Long-term follow-up of Total Therapy IV: a phase 3 clinical trial for standard-risk multiple myeloma

Multiple myeloma (MM), historically perceived as an incurable malignancy, now demonstrates excellent long-term survival. 122]3 This paradigm shift reflects the ongoing progress in the understanding of the disease's molecular complexities and the development of innovative treatment modalities, including the introduction of immunomodulatory drugs, proteasome inhibitors, anti-CD38 monoclonal antibodies, and high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT). 45]6 The absence of robust long-term follow-up data in phase 3 trials for MM underscores a critical gap in our understanding of the durability of treatment responses and the eventual outcomes for patients. 7thin our Total Therapy (TT) program, the strategic application of all MM-active agents upfront, aimed at diminishing the development or survival of drug-resistant subclones, has resulted in significant progress. 89]1011 Initial results of the randomized TT IV phase 3 clinical trial after a median follow-up of 4.5 years were previously published. 12This report presents the analysis of the longest-term follow-up of any phase 3 clinical trial in MM by focusing on clinical outcomes in patients classified as having low-risk MM based on their gene-expression profile that were enrolled in the TT IV trial (NCT00734877).The protocol, treatment details along with consort diagram of the trial, has been described previously (supplemental). 12After enrolling and randomizing 289 patients, the Data Safety Monitoring Board recommended closing the long-term TT IV (L-TT IV) arm due to the absence of a reduction in toxicity compared with short-term TT IV (S-TT IV).A total of 94 patients were enrolled to S-TT IV without randomization.Detailed methods, end points, and statistical analysis are summarized in the supplemental.The study was approved by the University of Arkansas for Medical Sciences Institutional Review Board.The study enrolled a total of 380 patients, 238 of which were enrolled into S-TT IV and 142 of which were enrolled into L-TT IV.Patient characteristics are summarized in Table 1.The median follow-up for the S-TT IV arm was 11.1 years (interquartile range IQR, 9.2-13.0),whereas the L-TT IV arm had a median follow-up of 13.1 years (IQR, 11.6-13.9).The overall median follow-up was 11.8 years (IQR, 10.1-13.4).No difference in adverse events was found between both arms apart from lower grade 3/4 infection in patients who were enrolled in S-TT IV.