Measurable residual disease in newly diagnosed multiple myeloma: Experience from a large cohort from an academic medical center Free

Introduction

Achieving undetectable measurable residual disease (MRD) is associated with improved progression-free survival (PFS) and overall survival (OS) in patients with multiple myeloma (MM). In the era of novel therapies that provide prolonged disease control, MRD serves as a key surrogate marker of efficacy, and may guide therapeutic strategies such as treatment intensification or discontinuation.

Materials

Clinical records of patients with MM and at least one bone marrow MRD assessment at University of California San Francisco (UCSF) between November 2017 and May 2024 were reviewed. Among 636 patients, 440 patients were evaluated from the start of first-line therapy, and prior to disease progression. MRD was assessed in BM samples with the clonoSEQ® assay. A cutoff of 10^-6 was used to define negative MRD (MRD-). High-risk cytogenetics was defined as t(4;14), t(14;16) or del(17p).

Results

Baseline characteristics are summarized in Table 1. Median age at treatment initiation was 62 years (interquartile range, IQR 55-67). Cytogenetic analysis was available in 388 patients (88%), with 96 (25%) classified as high-risk. Of 362 patients with ISS staging, 36%, 34% and 30% were stage I, II and III, respectively. A total of 362 patients underwent up-front autologous stem cell transplantation (ASCT). In this cohort, induction, consolidation and maintenance regimens were highly heterogenous, as illustrated in Figure 1 (VCD 58 pts, VRD 181 pts, KRD 29 pts, DVRD 47 pts, Other 47 pts).

MRD- status was achieved at any time by 186 patients (42.3%) — 165 in the ASCT group (45.6%) and 21 (26.9%) in the non-ASCT group — and was associated with significantly improved PFS (Hazard Risk, HR, 0.45, 0.22-0.94) and OS (HR 0.5, 0.34-0.73) (Figure 2A and B). Median follow-up was 42.5 and 45 months for ASCT patients (MRD- and non-MRD-, respectively), and 33 and 34 months for non-ASCT patients (MRD- and non-MRD-, respectively). None of the 21 non-ASCT patients reaching MRD- relapsed during follow-up. Subsequent analysis focused on the ASCT group, given the larger sample size and number of MRD evaluations. We investigated the prognostic value of MRD at specific time points: post-ASCT (within 3 months), 1 year post-ASCT (±3 months), and 2 years post-ASCT (±3 months). Notably, MRD- status was predictive of better PFS only at the latter two time points (HR 0.31, 0.13-0.76; HR 0.3, 0.12-0.75, respectively) (Figures 2C, D and E).

Conclusions

In this large real-world cohort of patients with newly diagnosed MM, MRD- status was associated with improved PFS and OS. Interestingly, MRD shortly after ASCT was not prognostic, whereas MRD- at 1 and 2 years post-transplantation demonstrated predictive value. This may reflect delayed tumor clearance or the impact of maintenance therapy and other post-ASCT interventions. In daily practice, patients may go through different regimens before progression, due to performance status or insurance issues. This heterogeneity may not be captured by clinical trials and underscores the need of real-world studies to validate the clinical value of MRD.