New criteria for response assessment: role of minimal residual disease in multiple myeloma

Abstract

Assessment of minimal residual disease (MRD) is becoming standard diagnostic care for potentially curable neoplasms such as acute lymphoblastic leukemia. In multiple myeloma (MM), the majority of patients will inevitably relapse despite achievement of progressively higher complete remission (CR) rates. Novel treatment protocols with inclusion of antibodies and small molecules might well be able to further increase remission rates and potentially also cure rates. Therefore, MRD diagnostics becomes essential to assess treatment effectiveness. This review summarizes reports from the past 2 decades, which demonstrate that persistent MRD by multiparameter flow cytometry, polymerase chain reaction, next-generation sequencing, and positron emission tomography/computed tomography, predicts significantly inferior survival among CR patients. We describe the specific features of currently available techniques for MRD monitoring and outline the arguments favoring new criteria for response assessment that incorporate MRD levels. Extensive data indicate that MRD information can potentially be used as biomarker to evaluate the efficacy of different treatment strategies, help on treatment decisions, and act as surrogate for overall survival. The time has come to address within clinical trials the exact role of baseline risk factors and MRD monitoring for tailored therapy in MM, which implies systematic usage of highly sensitive, cost-effective, readily available, and standardized MRD techniques.

Figure 1

Graphical representation of the increasing number of publications in PUBMED and abstracts reported in the Annual Congress of the American Society of Hematology (ASH) on MM MRD during the past decades. (A) Publications per 5-year periods on MRD studies in MM (PUBMED). (B) Abstracts reported per year at the ASH meetings on MRD studies in MM.

Figure 2

Schematic representation to illustrate the paradigm of the deeper the response, the longer the (progression-free) survival (filled lines). However, distinct biological subgroups exist, and their clinical course may differ from the paradigm (dotted lines): a, those patients with a baseline MGUS-like signature and prolonged survival irrespectively of CR; b, those patients with unsustained CR (high-risk cytogenetics and persistent MRD); c, MRD-positive patients who may also experience extended outcomes if small residual clones are quiescent (MGUS-like) or under control (eg, by immune cells); d, an MRD-negative result does not preclude the risk of relapse, and optimization of MRD monitoring together with follow-up MRD studies are likely crucial to predict relapses early on; e, long-term disease control (ie, functional cure) could potentially be achieved if therapy eradicates (detectable) MRD levels. This is a hypothetical model, which does not translate to the real behavior of individual patients.

Figure 3

Number of studies published in PUBMED per MRD technique showing prognostic value for progression-free survival (PFS) and overall survival (OS) specifically among patients in CR after therapy. Numbers refer to the literature cited in the present review.

Figure 4

MRD monitoring (ie, black solid line arrows) has been reported (numbers refer to the literature cited in the present review) to be prognostically informative among cytogenetically defined standard- and high-risk MM patients after induction chemotherapy, HDT/ASCT, and consolidation; during follow-up; and after salvage therapy.