The treatment landscape of multiple myeloma (MM) has evolved significantly over four decades, driven by novel therapies and optimized supportive care. However, the attrition rate (AR), defined as the proportion of patients who die without advancing to the next line of therapy (LOT) after treatment failure, remains a major challenge. To assess how treatment patterns and outcomes have evolved, we analyzed 1,297 MM patients treated between 1980 and 2020, stratified by diagnosis period and age. ARs declined from 38-55% in the 1980s to 15-20% in 2010-2020, but remained high in older patients, with 46.9% of those over 80 unable to proceed beyond first LOT. While progression-free survival gains were primarily observed in the first LOT (15.8 to 24.1 months, p = 0.001), overall survival (OS) improved across all LOTs and age groups, likely due to more effective salvage therapies and supportive care. Achieving a complete response in first-line therapy was associated with a significant OS benefit (4.5 vs. 1.6 years, p < 0.001), underscoring its importance, as many patients, particularly older ones, are less likely to reach subsequent LOTs. Despite advances in MM treatment, patient loss to attrition remains a challenge, highlighting the need for more effective therapies early in the disease course.