title: Total Therapy 3 for multiple myeloma: prognostic implications of cumulative dosing and premature discontinuation of VTD maintenance components, bortezomib, thalidomide, and dexamethasone, relevant to all phases of therapy.
abstract: The impact of cumulative dosing and premature drug discontinuation (PMDD) of bortezomib (V), thalidomide (T), and dexamethasone (D) on overall survival (OS), event-free survival (EFS), time to next therapy, and post-relapse survival in Total Therapy 3 were examined, using time-dependent methodology, relevant to induction, peritransplantation, consolidation, and maintenance phases. Univariately, OS and EFS were longer in case higher doses were used of all agents during induction, consolidation (except T), and maintenance (except V and T). The favorable OS and EFS impact of D induction dosing provided the rationale for examining the expression of glucocorticoid receptor NR3C1, top-tertile levels of which significantly prolonged OS and EFS and rendered outcomes independent of D and T dosing, whereas T and D, but not V, dosing was critical to outcome improvement in the bottom-tertile NR3C1 setting. PMDD of V was an independent highly adverse feature for OS (hazard ratio = 6.44; P < .001), whereas PMDD of both T and D independently imparted shorter time to next therapy. The absence of adverse effects on postrelapse survival of dosing of any VTD components and indeed a benefit from V supports the use up-front of all active agents in a dose-dense and dose-intense fashion, as practiced in Total Therapy 3, toward maximizing myeloma survival.
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Frits
authors.initials: F
authors.lastname: van Rhee
authors.forename: Jackie
authors.initials: J
authors.lastname: Szymonifka
authors.forename: Elias
authors.initials: E
authors.lastname: Anaissie
authors.forename: Bijay
authors.initials: B
authors.lastname: Nair
authors.forename: Sarah
authors.initials: S
authors.lastname: Waheed
authors.forename: Yazan
authors.initials: Y
authors.lastname: Alsayed
authors.forename: Nathan
authors.initials: N
authors.lastname: Petty
authors.forename: John D
authors.initials: JD
authors.lastname: Shaughnessy
authors.forename: Antje
authors.initials: A
authors.lastname: Hoering
authors.forename: John
authors.initials: J
authors.lastname: Crowley
authors.forename: Bart
authors.initials: B
authors.lastname: Barlogie
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D003907:Dexamethasone / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D005500:Follow-Up Studies; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016133:Polymerase Chain Reaction; D011719:Pyrazines / Q000008:administration & dosage; D011965:Receptors, Glucocorticoid / Q000235:genetics; D015996:Survival Rate; D013792:Thalidomide / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D001897:Boronic Acids; C497713:NR3C1 protein, human; D011719:Pyrazines; D011965:Receptors, Glucocorticoid; D013792:Thalidomide; D000069286:Bortezomib; D003907:Dexamethasone