Immune-MRD Status Informs Tumor-MRD Outcome Prognostication in Multiple Myeloma Patients on Lenalidomide Maintenance

• Published in: Blood 2024-11, Vol.144, p.672-672
• Main Authors: Firestone, Ross S, Simhal, Anish Kumar, McAvoy, Devin, Jurgens, Eric M, Garcés, Juan-José, Nemirovsky, David, Derkach, Andriy, Maclachlan, Kylee H, Hultcrantz, Malin, Mailankody, Sham, Shah, Urvi A., Tan, Carlyn Rose, Korde, Neha, Hassoun, Hani, Rajeeve, Sridevi, Hashmi, Hamza, Landau, Heather J., Scordo, Michael, Shah, Gunjan L., Giralt, Sergio, Diamond, Benjamin, Maura, Francesco, Hosszu, Kinga K., Chung, David J., Landgren, Ola, Usmani, Saad Z., Lesokhin, Alexander M.
• Format: Article
• Language: English
• ISSN: 0006-4971
• DOI: 10.1182/blood-2024-206646

Introduction: Measurable residual disease negativity (MRD-) is predictive in newly diagnosed (ND) multiple myeloma (MM). However, the clinical significance of MRD resurgence (MRDres), where MRD- patients show re-emergence of MRD positivity (MRD+), is incompletely understood. Additionally, the significance of patient-specific immune profiling has not been thoroughly explored in MM patients with no evidence of measurable disease. Methods: We prospectively followed 108 MM patients in a now completed phase 2, single arm study of 5 years of continuous lenalidomide (Len) maintenance following unrestricted frontline therapy. Dynamic MRD assessments were made via annual bone marrow (BM) biopsies (MRD- defined as 10-5 by multicolor flow). Exploratory peripheral blood (PB) T cell profiling was performed via high-dimensional spectral cytometry using two ~40-color T cell focused panels inclusive of lineage, exhaustion, activation markers and intracellular transcription factors and granzymes. T cell profiling results were analyzed with dimensionality reduction analysis with UMAP and algorithm assisted cell clustering with Phenograph and were correlated to dynamic MRD status and clinical outcomes. Statistical analysis for immune profiling results was performed using unpaired t-tests with multiple comparisons correction via the Boneferroni method. Results: In line with prior datasets, patients MRD- at the start of Len maintenance (N = 46) had superior progression free survival (PFS) compared to MRD+ patients (N = 62, P = 0.0021). MRDres was observed in 11 patients; however, only 4/11 had subsequent progression of disease (POD), with a median post-MRDres follow-up time of ~2 years. Patients with MRDres had poorer outcomes than those with sustained MRD- status at both the 1-year (P = 0.036) and 2-year landmarks (P = 0.0014); however, there were no significant differences in PFS between MRDres patients and MRD+ patients at either the 1-year (P = 0.68) or 2-year (P = 0.27) landmarks. PB T cell profiling experiments performed at the time of MRDres (matched control timepoints in sustained MRD- patients) showed that patients with MRDres but without subsequent POD had nearly identical T cell characteristics to those with sustained MRD- status. Patients with MRDres and with subsequent POD within 18 months of MRDres showed highly distinct T cell profiles enriched with T cell clusters corresponding to CD8+CD45RO+CCR7- effector memory (TEM, 2.5 fold increase, P = 0.003), and CD4+CD4