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 myeloma. The AQUILA trial compared daratumumab with active monitoring in high-risk SMM and led to regulatory approval and guideline updates. However, several challenges complicate interpretation of contemporary trials. 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. Additionnaly, OS was a secondary endpoint in AQUILA and in previous trials, none of which were powered for survival. Overal, before strong evidence showing otherwise, observation should remain the standard for high-risk smoldering multiple myeloma. • MGUS, SMM, and MM form a continuum, and not all smoldering cases progress • Progression definitions differ across trials, precluding comparison. • Most AQUILA progression events are SLiM, with unknown clinical benefit. • Informative censoring in AQUILA likely affects PFS and OS validity. • Before stronger evidence, we posit observation should remain a standard option