Measurable Residual Disease Assessment in Multiple Myeloma: How Deep Is Enough?

Abstract

The introduction of new and more effective therapeutic options for Multiple Myeloma (MM) has significantly deepened and prolonged patients’ remission. As currently used treatment protocols induce high rates of complete responses, Measurable Residual Disease (MRD) assessment has become essential to enhance the evaluation of treatment efficacy. Detection of MRD has improved with the development of highly sensitive and standardized techniques such as Next Generation Flow or Next Generation Sequencing, complemented by functional imaging techniques. These advances offer a valuable opportunity to further optimize criteria of response to treatment. Currently, extensive data demonstrate that MRD status is a valuable prognostic factor of survival. Since MRD represents a real measurement of disease burden, its incorporation in clinical trials to guide treatment decisions will certainly translate into clinical benefits. Sustained MRD negativity can be used to consider optimal candidates for treatment discontinuation, whereas MRD positive high-risk patients may have access to novel immunotherapeutic strategies such as bispecific drugs or CAR T cell therapy. In this review, we describe the available techniques to detect MRD, address the current data regarding MRD as a surrogate endpoint within clinical trials, examine how MRD can be introduced into the clinical management of MM patients, and discuss the future of MRD monitoring.

Dose Titration of Ixazomib Maintenance Therapy in Transplant‐Ineligible Multiple Myeloma: Exposure–Response Analysis of the TOURMALINE‐MM4 Study

“…Indeed, MRD status has increasingly been used as a metric of response depth, and deeper responses in turn have been associated with longer overall survival. [7][8][9][10] Together, these end points reflect the emphasis on prolongation/deepening of clinical response in the maintenance setting, while ensuring an acceptable safety profile over extended treatment durations. 11,12 In conjunction with these end points, we investigated the likelihood of dose modifications -namely, the probability of escalating from 3 to 4 mg at the end of Cycle 4, as well as the probability of dose reductions after either Cycle 1 Day 1 (C1D1) or Cycle 5 Day 1 (C5D1), to further support the posology.…”

“…Critically, we evaluated the relationships between ixazomib exposure and several end points reflective of the therapeutic setting: maintenance of complete response (CR), improvement from partial or very good partial response (PR, VGPR), maintenance of minimal residual disease (MRD)–negative status, and conversion from MRD‐positive to MRD‐negative status. Indeed, MRD status has increasingly been used as a metric of response depth, and deeper responses in turn have been associated with longer overall survival. 7–10 Together, these end points reflect the emphasis on prolongation/deepening of clinical response in the maintenance setting, while ensuring an acceptable safety profile over extended treatment durations 11,12 .…”