Minimal Residual Disease in Multiple Myeloma: Past, Present, and Future

Abstract

Responses to treatment have improved over the last decades for patients with multiple myeloma. This is a consequence of the introduction of new drugs that have been successfully combined in different clinical contexts: newly diagnosed, transplant-eligible or ineligible patients, as well as in the relapsed/refractory setting. However, a great proportion of patients continue to relapse, even those achieving complete response, which underlines the need for updated response criteria. In 2014, the international myeloma working group established new levels of response, prompting the evaluation of minimal residual disease (MRD) for those patients already in complete or stringent complete response as defined by conventional serological assessments: the absence of tumor plasma cells in 100,000 total cells or more define molecular and immunophenotypic responses by next-generation sequencing and flow cytometry, respectively. In this review, we describe all the potential methods that may be used for MRD detection based on the evidence found in the literature, paying special attention to their advantages and pitfalls from a critical perspective.

Keywords: MRD; PCR; PET-CT; flow cytometry; multiple myeloma; next-generation sequencing.

Figure 1

Levels of response in multiple myeloma. Serological methods provide enough sensitivity to detect partial or nearly complete disappearance of tumor cells by detection and quantification of the M-protein. However, even in patients achieving (stringent) complete responses, there is frequently still a minor population of tumor plasma cells (minimal residual disease, MRD) that are detectable only by highly sensitive methods in or outside the bone marrow. Therefore, the absence of detectable residual disease identifies a subset of patients with, in principle, longer progression-free and overall survival probabilities. The magnitude of reduction of the tumor burden is usually associated with the time required for progression [8], although many other factors—current and prior treatment regimens, risk markers associated with tumor biology, other co-morbidities, and more—play a role in this matter.