Distinct trajectory and prognosis of measurable residual disease (MRD) in t(11;14) multiple myeloma (MM) treated with upfront quadruplet (QUAD) therapy and autologous stem cell transplantation (ASCT)

Abstract Introduction QUAD induction with a proteasome inhibitor, an immunomodulatory agent, anti-CD38 monoclonal antibody, and dexamethasone followed by ASCT lead to high proportion of MM patients (pts) achieving MRD negativity with improved outcomes. MM harboring t(11;14) has unique biological features and may have different kinetics of response to systemic therapy, as described in the pre-QUAD era. It is unknown whether MRD reduction dynamics in t(11;14)pos are similar to t(11;14)neg MM and if t(11;14) status affects the role of MRD as prognostic factor. Methods We analyzed 302 pts. with newly diagnosed MM (NDMM) who received QUAD induction followed by ASCT. Post ASCT consolidation/maintenance varied and was informed by MRD status per clinical trial design (N=111) or institutional practice (N=191). All patients had MRD assessed post induction, post ASCT and at least yearly thereafter regardless of International Myeloma Working Group response. We describe achievement of MRD negativity and sustained MRD negativity (S-MRD, two consecutive MRD negative tests ≥ 12 months apart, not interrupted by a positive test) at 10-5 and 10-6 thresholds. We utilized Cox regression to build predictive models of disease progression by inputting MRD as time-varying covariate. Results Median age of the pts. was 62 years (IQR 56-69), and 47 (16%) had t(11;14)pos MM. Median duration of follow up was 40.6 mo., 36.5 mo. for t(11;14)pos and 41.5 mo. for t(11;14)neg pts. MRD negativity rate at 10-5threshold for t(11;14)pos vs. t(11;14)neg patients was 9% vs. 31% (P=0.01), 36% vs. 59% (P=0.03), and 51% vs. 75% (P<0.001) at post induction, post ASCT and at any time on follow up, respectively. Corresponding figures for 10-6 threshold were 4% vs. 16% (P=0.03), 23% vs. 46% (P=0.05), and 45% vs. 62% (P=0.03), respectively. The rates of S-MRD negativity at 10-5 threshold were 38% vs. 45% (P=0.41), and at 10-6threshold 30% vs. 37% (P=0.35). Median time to achieve MRD negativity at 10-5 was 13.6 vs 7.7 vs. mo (P=0.002) and at 10-6 was 29.0 vs. 11.6 mo. (P=0.023) for t(11;14)pos vs t(11;14)neg, respectively. Four-year progression-free survival (PFS) was 93% for t(11;14)pos and 73% for t(11;14)neg patients (P=0.017). Among pts with no high-risk chromosome abnormalities [del(17p); t(4;14),t(14;16), gain/amp(1q)], 4-year PFS was 100% vs. 86% for t(11;14)posvs t(11;14)neg pts (P=0.06). In multivariate analysis, both the achievement of S-MRD negativity at 10-5 (HR 0.37, P<0.001) and the presence of t(11;14) (HR 0.32, P=0.58) were associated with reduced risk of progression or death. Due to small number of PFS events (N=3, all in patients who did not achieve S-MRD negativity) the protective effect of MRD could not be demonstrated exclusively among t(11;14)pos patients. Conclusion In the setting of QUAD therapy + ASCT with MRD-adapted post ASCT therapy, patients with t(11;14)pos MM have outstanding prognosis despite slower conversion to MRD negativity than in t(11;14)neg pts. The overall rate of S-MRD negativity appears comparable in t(11;14)pos and t(11;14)neg patients. In the setting of QUAD + ASCT therapy for NDMM, both S-MRD negativity and t(11;14)pos status are associated with lower risk of progression or death.