bortezomib, cyclophosphamide, and dexamethasone showed improved cancer response in patients with systemic immunoglobulin light-chain amyloidosis.
2. The daratumumab group presented with an increase in serious adverse events such as lymphopenia, cardiac failure, and infections.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Immunoglobulin light-chain amyloidosis (AL) is a disease of increased misfolded amyloid fibril deposition produced by CD38+ plasma cell clones. The combination of bortezomib, cyclophosphamide, and dexamethasone is a common treatment of this plasma cell dyscrasia. However, treatment response and survival remained suboptimal. Daratumumab, an IgG monoclonal antibody targeting CD38, has shown an effect in refractory or relapsed AL amyloidosis. As such, this trial evaluated the safety and efficacy of bortezomib, cyclophosphamide, dexamethasone with or without daratumumab in patients with newly diagnosed AL amyloidosis. There was a greater hematological, cardiac, and renal response, as well as improved survival free from organ deterioration or hematological progression with daratumumab. Adverse events that were more common in the daratumumab group included pneumonia, lymphopenia, and cardiac failure. A limitation was the use of a compositive survival outcome measure and the lack of overall survival data. In general, this trial demonstrated that the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone resulted in improved outcomes for patients with newly diagnosed AL amyloidosis.
Click here to read the study in the NEJM
In-Depth [randomized controlled trial]: This was a phase 3, randomized, open-label trial that enrolled 388 patients at 109 sites in 22 countries. Patients at least 18 years of age with newly diagnosed light-chain amyloidosis and measurable hematologic disease were included in the study. Patients with symptomatic multiple myeloma or who received previous therapy for AL amyloidosis were excluded from the study. Patients were randomized in a 1:1 ratio to receive either bortezomib, cyclophosphamide, dexamethasone, daratumumab, and then single-agent daratumumab treatment or bortezomib, cyclophosphamide, and dexamethasone treatment, respectively. The primary endpoint was a hematologic complete response at the time of clinical cutoff. The median follow-up was 11.4 months (range, 0.03 to 21.3). The daratumumab group (53.3%) had improved hematological complete response compared to the control group (18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P < 0.001). Survival free from major organ deterioration or hematologic progression was better with daratumumab treatment compared to the control group (hazard ratio, 0.58; 95% CI, 0.36 to 0.93; p = 0.02). Additionally, cardiac (daratumumab group, 41.5%; control group, 22.2%) and renal (daratumumab group, 53.0%; control group, 23.9%) responses favored daratumumab. Deaths were similar between both groups (daratumumab group, 27 deaths; control group, 29 deaths). The addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone is promising due to the improved cancer response, but the maturation of overall survival data will help inform future practice.
Image: PD
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