Single Versus Multiple Transplants for Multiple Myeloma: Insights from In Vivo and In Silico Studies.

Background: The advent of high-dose therapy and autologous stem cell transplantation (HDT-ASCT) has significantly improved response rates and survival for patients with multiple myeloma (MM). However this form of therapy is potentially toxic and does not cure patients from their disease. The response to HDT-ASCT is variable and approximately 40% of patients achieve a complete response (CR). Patients with a CR have a significantly improved time to progression (TTP) compared to patients who do not achieve CR (nCR). Optimal timing of HDT-ASCT and considerations of the relapse kinetics may assist treatment planning for this disease. We analyzed myeloma tumor burden and kinetics before and after HDT-ASCT in order to define optimal timing of this therapy for the individual patient.

Patients and Methods: A cohort of 265 patients with MM who underwent HDT-ASCT at Mayo Clinic Rochester was studied. Disease burden before and after HDT-ASCT was estimated from serial M-spike measurements. The estimated tumor burden data were fitted to the Gompertz function and its parameters alpha and beta estimated using a non-linear least squares method. Cohorts of patients with CR and nCR were studied separately. Functions that coupled disease burden and kinetics with TTP were derived and used to determine the optimal timing of single and tandem transplantation.

Results: The Gompertz parameters alpha and beta for patients who achieved CR and for those who did not achieve CR with HDT were determined. Our values were lower than those of Sullivan and Salmon although the ratio of alpha/beta was of a similar order (implying the same carrying capacity). Using the idealized Gompertz parameters, simulations of single versus tandem transplants were performed. Our model predicts that tandem transplantation increases CR rate by approximately 10%. When the time between transplants was studied as a variable, our model suggests that the optimal time between transplants is 7 months.

Conclusions: Our modeling provides a theoretical understanding of tumor burden and kinetics for patients with MM who undergo HDT-ASCT. Patients who achieve CR with the first episode of HDT-ASCT should not be routinely offered tandem transplantation but carefully monitored and re-transplanted at an optimal disease burden. If CR is not achieved with a first cycle of HDT-ASCT, the probability of CR after a second trial of HDT is ~10% (similar to that reported by Attal et al 2003) although this depends on the tumor burden before the second transplant. 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 improve results.