Fig 3.

Lead-time bias, cumulative multiple myeloma (MM) –specific mortality, and monoclonal gammopathy of undetermined significance (MGUS) to MM progression variability. All simulations were performed with populations of 10⁸ healthy individuals (20% high risk). (A) Potential lead-time bias, comparing median survival after MM diagnosis without screening (blue: median survival, 4 years) and with screening (gold: median survival, 15 years; gray: median survival, 17 years after MGUS screen, respectively). Without screening, disease detection was the event of MM diagnosis. With screening, disease detection was diagnosis of asymptomatic MGUS. (B) Cumulative MM-specific mortality in years after MGUS detection was measured for the groups of 50, 60, and 70 years of age at MGUS detection (a₀ = 50 years, Δa = 1, and r = 1). In older patients, death resulting from other cause becomes more dominant. (C) MM-specific mortality changed dramatically with r (a₀ = 50 years, Δa = 1), here shown for individuals diagnosed with MGUS at age 60 years, sampled from simulations. (D) MM-specific mortality is influenced by variability in MGUS to MM progression rate²³ (inset, truncated normal distribution\; mean, 0.01; standard deviation, 0.03), for different r, using the analytic model (Δa = 1; Data Supplement). (E) Simple evolving MGUS progression rates [β × (1 − β)^t], fitted to data from Rosiñol et al²⁵ (filled circles; nonevolving: 10% at 10 years, 13% at 20 years follow-up; evolving: 55% at 10 years, 80% at 20 years follow-up), for which we show 95% CIs. Nonevolving MGUS confirms the low value of β (here 0.007; R² = 0.996), corresponding to constant progression risk p (Table 1). Evolving MGUS led to a progression rate of p = .071 (R² = 0.975). (F, G) Impacts of age at MGUS detection and progression risk reduction r on MM-specific mortality as a function of evolving progression rate calculated as described in Data Supplement: (F) r = 0.61 and (G) age at MGUS detection 60 years.