AQUILA Trial Insights: Daratumumab for the Treatment of High-Risk Smoldering Myeloma
Key Points
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At 5 years, data from the AQUILA trial demonstrated improved progression-free survival and overall survival (OS) with the use of daratumumab in patients with high-risk smoldering multiple myeloma.
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Daratumumab has an established safety profile, with the greatest toxicity being pneumonia in the AQUILA study.
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A central question remains whether early therapy meaningfully alters long-term outcomes.
Data from the pivotal AQUILA trial led to the FDA approval of daratumumab for the treatment of people with high-risk smoldering multiple myeloma. In a recent episode of the Oncology Brothers podcast, cohosts Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, spoke with Vincent Rajkumar, MD, of Mayo Clinic, who provided expert perspective on the biology of smoldering myeloma, risk stratification, and the evolving rationale for early therapeutic intervention.
Across the Plasma Cell Disorder Spectrum
Dr. Rajkumar began by describing how smoldering myeloma fits within the broader spectrum of plasma cell disorders. At one end is monoclonal gammopathy of undetermined significance (MGUS), a generally benign condition associated with a low annual risk of progression. At the other end is multiple myeloma (MM), a malignant disease requiring immediate treatment. Smoldering myeloma is in the middle, he said, and is typically associated with a 10% per year risk of progression, with about a 50% chance of developing symptomatic MM within the first 5 years after diagnosis. However, Dr. Rajkumar said that smoldering myeloma is biologically heterogeneous, and not all patients share the same risk.
Over the past 25 years, several studies have attempted to determine whether treating patients during the smoldering phase could delay progression or improve survival, Dr. Rajkumar said. Early randomized trials comparing immediate treatment versus observation did not consistently demonstrate meaningful benefit, in part because they enrolled unselected smoldering populations. Researchers then shifted focus toward identifying and treating only patients with high-risk smoldering myeloma, which accounts for roughly one-third of all smoldering cases, he said.
AQUILA: What the Trial Means for Smoldering MM
Using this framework, the AQUILA trial was designed to examine high-risk patients who were treated with daratumumab (n=194) or observation (n=196). The primary endpoint was time to progression to symptomatic MM, with secondary endpoints including response rates, OS, and safety outcomes. The trial showed that 63% of patients treated with daratumumab remained progression-free compared with 41% in the observation arm. Investigators also observed an early signal suggesting improved OS.
Dr. Rajkumar emphasized that the central question is whether early therapy meaningfully alters long-term outcomes. “Early therapy may prevent patients from going into a state where they are not able to get adequate therapy quick enough to prevent deaths,” he said.
In AQUILA, daratumumab was administered for 3 years based on tolerability and clinical feasibility. Ongoing studies continue to refine the optimal treatment duration.
Daratumumab Safety Profile
Daratumumab has an established safety profile across multiple FDA-approved indications in myeloma, Dr. Rajkumar explained. In the AQUILA study, grade 3 or 4 toxicities were more common in the treatment arm, with infections like pneumonia representing the primary concern. However, Dr. Rajkumar said that the overall toxicity profile is manageable, which contributed to the FDA’s decision to approve the indication.
“This is an exciting time in MM,” he said. “We’ve had 20 drugs approved in 20 years. New discoveries are being made, and those discoveries will translate into smoldering myeloma.”