Minimal residual disease in multiple myeloma: bringing the bench to the bedside

Abstract

Outcomes for patients with multiple myeloma (MM) have improved substantially in the past decade, with improvements in both progression-free survival and overall survival. Many patients are now achieving a complete response to treatment, and consequently highly sensitive assays are needed for detection of minimal residual disease (MRD) in patients with MM. Results of multicolour flow cytometry and deep-sequencing studies suggest that among patients achieving a complete response, MRD-negative status is associated with significant improvements in progression-free survival and overall survival. Despite the increasing need for MRD testing in patients with MM, considerable heterogeneity in techniques for MRD detection hinders the clinical interpretation of their results. The criteria used to define MRD, strengths and weaknesses of the major types of tests (flow cytometry versus molecular testing), and the optimal sample type (bone marrow aspirate versus peripheral blood) are all unresolved dilemmas in MRD testing. This Review presents an overview of the various techniques for MRD detection in patients with MM. In addition, this article discusses challenges and opportunities for the routine use of MRD testing, possible future directions for clinical trials and implications for drug approval processes.

Conflict of interest statement

Competing interests

O.L. declares that he has acted as a consultant for BMJ Publishing, Celgene, Medscape, Millennium and Onyx. The other authors declare no competing interests.

Figures

Figure 1 |

Treatment response rates achieved with commonly used induction regimens in patients with MM. Response rates, including ≥VGPR and overall responses have improved with the introduction of newer induction therapy regimens for the treatment of patients with MM. Abbreviations: CRd, carfilzomib, lenalidomide and dexamethasone; CTD, cyclophosphamide, thalidomide and dexamethasone; Dex, dexamethasone; Len–Dex, lenalidomide and dexamethasone; MM, multiple myeloma; OR, overall response; RVD, revlimid, bortezomib and dexamethasone; Thal–Dex, thalidomide and dexamethosone; VAD, vincristine, doxorubicin and dexamethasone; VCD, bortezomib, cyclophosphamide and dexamethasone; VGPR, very good partial response; VRDC, bortezomib, lenalidomide, dexamethasone and cyclophosphamide; VTD, bortezomib, thalidomide and dexamethasone. Modified with permission from Springer Science+Business Media © Kumar, S. Med. Oncol.27 (Suppl. 1), S14–S24 (2010).

Figure 2 |

Flow cytometry testing for minimal residual disease in patients with treated multiple myeloma. This technique relies on differentiation of normal from malignant plasma cells on the basis of their differences in cell-surface marker expression. Key characteristics distinguish malignant plasma cells from normal plasma cells: CD19− (all panels); a | expression of less CD38; b | CD45−; c | CD56+; d | CD117+; e | CD27−; and f | CD81−.

Figure 3 |

Effect of sample size on flow cytometry testing for minimal residual disease in treated patients with multiple myeloma. The total number of acquired events (that is, the number of cells assessed in bone marrow aspirate) analysed by multicolour flow cytometry has a substantial effect on the reliability of the test results. All panels depict healthy (black) and malignant (green) plasma cells in a bone marrow sample obtained from the same patient. a | 84 malignant plasma cells were detected by analysing 3,000,000 events. b | 30 cells were detected in 1,000,000 events. c | 14 malignant cells were detected in 500,000 events. d | Only 6 malignant cells were detected in 100,000 events.