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Curing myeloma at last: defining criteria and providing the evidence

Bart Barlogie, Alan Mitchell, Frits van Rhee, Joshua Epstein, Gareth J. Morgan and John Crowley

Abstract

We examine whether the historical dogma of multiple myeloma being incurable still holds true. The genomic chaos and resulting resistance to apoptosis of myeloma, long considered an obstacle to cure, formed the basis of the Arkansas Total Therapy (TT) program. The TT approach employs all myeloma-active drugs up-front to target drug-resistant sub-clones during initial treatment to prevent later relapse. Long-term follow up of altogether 1202 patients enrolled (TT1: n=231, median follow up: 21yr; TT2: 668, median follow up: 12yr; TT3a: n=303, median follow up: 9yr) permitted investigation of whether progression-free survival (PFS) and complete response (CR) duration were consistent with curability, i.e. observation of plateaus in Kaplan-Meier plots for PFS and CR duration. In the subset of 627 patients with plasma cell gene expression profiling data, cure plateaus were apparent at 5 years in the 14% with high-risk myeloma compared to 10 years in the remainder with low-risk disease. A parametric model based on PFS and CR duration supported an increase in curability with successive trials. Thus, 10-yr PFS and CR estimates increased from 8.8%/17.9% in TT1 to 15.5%/28.2% in TT2's control arm to 25.1%/35.6% in TT2's thalidomide arm and to 32.9/48.8% in TT3a. Toward developing novel therapies, we recommend a concerted focus on patients with high-risk myeloma whose outcome has not been advanced.

  • Submitted July 25, 2014.
  • Accepted September 19, 2014.