High-dose therapy and autologous stem cell transplantation (HDT-ASCT) have significantly improved survival in multiple myeloma (MM). However, patients are not cured, responses are variable and only about 40% of patients achieve a complete response (CR). Optimal timing of the procedure and knowledge of the relapse kinetics may assist physicians when they consider this therapeutic modality for their patients. We analyzed myeloma tumor burden and kinetics before and after HDT-ASCT in a cohort of 265 patients. Disease burden was estimated from serial M-spike measurements and the data fitted to the Gompertz function to determine the general parameters for all patients. Functions that couple disease burden and kinetics with time to progression (TTP) were derived and used to determine the optimal timing of transplantation. Patients who achieve CR with the first episode of HDT-ASCT should not be routinely offered tandem transplantation but carefully monitored and transplanted at an optimal disease burden. If CR is not achieved with a first trial of HDT-ASCT, the probability of CR after a tandem second trial is approximately 10%. TTP after tandem transplants (with its higher associated mortality) cannot be superior to TTP achieved with optimally timed serial transplants. Individualized HDT-ASCT for patients with MM is possible and may optimize results.