Chapter 2 – Diagnosis and staging

Contributors: Carlos Fernández de Larrea and Joan Bladé

6 – Minimal residual disease

Achievement of immunofixation-negative complete remission is a crucial step forward for long-lasting response and survival in MM, either in the transplantation setting or in elderly patients. The introduction of new agents have resulted in improved complete remission rates, with twenty to thirty percent of the patients achieving sustained complete remission without relapse beyond 10 years from autologous transplantation, representing the so-called ‘cure fraction’ or ‘operational cure’ [29]. Recently, the combination of these new agents with high-dose therapy and/or ASCT, consolidation, and prolonged maintenance therapy shows an increase in not only complete response rates but also the response depth [30]. It is evident that maintaining complete remission is crucial to achieve a prolonged survival [31].

With the availability of novel technologies in biomedicine, the achievement of immunofixation-negative complete remission should no longer be the ultimate goal in the treatment of MM. Recent trials have shown the benefit for minimal residual disease (MRD)-negative status surpassing the prognostic value of CR achievement for PFS and OS in both transplant-eligible and transplant-ineligible patients [32]. Given the prognostic value of MRD status, the IMWG has proceeded to define new response categories of MRD negativity with the aim to facilitate uniform reporting, both in and out of clinical trials (see Table 2.16) [33].

Table 2.15: Surface markers used for minimal residual disease detection.

MM, multiple myeloma. All rights reserved. Kumar et al [33].

Table 2.16: IMWG MRD criteria.

*Subsequent evaluations can be used to further specify the duration of negativity (e.g. MRD-negative at 5 years). **Using EuroFlow standard operation procedure for MRD detection in MM, or validated equivalent method. ***Presence of a clone defined as less than two identical sequencing reads obtained after DNA sequencing of bone marrow aspirates using the LymphoSIGHT platform or validated equivalent method. MRD, minimal residual disease; PET/CT, positron emission tomography–computed tomography. All rights reserved. Kumar et al [33].

There are several different strategies for MRD being reported:

  • Bone marrow response: multiparametric flow cytometry (MFC) is based on the abnormal expression of surface antigens by malignant plasma cells (Table 2.15) [34] and is now a key tool in the management of hematological malignancies. The presence of malignant plasma cells by MFC after autologous stem cell transplant (ASCT) in bone marrow has been identified as an important prognostic factor in MM, but also in patients receiving non-myeloablative therapy [35,36]. The sensitivity of MFC for detecting MRD is dependent on the quality of the specimen collected, the number of cells analysed and the capability of the antibody panel to distinguish abnormal from normal plasma cells [37]. Advances in MFC technology have allowed for the interrogation of more cells which has resulted in significantly improved sensitivity [33].
  • Molecular biology studies: these techniques can measure the highest level of response; for instance a quantitative PCR using the heavy chain rearrangement in malignant plasma cells as target. Using this technique, a sustained molecular complete remission has been associated with a better prognosis after either ASCT or allogeneic transplantation [38,39]. Molecular studies have the disadvantage of being time- and resource-consuming with a limited applicability to only a subgroup of patients.
  • Serological approaches: the impact of sCR (normal serum free light-chain ratio and absence of clonal plasma cells in bone marrow) is under investigation [40].

Both techniques (molecular and MFC) limit the possibility of patchy infiltration of malignant plasma cells in bone marrow, as well as the presence of isolated extramedullary progression in the absence of medullary disease. Blood-based molecular assays, particularly using next generation flow cytometry (NGF) and sequencing (NGS) approaches, are promising in this regard as they are more sensitive than the standard MFC and can be uniformly applied [41]. First generation MFC is based on a four-color technique with a sensitivity of ≤10-4, whereas the more recently developed NGF uses an eight- or even 10-colour method with a sensitivity of ≥10-5. The NGS is also predicted to achieve a sensitivity superior to the conventional MFC of up to 10-6. Based on the correlation between MRD negativity and a better outcome, the IMWG have encouraged the use of these more sensitive methods in future trials to better define their optimal use so as to incorporate them into daily clinical practice (Table 2.16) [33].

Despite these improved methods of MRD detection, the probability of a false-negative assessment remains relatively high because of the irregular pattern of bone marrow plasma-cell infiltration in MM as well as the increasing frequency of extramedullary involvement [25]. Therefore, it is beneficial to couple the sensitive bone marrow assays with functional imaging techniques which can detect MRD outside of the bone marrow. Several studies have investigated the prognostic impact of PET-CT negativity. A retrospective study analyzed the use of ¹⁸F-FDG PET/CT at diagnosis and after treatment in ASCT-eligible and ASCT-ineligible patients. On multivariate analysis, post-treatment ¹⁸F-FDG PET/CT negativity was shown to be an independent prognostic factor which could predict prolonged PFS and OS [42]. The same association was found in a Turkish study among patients achieving a VGPR but could not be confirmed in patients achieving CR due to a small sample size [43]. In contrast, a study focusing on patients treated upfront with a three drug regimen including carfilzomib, no association was found between ¹⁸F-FDG PET/CT scans, clinical response and MRD status. The value of ¹⁸F-FDG PET/CT in detecting MRD in the context of emerging therapies remains an open question [25].