The availability of highly effective combination chemotherapeutic regimens has raised the question of whether treatment with high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) benefits patients with multiple myeloma. To address this question, clinical trials have been initiated in which outcomes are compared between patients receiving induction with combination chemotherapy followed by treatment with a myeloablative regimen together with ASCT and those receiving the same induction regimen but without the subsequent myeloablative regimen in combination with ASCT. In some cases, the studies are also designed to test the value of maintenance therapy in the two treatment arms. The large enrolment of these multi-institutional (and in some cases multinational) studies provides opportunities to address other issues that might impact on management of patients with multiple myeloma. For example, within each treatment arm, establishment of parameters that predict outcome would allow identification of subcategories of patients who might benefit from alternative treatment modalities. One measure that has been used prognostically is complete response (CR) (achieved when the M-protein becomes undetectable by immunofixation electrophoresis). CR is a valuable, but imperfect predictor of outcome, leading investigators to seek other parameters, including assessment of minimal residual disease (MRD), which might have greater predictive value. Multiple myeloma especially lends itself to measurement of MRD as the malignant cells have both a distinct immunophenotype and specific clonal genetic markers. Thus, both flow-cytometric and polymerase-chain-reaction (PCR)-based techniques can be used to assess MRD in patients with multiple myeloma.
The current paper reports the results of analysis of MRD in patients with multiple myeloma treated on the British Medical Research Council Myeloma IX trial. Multiparameter flow cytometry (MFC) was used to assess MRD after completion of induction therapy (n=378) and at day 100 after ASCT (n=397) in the intensive-pathway patients (those who underwent induction therapy followed by treatment with high-dose chemotherapy in combination with ASCT) and at the end of induction therapy in the non-intensive-pathway patients (n=245) (those who underwent treatment with the same induction regimen but who did not go on to receive high-dose chemotherapy in combination with ASCT). For the intensive-pathway patients, absence of MRD at day 100 after ASCT was predictive of a favorable outcome (P<0.001 for progression free survival; P=0.0183 for overall survival) and was demonstrable in patients with either favorable or adverse cytogenetics and also in patients who achieved an immunofixation-negative CR (P=0.0068 for progression free survival). The study also demonstrated that maintenance therapy could improve MRD status, as 28 percent of MRD-positive patients who received maintenance thalidomide subsequently became MRD-negative. MRD-positive patients who did not receive maintenance therapy had the shortest PFS, while MRD-negative patients who received maintenance thalidomide had the longest PFS. Notably, MRD status after induction therapy in the non-intensive-pathway patients was not predictive of outcome (PFS, P=0.1).
In Brief
The results of the studies of Rawstron and colleagues suggest that MRD status has prognostic significance for patients with myeloma who have undergone treatment with myeloablative chemotherapy followed by ASCT, and the technique used in the current study can identify among patients who achieve a immunofixation-negative CR a subgroup of patients (i.e., those who are MRD-negative) with a more favorable outcome as measured by PFS. Thus, an argument can be made that assessment of MRD should be included among the prognostic parameters used to evaluate response to treatment in patients with myeloma who receive the regimen of high-dose chemotherapy followed by autologous stem cell rescue. However, there are challenges to the routine incorporation of MRD assessment in the management of multiple myeloma including identifying the most appropriate assay and determining the most meaningful time point or points at which to measure MRD. Methods used to quantify MRD include allele-specific oligonucleotide PCR (ASO-PCR) that can detect as few as one clonal cell among 105 normal cells and MFC assays, like the one used in the current study that can detect one clonal cell in 104 normal cells. Although ASO-PCR is more sensitive and specific than MFC, for technical reasons, it is applicable in a lower proportion of myeloma patients compared with MFC (75% vs. 90%, respectively). Further, ASO-PCR is more time-consuming than MFC as it requires the generation of patient-specific primers. Advantages of MFC include the general availability of equipment and expertise to perform the assay and short turnaround time. MFC can be automated, but sophisticated engineering and software design are required to generate accurate, reproducible results. Recently, a sequencing-based method that uses consensus primers to universally amplify rearranged IgH and kappa gene segments, followed by high-throughput sequencing and informatic algorithms to quantify these rearrangements has been developed as a tool to assess MRD in patients with myeloma.1 The advantage of this assay over ASO-PCR is that it does not require patient-specific customization of primers, thereby improving scalability and reducing assay time and cost. Still, dealing with a constantly evolving tumor is formidable, and more challenges to developing comprehensive prognostic parameters lie ahead as next-generation sequencing techniques have identified myeloma subclones with discrete molecular signatures. Even more problematic is the identification of distinct clones at different sites within the bone marrow of patients with myeloma.2 The task of defeating myeloma seems Sisyphean, but, as the studies of Rawstron and colleagues demonstrate, myeloma researchers differ from Sisyphus for two reasons: his task was in essence a useless exercise; and he failed to make even incremental progress in getting the rock to the top of the hill.
References
Competing Interests
Dr. Leleu indicated no relevant conflicts of interest.
