Curing myeloma at last: Defining criteria and providing the evidence

Does the dogma that multiple myeloma is incurable still hold?. The genomic chaos and resulting resistance to apoptosis of myeloma, long considered an obstacle to cure, formed the basis of Total Therapy (TT) program. The TT approach uses all myeloma-active drugs upfront to target drug-resistant subclones during initial treatment to prevent later relapse. Long-term follow-up of 1202 patients (TT1:n=231, median follow-up: 21 years; TT2: 668, median follow-up: 12 years; TT3a:n=303,medianfollow-up: 9 years) permitted investigationofwhether progression-free survival (PFS) and complete response (CR) duration were consistent with curability, ie observation of plateausinKaplan-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 with10yearsintheremainderwithlow-risk disease. Aparametric model basedonPFS and CR duration supported an increase incurability: 10-year PFSandCRestimates increasedfrom8.8%/17.9%inTT1to15.5%/ 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.