Minimal residual disease following autologous stem cell transplant in myeloma: impact on outcome is independent of induction regimen.

Minimal residual disease (MRD) is a powerful determinant of overall outcome in multiple myeloma (MM). Previous studies have demonstrated that the presence of MRD at the traditional day 100 assessment point following autologous stem cell transplant (ASCT) independently predicts for both progression-free (PFS) and overall survival (OS). This effect on outcome is demonstrable in patients achieving a complete response (CR) and in those with both high-risk and standard-risk cytogenetics. As a consequence, MRD assessment is currently being considered as a surrogate end point for survival in academic clinical trials and for regulatory drug approval. Surrogate end points are clearly desirable in MM given the increasing complexity of treatment schedules and continually improving complete response rates and survival, such that trials of up-front therapy require 5-10 years of follow up in order to demonstrate survival differences. Acceptance of MRD as an appropriate end point would also ideally require the demonstration that this effect was independent of the treatment received. We have, therefore, assessed the impact of induction regimen and MRD on outcome in the context of the Medical Research Council (MRC) Myeloma IX trial (ISRCTN68454111). MRC Myeloma IX was a multi-center, randomized phase III trial with protocol and clinical results previously reported. All patients provided written informed consent. This analysis involves 397 patients randomly assigned to CTD (cyclophosphamide, thalidomide, and dexamethasone; n=189) or CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone; n=208) for 4-6 cycles, then high-dose melphalan (HDM, 200 mg/m) and ASCT. Bone marrow (BM) aspirates for MRD assessment were obtained at the end of induction (n=252) and at day 100 post ASCT (n=397). Patients were then randomly assigned to maintenance thalidomide (50-100 mg daily) or no further therapy. Flow cytometry for MRD detection was performed as reported previously. Briefly, we assessed 500,000 cells incubated with 6-color antibody combinations including CD138/CD38/CD45/CD19 with CD56/CD27 in all cases and CD81/CD117 in some cases as required. Statistical analyses were landmarked from date of MRD assessment, with a median follow up of 71 months. Fisher’s exact test was used to perform between-group comparisons and survival (OS and PFS) was analyzed using Kaplan-Meier and the log rank tests with a 5% significance level. We have previously reported that the CTD regimen showed superior categorical response rates to CVAD. Overall response rate was 82.5%: CTD versus 71.2% with CVAD (P<0.0001). Similarly, the CR rate was 13.0% versus 8.1% when assessed at the end of induction and 50.0% versus 37.2% post ASCT (P=0.008 and 0.0005, respectively). MRD analysis was performed in a subset of 397 patients and a greater proportion of patients became MRD-negative with CTD than with CVAD both at the end of induction (25% vs. 13%; P=0.0039) and post ASCT (71% vs. 54%; P<0.001). When outcome is assessed according to MRD status post ASCT, there is a highly significant outcome advantage for those who are MRD negative (median PFS 28.6 vs. 15.9 months, P<0.001; median OS 80.6 vs. 59.0 months, P=0.018). When this effect is also assessed according to the induction therapy received, it is clear that the prognostic effect of MRD negativity is identical in those who received CTD and those who received CVAD. For MRD-negative patients, the median PFS was 28.9 months with CTD versus 28.7 months with CVAD (P=0.54) (Figure 1A) while the median OS was 80.6 months versus not reached (P=0.81) (Figure 1B). Similarly, in MRD-positive patients, outcome was identical with each induction regimen,