Introduction: Therapeutic options for multiple myeloma (MM) have evolved rapidly with the introduction of proteasome inhibitors, immunomodulatory agents, monoclonal antibodies, and T-cell engagers, leading to deep and durable responses. Measurable residual disease (MRD) testing, using sensitive methods such as flow cytometry (FC) and molecular-based techniques (mMRD) including polymerase chain reaction and next-generation sequencing, provides critical insight into the depth of response beyond conventional metrics. Initially adopted in clinical trials, MRD testing is being explored to guide treatment decisions in real-world (RW) settings. MRD in MM has a strong correlation with long-term outcomes and was adopted as a regulatory endpoint by the FDA. mMRD offers higher sensitivity and is becoming more accessible in community oncology practices. However, data on RW adoption, testing patterns, and impact on treatment courses in MM remain limited.

Methods: This longitudinal, retrospective cohort study used patient-level data from the US-based Flatiron Health Research Database, an electronic health record (EHR)-derived, deidentified database, that includes structured and unstructured data from both academic and community oncology practices across the US. Data were curated through technology-enabled abstraction and underwent rigorous quality assurance. Patients with MM who received first-line (1L) treatment were eligible for the study. Algorithms/large language models were used to identify line of therapy (LOT) and MRD testing. MRD status was assigned per LOT using a hierarchical approach: patients with ≥1 MRD-negative result were classified as MRD-negative (indexed to earliest negative test); those with only positive results were MRD-positive (indexed to earliest positive test). Descriptive statistics summarized MRD testing patterns and clinical characteristics. Associations between MRD status and outcomes—including time to next treatment (rwTTNT) and overall survival (rwOS)—were analyzed using Kaplan-Meier and Cox models.

Results: Of 11,952 patients with MM, 2,389 (20%) had MRD testing totaling 5,677 tests (median, 2; range, 1-20). Among those tested, 53% had ≥1 MRD-negative result, 62% had ≥1 positive, and 9% had only unknown results. MRD was assessed via FC (52%) or mMRD (41%), with mMRD use rising post-2020 (21%-44%).

A significant number of MRD tests were conducted in the relapsed setting (57%) and among autologous stem cell transplant (ASCT) recipients (71%). Notably, >50% of testing in this data set occurred in community practices.

In 1L treatment, MRD-negativity was more common among transplant recipients compared to non-transplant recipients (52% vs 39%). Regimens associated with achieving the highest MRD negativity rates included anti-CD38 quadruplets (50%), followed by anti-CD38 triplets (38%), regardless of receipt of ASCT. For proteasome inhibitor-based triplets, MRD negativity was 34% without ASCT and 54% with ASCT. Lower rates of MRD-negativity were observed with doublets.

Across all LOTs, MRD-negative patients had significantly longer rwTTNT than MRD-positive patients (median, 30.8 vs 6.9 months; HR, 0.49; 95% CI, 0.44-0.54; P < 0.001). This association held in 1L (median, 39.4 vs 10.0 months; HR, 0.54, 95% CI, 0.46-0.63; P < 0.001) and was similar regardless of transplant status. Among MRD-negative patients in 1L, rwTTNT was comparable between those who received ASCT and those who did not (39.4 vs 36.4 months; HR, 1.12; 95% CI, 0.86-1.46; P = 0.40). MRD negativity in 1L was also associated with improved rwOS (HR, 0.67; 95% CI, 0.48-0.93; P = 0.016).Conclusions: MRD testing is increasingly integrated into MM care, with uptake in community settings and increased mMRD testing. RW MRD-negativity rates with anti-CD38 quadruplets align with clinical trial findings. MRD-negativity was strongly associated with prolonged rwTTNT and commonly observed among patients who received ASCT and modern regimens. Among MRD-negative patients in 1L, similar rwTTNT regardless of ASCT suggests prolonged benefit independent of transplant. MRD negativity in 1L was also associated with improved rwOS. The rise of mMRD enables scalable, high-sensitivity monitoring and clonal tracking. These findings support MRD testing as a prognostic and actionable tool. Further incorporation of MRD-guided strategies, including risk-adapted treatment duration, is warranted and aligns with ongoing prospective studies.

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2025
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