P-076: The impact of heterogeneous disease distribution on MRD detection in patients with relapsed multiple myeloma

Introduction: The minimal residual disease (MRD) status is becoming increasingly important as an endpoint for clinical trials in multiple myeloma (MM). For newly diagnosed patients, a strong association between MRD-negativity and long-term survival has been established. However, relapsed MM (RMM) patients often show a short time to next relapse even after having achieved MRD-negativity during salvage therapy. This also holds true for novel immunotherapies, such as bispecific antibodies (BsAb) or CAR-T cells. One explanation could be an increasingly heterogeneous disease distribution with treatment-resistant tumor cells at bone marrow or extramedullary sites other than the iliac crest.
We performed a prospective study to address the question if functional imaging complements MRD-diagnostics in RMM patients and at which timepoints residual disease monitoring should be performed.

Methods: We included 40 patients with at least 2 prior lines of therapy receiving novel agents-based salvage therapy (n=18) or modern immunotherapy (CAR-T or BsAb, n=22). Bone marrow biopsies for MRD detection using the Euroflow-assay (median sensitivity of 3x10-6) and next-generation sequencing (NGS) were taken before initiation of salvage therapy (baseline), and after 3, 6 and 12 months. Whole body MRI including diffusion weighted imaging (DWI) was performed at baseline, and after 1, 3, 6 and 12 months, while 18-F FDG-PET-CT was performed at baseline and after 6 months.

Results: Here, we present results of an interim analysis at a median follow-up time of 6.4 months (data cutoff May 2023). Notably, at baseline 6 patients (15%) were already Flow-MRD-negative and 5 patients (13%) had very low MRD levels ( < 1x10-4). All these patients showed active lesions in both MRI and PET-CT and none of them became MRD-positive during follow-up, demonstrating a highly unbalanced disease distribution. After 3 months, 11/20 patients with at least a VGPR were MRD-negative. Using DWI, active residual lesions were detectable in 4 of the MRD-negative patients (36%). After 6 months, both DWI and PET-CT were applied and the proportion of MRD-negative patients with detectable active lesions increased to 7/11 (64%). PET-CT was more sensitive than DWI in detecting residual disease with 4/7 patients being positive in PET-CT only. Notably, 5/7 patients had received modern immunotherapies, highlighting the prevalence of discrepant findings in this setting.

Conclusions: Our data suggest that Flow-MRD negativity in RMM patients during salvage therapy needs to be interpreted with caution. The next step will be to test whether NGS can improve the MRD detection rate. Functional imaging also complements MRD-diagnostics after modern immunotherapies. Yet, it remains to be investigated if detected lesions represent active disease or disease remnants and if this combination allows for a better prediction of time to next relapse.