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
Blood. 2010 May 25;[Epub Ahead of Print], F van Rhee, J Szymonifka, E Anaissie, B Nair, S Waheed, Y Alsayed, N Petty, JD Shaughnessy Jr, A Hoering, J Crowley, B Barlogie
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 (TNT) and post-relapse survival (PRS) in Total Therapy 3 were examined, employing time-dependent methodology, relevant to induction, peri-transplantation, 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, while T and D but not V dosing were critical to outcome improvement in the low-tertile NR3C1 setting. PMDD of V was an independent highly adverse feature for OS (hazard ratio, 6.44; p<0.001), while PMDD of both T and D independently imparted shorter TNT. Absence of adverse effects on PRS 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 TT3, toward maximizing myeloma survival. This study was registered at http://clinicaltrials.gov as NCT00081939.
