Professor of Medicine Myeloma Center, University of Arkansas of Medicine Little Rock, Arkansas, United States
Introduction: The introduction of novel agents in myeloma together with high dose chemotherapy has made it possible to strive for an operational cure at least in a proportion of patients. However, this requires long-term follow-up, which is outside the scope of many clinical trials. MRD negativity has been associated with a deeper response and better progression free survival (PFS). Herein, we examine whether serial MRD measurements in the first 5 years after diagnosis can serve as a surrogate for long-term outcome.
Methods: 1744 patients received a single or tandem autologous stem cell transplant for newly diagnosed myeloma. Standard demographic variables were collected. Bone marrow examinations were performed every 6-12 months and subjected to 8-color flow cytometry with a sensitivity of 10-5. All patients had at least 3 serial MRD tests performed in the first 5 years. Patients were allocated to three groups: Group 1 patients (n=487) had 3 serial MRD negative tests in the first 5 years and remained MRD negative. Group 2 patients (n=872) had both negative and positive MRD tests. Group 3 patients (n=385) were always MRD positive at every test. PFS was calculated using the Kaplan-Meier method from the date of first autologous stem cell transplant (ASCT) and compared with the log-rank test. The study was approved by the institutional IRB.
Results: The median age was 62.7 (range 29.4-85.9); 716 were >65 years. There were 303 (25.7%), 721 (61.0%) and 157 (13.3%) patients with R-ISS stage, R-ISS stage 2 and R-ISS stage 3 respectively. An elevated LDH (>190) was present in 410/1739 (23.6%). Abnormal cytogenetics were present in 410/1739 (50.6%). 1744 patients received one ASCT and 945 two ASCT (54.2%). High risk GEP was present in 209/1190 (17.6%). Overall, the median follow-up was 4.4 years (range: 0.1-17.3) Group 1 and Group 2 patients had a similar median MRD tests performed in the first 5 years post ASCT: 10 (range 3-24) and 9 (range 3-23) respectively. Group 3 had a lower median MRD test due to more early relapses (7:range 3-29) A similar observation applied to the total number of MRD test performed in each group; Group 1 median 11 tests (range 3-31), Group 2 median 12 tests (range 3-35), and Group 3 median 7 tests (range 3-29). The PFS at 5 years landmarked from first ASCT for group 1,2 and 3 were respectively 90, 48 and 8%.The PFS at 10 years were respectively 74, 30 and 1%. These differences were highly statistically different (P < 0.001). Group 3 were more likely to be older (p-value < 0.001), have baseline ISS and RISS stage III disease (p-value < 0.001 and 0.045), have abnormal cytogenetics profile (p-value < 0.001), abnormal FLC (p-value < 0.001) and have a high-risk GEP profile (p-value=0.0319) compared to Group 2 patients.
Conclusions: Achievement of 3 serial MRD negative tests in the first 5 years of therapy is predictive of an excellent long-term outcome with few treatment failures.
