Minimal Residual Disease in Multiple Myeloma: Current Landscape and Future Applications With Immunotherapeutic Approaches

Abstract

The basic principle that deeper therapeutic responses lead to better clinical outcomes in cancer has emerged technologies capable of detecting rare residual tumor cells. The need for ultra-sensitive approaches for minimal residual disease (MRD) detection is particularly evident in Multiple Myeloma (MM), where patients will ultimately relapse despite the achievement of complete remission, which is commonplace due to remarkable therapeutic advances. Consequently, current response criteria on MM have been amended based on MRD status and MRD negativity is now considered the most dominant prognostic factor and the most valuable indicator for a subsequent relapse. However, there are particular limitations and several aspects for MRD assessment that remain open. This review summarizes current data on MRD in the clinical management of MM, highlights open issues and discusses the challenges and the endless opportunities arising for both patients and clinicians. Furthermore, it focuses on the current status of MRD in clinical trials, its dynamics in addressing debatable aspects in the clinical handling and its potential role as the prevailing factor for future MRD-driven tailored therapies.

Deep Phenotyping Reveals Distinct Immune Signatures Correlating with Prognostication, Treatment Responses, and MRD Status in Multiple Myeloma

“…In a previous study by Paiva et al, the authors proposed unique BM signatures correlating with distinct outcomes [52]. In particular, a profile by elevated erythroblasts and B cell precursors and decreased levels of naïve and memory B cells conferred the most inferior outcome, which was independent from patients' MRD status, thus implying that immune profiling could supplement MRD status for improved risk stratification [22]. Our analysis revealed a distinct immune profile between MRD+ and MRD-patients, with the latter showing a more experienced adaptive immunity (i.e., CD4+ and CD8+ T cells) phenotype, probably indicative of competent immune surveillance keeping myeloma burden in repression.…”

“…The evaluation of MRD has emerged as the strongest prognostic factor in MM informing for the depth of response to treatment and has been recently considered as a valuable endpoint to clinical trials and in some cases a critical point for tailored therapeutic strategies [21,22]. Although there are numerous studies highlighting the favorable prognostication of patients achieving MRD negativity [23,24], there is limited information regarding the underlying biology and immune profiling of MRD status.…”

Prognostic and Predictive Factors in Newly Diagnosed Multiple Myeloma Patients with Early Mortality with Prediction Matrix and Three and Five-Year Overall Survival

“…An evolving consensus is that achieving MRD-negative status at the time of induction therapy should be the goal of therapy. Though not-yet involved in staging systems, MRD-focused treatment assessments are becoming increasingly important with time [72].…”

Evaluation of measurable residual disease in multiple myeloma by multiparametric flow cytometry: Current paradigm, guidelines, and future applications

“…[16][17][18][19] Unlike NGF, NGS is considered to have a similar or slightly lower level of detection, can be performed on fresh or stored samples, but often requires the sequence of a diagnostic sample, making it applicable to only 90% of the patients. 20 Before a flow-based MRD assay can be applied to reliably evaluate rare myeloma cells, its accuracy and detection sensitivity need to be optimized. Important components to consider include factors such as (i) number of prior BM aspirate pulls being tested, (ii) optimal time points post-treatment for MRD assessment, (iii) focal nature of the disease, (iv) transportation and storage conditions of marrow aspirates, (v) antibody combination used for the identification and separation of normal vs abnormal PCs, (vi) prior administration of antibody-based immunotherapy, (vii) processing of BM cells for flow cytometric assessment, (viii) optimization of flow cytometers used for acquiring millions of events and (ix) data analysis and interpretation strategies.…”