Background: Despite improved survival with advanced multiple myeloma (MM) treatments (Tx), 15–20% of pts experience early relapse. We assessed the economic impact of early progression among non-stem-cell transplant NDMM pts. Methods: NDMM pts with ≥ 1 Tx (1^st claim date: index date) from 01Jan2011–31Dec2015 were identified from the 100% Medicare database. Eligible pts had ≥ 1 full cycle of therapy and continuous health plan enrollment from 6 months pre-index or first MM diagnosis date until ≥ 12 month post-index date unless pts died < 12 months post-index date. First line of therapy (LOT1) included all Txs prescribed ≤ 60 days post-index date. Among pts who progressed to LOT2, median time to next Tx (TTNT) was estimated from a Kaplan–Meier curve as duration from LOT1 start until the earliest of an addition/switch/restart of non-maintenance MM Tx, or dose increase from maintenance to relapse therapy. Pts who progressed to LOT2 prior to and after median TTNT were included in the early and delayed progression cohorts, respectively. Annual all-cause and MM-related healthcare costs estimated from a generalized linear model were compared between doublet therapy pts in LOT1 in the early and delayed progression cohorts. Results: Of 3,768 MM pts with LOT1, 36.1% progressed to LOT2 with median TTNT of 302 days; 81.3% pts initiated doublet therapy in LOT1, of which 19.2% (n = 589) and 17.3% (n = 533) were included in the early and delayed progression cohorts, respectively. Pts in the early progression cohort were younger and incurred higher all-cause inpatient ($17,332 vs $10,455), outpatient hospital ($18,183 vs $15,097), emergency department ($462 vs $395), office ($37,728 vs $29,174), and total costs ($130,948 vs $108,003) compared with the delayed progression cohort. Similarly, the early progression cohort had higher MM-related total costs ($87,284 vs $72,150) including inpatient and outpatient costs (all P< 0.001). All-cause and MM-related pharmacy costs were similar between cohorts. Conclusions: Early progression after LOT1 is associated with substantially higher economic burden indicating the need for future studies of therapies that delay progression and potentially result in cost savings.