{"entity":{"id":"melflufen","kind":"drug","name":"Melphalan flufenamide","aka":[],"tldr":"A myeloma drug given accelerated approval in 2021 and withdrawn in the US months later when its confirmatory trial suggested it shortened survival.","summary":"Melflufen is a lipophilic peptide-conjugated alkylator activated by aminopeptidases enriched in myeloma cells. Accelerated approval (February 2021) rested on the single-arm HORIZON response rate. The confirmatory OCEAN trial met its PFS endpoint but showed an overall survival detriment in a subgroup (patients with prior autologous transplant), leading to a partial clinical hold, an ODAC vote against, and US withdrawal (2021; formal FDA withdrawal 2024). It remains approved in the EU with restrictions.\n\nLesson: accelerated approval on response rate carries real risk when the confirmatory trial shows harm; the same subgroup could be a true signal or noise, and regulators in the US and EU read it differently.","status":"withdrawn","asOf":"2026-09-06","wikipedia":"https://en.wikipedia.org/wiki/Melphalan_flufenamide","links":[{"label":"FDA withdrawal of Pepaxto approval (Feb 2024) (page moved; nearest live section)","url":"https://www.fda.gov/drugs/drug-safety-and-availability/"}],"tags":["failure","lesson:regulatory"],"related":[],"cancers":["multiple-myeloma"],"sections":[],"technologies":["peptide-drug-conjugate"],"targets":[],"drugs":[],"companies":["oncopeptides"],"institutions":[],"pathways":[],"terms":["accelerated-approval"],"trials":["nct03151811","nct04649060","nct02963493"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"brand":"Pepaxto","code":"melflufen","modality":"Peptide-drug conjugate","mechanism":"Peptidase-activated alkylating prodrug of melphalan.","approvals":[],"mechanismSteps":[],"toxicity":[],"access":[],"regulatoryEvents":[{"date":"2021-02-26","type":"accelerated-approval","region":"US","note":"Accelerated approval on a surrogate endpoint, with a confirmatory trial required.","source":"https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-melphalan-flufenamide-relapsed-or-refractory-multiple-myeloma","indication":"In combination with dexamethasone for the treatment of adult patients with relapsed or refractory (R/R) multiple myeloma (MM) who have received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD-38 directed monoclonal antibody"},{"date":"2024-02-23","type":"withdrawal","region":"US","note":"Withdrawn: the indication came off the label 3.0 years after its accelerated approval.","source":"https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-melphalan-flufenamide-relapsed-or-refractory-multiple-myeloma","indication":"In combination with dexamethasone for the treatment of adult patients with relapsed or refractory (R/R) multiple myeloma (MM) who have received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD-38 directed monoclonal antibody"}]},"route":"/drugs/melflufen/","neighbours":{"cancer":[{"id":"multiple-myeloma","kind":"cancer","name":"Multiple myeloma","route":"/cancers/multiple-myeloma/"}],"technology":[{"id":"peptide-drug-conjugate","kind":"technology","name":"Peptide-drug & small-molecule-drug conjugates","route":"/technologies/peptide-drug-conjugate/"}],"company":[{"id":"oncopeptides","kind":"company","name":"Oncopeptides","route":"/companies/oncopeptides/"}],"term":[{"id":"accelerated-approval","kind":"term","name":"Accelerated approval","route":"/terms/accelerated-approval/"}],"trial":[{"id":"nct02963493","kind":"trial","name":"A Study of Melphalan Flufenamide (Melflufen) Plus Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma","route":"/trials/nct02963493/"},{"id":"nct03151811","kind":"trial","name":"A Study of Melphalan Flufenamide (Melflufen)-Dex or Pomalidomide-dex for RRMM Patients Refractory to Lenalidomide","route":"/trials/nct03151811/"},{"id":"nct04649060","kind":"trial","name":"Study of Melflufen (Melphalan Flufenamide) in Combination With Daratumumab in Relapsed-Refractory Multiple Myeloma","route":"/trials/nct04649060/"}],"bottleneck":[{"id":"b-negative-results","kind":"bottleneck","name":"Failures are hidden","route":"/bottlenecks/b-negative-results/"}]}}