Minimal Residual Disease in Multiple Myeloma

Progress in the treatment of multiple myeloma has increased extent and frequency of response, as well as prolonged progressionfree (PFS) and overall survival (OS). Randomized trials of high-dose therapy and autologous stem cell transplantation in the 1990s showed the latter to be superior to standard dose therapy and for the first time achieved complete responses. The advent of novel therapies in the past decade has further transformed treatment. In particular, immunomodulatory drugs (thalidomide/lenalidomide/pomalidomide) and the proteasome inhibitors (bortezomib, carfilzomib), when combined as initial therapy for newly diagnosed patients, can achieve universal responses and complete responses (CRs) in a significant fraction of patients. Finally, the use of consolidation and maintenance therapy with novel agents can now further increase CR rate and prolong duration of response. Along with these improvements in therapeutic strategy, the definition of CR has evolved over time. Studies 30 years ago, before the advent of transplantation, defined CR as greater than 75% reduction in myeloma paraprotein, which was achieved in only a small fraction of patients. With high-dose therapy significant cytoreduction was achieved, and the definition of CR evolved to include not only disappearance of clonal plasma cells in bone marrow, but also absence of paraprotein in urine and serum by immunofixation, which was achieved in up to 30% patients. Stringent CR, as more recently defined by the International Myeloma Workshop, includes these parameters along with a normal kappa:lambda free light chain ratio. However, the fact that all patients achieving CR, as defined in this way, go on to experience relapse suggests that clinically meaningful residual disease is not detectable by these parameters. Molecular complete responses (mCR), defined as absence of detectable disease by polymerase chain reaction for Ig gene rearrangement, was until recently observed only in a fraction of patients undergoing allogeneic transplantation and was associated with prolonged PFS and OS. These allogeneic transplantation studies suggested the clinical importance of achieving mCR, but this extent of response was not achievable in the autologous setting. The incorporation of novel therapies into the initial management of newly diagnosed myeloma has transformed therapy, with increased frequency and extent of response. It was therefore necessary to develop reproducible sensitive assays for detecting and monitoring minimal residual disease (MRD) and to define its prognostic value in predicting for PFS and OS, to allow for informing consolidation and maintenance strategies, and to evaluate the comparative efficacy of novel therapies. These methods include allele-specific oligonucleotide PCR (ASO-PCR) capable of detecting up to one clonal cell in 10 normal cells and immunophenotypic assays detecting one clonal cell in 10 normal cells by use of seven-color multiparameter flow cytometry (MPF) Although the ASO-PCR method may provide greater sensitivity, it remains a difficult assay to be performed, as it requires the generation of patient-specific primers. The advantages of MPF include the ready ability to perform the assay, as well as short turnaround time. In MPF, quantitating residual myeloma cells requires sophisticated analysis but is automated to promptly obtain objective results. A comparison of CR detection by negative immunofixation (CR), normal serum free light chain ratio (sCR), and undetectable myeloma cells by MPF (immunophenotyping CR iCR) in 102 patients with multiple myeloma treated with novel agents showed that 43% patients achieved CR, 30% achieved sCR, and 30% achieved iCR. There was no significant survival difference between patients with sCR versus CR; importantly, however, patients in iCR showed significantly increased PFS and time to progression (TTP) compared with those in sCR or CR, suggesting increased sensitivity of MPF to detect MRD. Although a head to head comparison between iCR assessed by MPF and mCR measured by ASO-PCR showed that ASO-PCR is slightly more sensitive and specific than MPF, it was applicable in a lower proportion of MM patients (75% versus 90%, respectively) and more time-consuming than MPF. Interestingly, in this study ASO-PCR and MPF were able to detect residual myeloma cells in 17 and 11 patients, respectively. Progression-free survival for those patients without versus with MRD detected by ASO-PCR was 34 versus 15 months, respectively (P .04) and by MPF was 27 versus 10 months, respectively (P .05). More recently, a novel sequencing-based method has been developed to quantify cells with specific molecular signatures. This method identifies clonal gene rearrangements in diagnostic samples using consensus primers to universally amplify rearranged IgH and k gene segments, followed by high-throughput sequencing and informatic algorithms to then quantify these rearrangements in follow-up MRD samples. Compared to the ASO-PCR method, this new assay does not require patient-specific customization, which improves scalability and reduces costs A comparison using such newer sequencing technologies with high resolution MPF is required to determine the relative specificity and sensitivity of these assays to detect MRD, as well as their relative ability to identify infrequent tumor clones. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 20 JULY 1