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EMN recommendations on MM diagnosis and monitoring
European Myeloma Network recommendations:
The International Staging System score and, whenever possible, the Revised International Staging System score, should be determined at diagnosis to assess prognosis. At least a minimal frailty assessment should be performed to aid the choice of induction therapy, dose amendments and supportive care. Although of interest due to their prognostic and predictive value, biomarkers, such as cereblon and CD38 protein expression, are not routinely assessed in daily multiple myeloma care, while fluorescence in situ hybridization for t(11;14) should be performed if treatment with venetoclax is a clinical option.
Response assessment
The implication of the results of an SFLC assay and MRD assessment prompted the IMWG to update MM response criteria.77 In 2011, two new categories, stringent complete response and very good partial response, were added. Correct disease assessment is not only crucial for reporting in clinical trials, it also indicates prognosis in individual cases.77,78 It is well known that patients who obtain a com- plete response following induction have improved progres- sion-free and overall survival after intensive treatment.79
Patients should, therefore, be evaluated before initiation of each treatment cycle to determine their response to ther- apy. For MM patients with intact immunoglobulins, the recommended method for monitoring is quantification of serum and urinary M-protein. Whether all serum (and urine) parameters have to be checked after each cycle, rather than after every two or three cycles is left to the dis- cretion of each physician, taking into account disease aggressiveness, organ (i.e. renal) impairment and various other factors. To confirm a stringent complete response, normalization of the SFLC values and disappearance of monoclonal PC infiltration in the BM should be added to negative immunofixation on serum and urine samples. The BM must be evaluated in order to confirm a complete response, but this can be done at some time after the end of treatment, allowing full recovery of the BM. Of note, BM infiltration can be heterogeneous with persisting focal lesions in an otherwise recovered BM (earlier referred to as patchy disease). The follow-up of patients with light-chain MM and measurable M-protein levels in urine should include 24 h urine collections. The SFLC assay generally allows response assessment in patients with oligosecretory disease with unmeasurable serum and urine M-protein lev- els [serum M-protein <1 g/dL (10 g/L) or urine M-protein <200 mg/24 h]. If the SFLC assay is not informative, BM plasmacytosis should be assessed.77
The definition of relapse applies to a patient in complete response who experiences reappearance of MM, while pro- gression refers to patients with an increasing disease burden from a baseline or persistent residual disease. An additional assessment for confirmation is mandatory before initiating a new line of therapy. MM progression can be determined biochemically (increase in an existing monoclonal peak), or by radiological and clinical criteria. The interested reader can find the criteria for relapse and disease progression recently described by the IMWG.77 Response assessment can be challenging, especially in cases of deep response after the use of monoclonal antibodies, which may interfere with quantification of the M-protein and may require spe- cific assays.80
Minimal residual disease
Current induction regimens, in association with autolo- gous stem cell transplantation, achieve very high
response rates and the responses are often deep. Unfortunately, however, MM often recurs due to residual MM cells, drug resistance and/or persistence of resistant dormant subclones.81 MRD can be assessed by multipara- meter flow cytometry, polymerase chain reaction (PCR)- based methods or next-generation sequencing to identify persistent clonal cells. Recent studies, listed in Table 5, confirmed the prognostic impact of MRD status as an independent variable for outcome.82 In the future, MRD will be more widely used in clinical trials to guide treat- ment choices and probably as a surrogate marker for pro- gression-free and overall survival.56
Conventional flow-MRD approaches, based on multi- ple institutional non-standardized protocols, can reliably identify malignant PC and discriminate aberrantly expressed cell surface markers in approximately 90% of patients (with a sensitivity of detecting 10−4 atypical PC in normal BM). Recent studies conducted by Spanish and UK groups have shown that negative MRD by multipara- meter flow cytometry is predictive for both progression- free survival and overall survival, even in patients who achieved a complete response.83,84 Recent technical advances have increased the sensitivity of next-genera- tion flow cytometry protocols down to the 10–6 range.85
MRD analysis by PCR detects persistent residual tumor cells through the amplification of a tumor-specific molec- ular marker. The IGH rearrangement is used as a marker of clonality in various B-cell malignancies.86 Allele-specific oligonucleotide PCR with primers complementary to the heavy chain variable sequence remains one of the most sensitive approaches to detect residual malignant PC, reaching a sensitivity of 10−5.87 Unfortunately, it is a labo- rious, time-consuming approach that is not widely avail- able because of its dependence on patient-specific primers and probes for quantitative PCR.
Next-generation sequencing of the IGH rearrangement segments provides insights into the architecture of the B- lineage repertoire with consensus primers. Since the B- lineage repertoire includes the malignant PC clone in BM, next-generation sequencing of IGH enables a quantitative determination of MRD, without per-patient customiza- tion, provided that the malignant clone was identified in a diagnostic sample or a sample taken during active dis- ease.88 Results from next-generation sequencing are high- ly concordant with flow-based MRD detection, highly reproducible and reach a sensitivity of 10−6.89-91 A lack of standardization and limited commercial availability are the main restraints for next-generation sequencing. Flow cytometry and molecular techniques both require an appropriate BM sample. Heterogeneous BM infiltration and peripheral blood dilution can be major hurdles to the evaluation of MRD. Since neither of these techniques is able to detect extramedullary disease, they should be combined with imaging studies.
Imaging is a third approach to evaluate MRD in MM. Both PET/CT and MRI have been evaluated in this set- ting.53,55 Regarding PET/CT, two large studies assessed the prognostic value of negative PET/CT after induction and autologous stem cell transplantation.55,92 Both studies found that PET/CT-negative patients had a better pro- gression-free and overall survival compared to PET/CT- positive patients (52 versus 38 months and 5-year esti- mates of 90% versus 71%, respectively).92 In the French IMAJEM study, MRD was evaluated in 86 patients via PET-CT and flow cytometry. Although the concordance
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