Evolving challenges in smoldering myeloma trials: shifting endpoint measurement and definitions.

Smoldering multiple myeloma (SMM) represents a biological continuum between monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM), and not all individuals with smoldering disease will progress to symptomatic multiple myeloma. The AQUILA trial compared daratumumab with active monitoring in high-risk SMM and led to regulatory approvals and guideline updates. However, several challenges complicate interpretation of contemporary trials, including QuiRedex (lenalidomide-dexamethasone) and ECOG E3A06 (lenalidomide). Progression definitions differ across studies. Progression-free survival (PFS) in SMM reflects progression to MM using the hypercalcemia, renal dysfunction, anemia, and bone disease (CRAB) criteria, but AQUILA uniquely included the "SLiM" biomarkers. Presymptomatic disease constituted most progression events, and the clinical benefit of delaying progression to SLiM multiple myeloma remains unknown. Imaging frequency and modality also vary, with advanced imaging in AQUILA increasing detection of asymptomatic lesions and limiting comparability with prior trials. AQUILA is further affected by concerns about informative censoring. In open-label trials, patient dropouts may not occur at random, and reconstructed Kaplan-Meier analyses and sensitivity analyses indicate that modest changes in censoring assumptions could eliminate the appearance of an OS advantage. Additionally, OS was a secondary endpoint in AQUILA and in previous trials, and none of which were powered for survival. Overall, before stronger clinical evidence showing otherwise, observation including appropriate surveillance should remain the standard of care for high-risk smoldering multiple myeloma.