MRD dynamics during maintenance for improved prognostication of 1280 patients with myeloma in the TOURMALINE-MM3 and -MM4 trials

Abstract

Measurable residual disease (MRD) evaluation may help to guide treatment duration in multiple myeloma (MM). Paradoxically, limited longitudinal data exist on MRD during maintenance. We investigated the prognostic value of MRD dynamics in 1280 transplant-eligible and -ineligible patients from the TOURMALINE-MM3 and -MM4 randomized, placebo-controlled, phase 3 studies of 2-year ixazomib maintenance. MRD status at randomization showed independent prognostic value (median progression-free survival [PFS]: 38.6 vs 15.6 months in MRD- vs MRD+ patients, HR 0.47). However, MRD dynamics during maintenance provided more detailed risk stratification. A 14-month landmark analysis showed prolonged PFS in patients converting from MRD+ to MRD- status vs those with persistent MRD+ status (76.8% vs 27.6% 2-year PFS rates). Prolonged PFS was observed in patients with sustained MRD- status vs those converting from MRD- to MRD+ status (75.0% vs 34.2% 2-year PFS rates). Similar results were observed at a 28-month landmark analysis. Ixazomib maintenance vs placebo improved PFS in patients who were MRD+ at randomization (median 18.8 vs 11.6 months, HR 0.65) or at the 14-month landmark (median 16.8 vs 10.6 months, HR 0.65); no difference was observed in patients who were MRD-. This is the largest MM population undergoing yearly MRD evaluation during maintenance reported to date. We demonstrate the limited prognostic value of a single timepoint MRD evaluation, because MRD dynamics over time substantially impact PFS risk. These findings support MRD- status as a relevant endpoint during maintenance and confirm the increased progression risk in patients converting to MRD+ from MRD- status.

A pooled analysis of outcomes according to cytogenetic abnormalities in patients receiving ixazomib- vs placebo-based therapy for multiple myeloma

“…As such, further study that includes the patients' copy number of 1q is needed in order to determine the impact of this abnormality on treatment outcomes. Furthermore, data on measurable residual disease (MRD) were not collected for all four studies, thus an analysis of the relationship between MRD and cytogenetics cannot be conducted; however, a recent publication by Paiva et al evaluates the implications of MRD in the TOURMALINE-MM3 and TOURMALINE-MM4 study populations [35]. Another limitation is the use of inconsistent cutoff values for defining the presence of high-risk cytogenetic abnormalities across the four studies in this analysis, limiting cross-trial comparisons.…”

Eight‐color multiparameter flow cytometry (EuroFlow‐NGF) is as sensitive as next‐generation sequencing in detecting minimal/measurable residual disease in autografts of patients with multiple myeloma

“…Conventional MRD detection methods such as NGS and NGF have been applied to BM because MM has a strong effect on BM. As a result, evidence to support the clinical significance of MRD detection in BM has accumulated [ 21 , 22 , 23 ]. According to the guidelines of International Myeloma Working Group, BM cells are recommended as a material to assess MRD levels, and the cutoff value is set to be 10 −5 because of a difficulty in obtaining sufficient cells.…”

Late versus early response and depth of response are associated with improved outcomes in patients with newly diagnosed multiple myeloma enrolled in the TOURMALINE‐MM2 trial

“…Patients with indolent disease may be slower to respond to therapy but an early response, characterised by higher plasma cell proliferation rates, may lead to an initial increased sensitivity to treatment and, consequently higher rates of loss of response and poorer long-term outcomes [15,16]. Due to significant differences observed in several baseline characteristics, we performed a multivariate analysis to eval- [20].…”

“…By assessing late responders for what drives this superior PFS, a higher proportion had deeper responses versus early responders. There is a clear association between deeper responses and improved outcomes, as demonstrated by the prolonged PFS in patients with measurable residual disease (MRD) negativity in a pooled analysis of two previous studies investigating ixazomib maintenance [20].…”