Dynamic evolution of minimal residual disease and normal plasma cells following autologous stem cell transplantation in multiple myeloma

Abstract High-dose melphalan followed by autologous stem cell transplantation (ASCT) has became a cornerstone of standard therapy for newly diagnosed multiple myeloma (MM). Patients undergoing ASCT often rely on minimal residual disease (MRD) monitoring disease status. Additionally, ASCT can improve the immune microenvironment and facilitate hematopoietic reconstitution, and plasma cell survival in the bone marrow depends on support from the marrow microenvironment, including contributions from other immune and stromal cells. Consequently, normal plasma cells (NPCs) in the bone marrow ,considered an incidental byproduct of MRD monitoring, could serve as a potential complementary biomarker reflecting post-transplant hematopoietic reconstitution.However, data on both post-ASCT MRD and NPCs remain limited.Therefore we retrospectively analyzed the dynamics of MRD and NPCs in the bone marrow of MM patients after first-line ASCT, and evaluated their prognostic significance. This study included 400 patients with newly diagnosed multiple myeloma (NDMM) who received first-line high-dose therapy followed by ASCT at the Blood Diseases Hospital of the Chinese Academy of Medical Sciences between August 30, 2005 and May 20, 2022. Among these patients, 356 had at least one MRD assessment, with a total of 1,351 MRD measurements included in the analysis. In our cohort, ASCT significantly improves MRD status, but this benefit was limited in patients with high pre-transplant tumor burden (≥10^−3), especially those harboring ≥2 high-risk cytogenetic abnormalities (HRCAs). As expected, MRD evolution patterns correlated with outcomes .Patients who sustained or converted MRD negativity after ASCT (neg-neg, n=102; pos-neg, n=122) had longer progression-free survival (PFS) than those who converted or sustained MRD-positive (neg-pos, n=31;pos-pos, n=70). Specifically, median post-translatation post-transplant PFS in the neg-neg, pos-neg, neg-pos, and pos-pos groups was 112.6, 59.6, 32.9, and 29.7 months, respectively (p<0.001). However, sustained MRD positivity (pos-pos) was not consistently associated with the poorest overall survival (OS) outcomes. Five-year post-ASCT OS rates were 87.1% for neg-neg, 85.95% for pos-neg, 78.58% for pos-pos, and 56.1% for neg-pos (p<0.001). According to comparing baseline characteristics among the four MRD subgroups ,we found the biggest difference in the incidence of the IgH translocation t(11;14) and it was less common in neg-neg compared to pos-pos and neg-pos (p < 0.001 and p = 0.013, respectively). Next, We analyzed the post-ASCT trend of the percentage of normal plasma cells among bone marrow mononuclear cells (NPC%). Overall, patients with MRD-positive status had significantly lower NPC% compared to MRD-negative patients and pos-pos had the lowest NPC% among all subgroups, especially. And we also observed heterogeneous trajectories of NPC recovery across MRD evolution groups, with the most favorable recovery seen in neg-neg, which presented a ”fast-then-slow” recovery pattern. To eliminate the influence of MRD negativity on NPCs, we focused on patients who were MRD-negative at 1 year post-ASCT (n = 162 ). At the time point, high NPC% group showed a strong trend toward longer PFS after transplant (median not reached vs. 55.6 months; p = 0.062) and obviously had higher immunoglobulin concentrations compared to the low NPC% group. Furthermore, NPC% was positively correlated with the different types of immunoglobulin levels. In conclusion, our results describe the pattern of MRD kinetics following ASCT and evaluate the prognostic Impact of MRD evolution. For the first time, we also outline the trajectory of NPC recovery post-ASCT and its correlation with immune reconstitution.