Multiple myeloma is a plasma cell malignancy that, while typically incurable, is now associated with a median life-expectancy of 8-10 years. Myeloma tends to affect older patients, with a prevalence of 0.2% among Medicare beneficiaries. Patients often receive treatment continuously over several years, and guidelines recommend triplet (or quadruplet) combinations, including both oral therapies (covered under Medicare Part D) and intravenous/subcutaneous therapies (covered under Medicare Part B), in both first- and second-line settings. Medicare Part B reimbursement is pegged to average sales prices in commercial markets, while Medicare Part D reimbursement depends on negotiation by individual plans and pharmacy benefit managers (PBMs). Plans and PBMs often lack substantial leverage to negotiate prices for Part D oncology drugs because Medicare is required by law to cover all cancer drugs. We hypothesized that Medicare spending on myeloma drugs has increased over time, and that spending per 30-day supply in Medicare Part D is higher than in Part B. We analyzed trends in Medicare use and spending on these drugs from 2013-2021. Methods We used publicly-available Medicare Part B and Part D data to determine annual spending on myeloma drugs, the number of beneficiaries who received these drugs, and the average spending per 30-day supply. We estimated net spending after rebates as <10%, based on various publicly available reports from Congress, MedPAC and the GAO, and adjusted spending to 2021 US dollars based on the consumer price index for all urban consumers. Institutional review board approval was not required, because the study used public, nonidentifiable data. Results The cohort included 6 oral drugs for myeloma covered under Medicare Part D and 8 intravenous/subcutaneous drugs under Medicare Part B. From 2013-2021, annual net Medicare spending on these 14 drugs increased from $2 billion (B) to $10.2B (432%). Annual net Part D spending increased from $1.8B to $7.8B (428%), and mean spending per 30-day supply increased from $9,971 to $14,154 (42%)(Figure 1). Lenalidomide (68%) and pomalidomide (52%) had the largest price increases. Annual net Part B spending on myeloma drugs increased from $539 million (M) to $2.36B (437%) and mean spending per 30-day supply increased only from $5,828 to $9,683 (66%) (Figure 2). Spending on the three myeloma drugs approved via accelerated approval but subsequently withdrawn from the market following confirmatory trials was $85,328,842 (melflufen: $859,764, belantamab: $31,749,711, panobinostat: $52,719,367). Spending data demonstrate prescriber sensitivity to route-of-administration-specific toxicities: almost no intravenous bortezomib was prescribed, and in 2021, >60% of patients on daratumumab received subcutaneous Darzalex Faspro. Second-in-class anti-CD38 antibody isatuximab offered daratumumab little competition (623 beneficiaries received isatuximab vs 20,573 receiving daratumumab). Discussion Medicare spending on myeloma drugs increased markedly from 2013 to 2021. Most of the rise occurred in Medicare Part D, where increased spending was partly due to increased use as the number of Medicare beneficiaries increased during the study period from 52.4 million people to 63.9 million people and survival for patients with myeloma improved, meaning longer treatment courses. But increased spending was also due to rising prices, particularly for lenalidomide and pomalidomide. By 2021, Medicare spending for a 30-day supply of lenalidomide was $16,650 and for pomalidomide was $18,728. By contrast, no medication for myeloma covered under Medicare Part B exceeded $13,000 per month except melflufen, which only 41 beneficiaries received in 2021. A limitation of using these Medicare databases was that the frequency and duration of maintenance and combination therapy could not be quantified. But our findings highlight how plans and PBMs in Medicare Part D were unable to prevent substantial price increases on myeloma drugs over the past decade. Our analysis underscores why the Inflation Reduction Act-and its key provisions of inflationary rebates and Medicare price negotiation-are vital to rein in Medicare spending. Generic competition, particularly for lenalidomide and bortezomib, whose patents expired recently, may also help reduce the high prices of myeloma drugs.