AQUILA Findings Fuel Debate Over Treatment Intensification in High-Risk Smoldering Myeloma

Clinical Summary:

• Mateo Mejia Saldarriaga, MD, examines the evolving treatment landscape for high-risk smoldering multiple myeloma, comparing single-agent strategies with more intensive combination approaches following the approval of daratumumab. 
• Single-agent daratumumab and lenalidomide have demonstrated progression-free survival benefits, although responses are often limited in depth, raising questions about whether these approaches meaningfully alter disease progression or prevent clinically significant complications. 
• These considerations highlight the importance of biologic risk stratification and individualized treatment intensity, particularly for patients with high-risk disease who may benefit from further investigation of combination treatment strategies. 

Mateo Mejia Saldarriaga, MD, discusses the evolving treatment landscape for high-risk smoldering multiple myeloma and the debate surrounding single-agent versus combination therapy. 

Dr Meja reviews evidence supporting single-agent daratumumab and lenalidomide, including findings from the AQUILA trial, while questioning whether improvements in progression-free survival benefits and predominantly partial responses translate into meaningful changes in disease trajectory. He also discusses the importance of genomic risk assessment and the potential for more intensive combination strategies to address patients with biologically aggressive disease who may be undertreated with single-agent approaches. 

Transcript:

My name is Mateo Mejia, I am an assistant professor of medicine at Weill Cornell Medicine and I work with the multiple myeloma and cell therapy group. We discussed today, or debated more so, the role of treatment in high-risk smoldering myeloma.

The big debate was should single treatment be used or should combination treatment be employed with these patients? 

It's a very relevant topic given the advances and the latest publication and approval of daratumumab, a single-agent treatment for high-risk smoldering myeloma, but also because we have gained insight into the biology of smoldering myeloma and understand that there's a lot of genetic underpinnings that really determine if a patient is going to develop disease or not.

Taking that into account, reviewing the data with single-agent treatment, not only with daratumumab, but also with lenalidomide, there's patients that have improved progression-free survival. They are positive trials, however, most of the responses are quite shallow– most of these patients achieve only a partial response, so we're not really changing the disease trajectory.

Furthermore, in AQUILA, even though there was an overall survival benefit, there was no differences in the rate of clinical progression, defined as fractures or clinically meaningful end point, most progression were biochemical. So, we're not really preventing an organ damage with this patient. 

The evidence at this point, even though we can provide single-agent treatment, we're not really changing the disease trajectory. In patients who have established myeloma that hasn't had any clinical manifestation, we might be under treating them.