Elena Zamagni

Role of 18F-FDG PET/CT in the diagnosis and management of multiple myeloma and other plasma cell disorders: a consensus statement by the International Myeloma Working Group

The International Myeloma Working Group consensus aimed to provide recommendations for the optimal use of 18fluorodeoxyglucose (18F-FDG) PET/CT in patients with multiple myeloma and other plasma cell disorders, including smouldering multiple myeloma and solitary plasmacytoma. 18F-FDG PET/CT can be considered a valuable tool for the work-up of patients with both newly diagnosed and relapsed or refractory multiple myeloma because it assesses bone damage with relatively high sensitivity and specificity, and detects extramedullary sites of proliferating clonal plasma cells while providing important prognostic information. The use of 18F-FDG PET/CT is mandatory to confirm a suspected diagnosis of solitary plasmacytoma, provided that whole-body MRI is unable to be performed, and to distinguish between smouldering and active multiple myeloma, if whole-body X-ray (WBXR) is negative and whole-body MRI is unavailable. Based on the ability of 18F-FDG PET/CT to distinguish between metabolically active and inactive disease, this technique is now the preferred functional imaging modality to evaluate and to monitor the effect of therapy on myeloma-cell metabolism. Changes in FDG avidity can provide an earlier evaluation of response to therapy compared to MRI scans, and can predict outcomes, particularly for patients who are eligible to receive autologous stem-cell transplantation. 18F-FDG PET/CT can be coupled with sensitive bone marrow-based techniques to detect minimal residual disease (MRD) inside and outside the bone marrow, helping to identify those patients who are defined as having imaging MRD negativity.

The Role of Minimal Residual Disease Testing in Myeloma Treatment Selection and Drug Development: Current Value and Future Applications.

Treatment of myeloma has benefited from the introduction of more effective and better tolerated agents, improvements in supportive care, better understanding of disease biology, revision of diagnostic criteria, and new sensitive and specific tools for disease prognostication and management. Assessment of minimal residual disease (MRD) in response to therapy is one of these tools, as longer progression-free survival (PFS) is seen consistently among patients who have achieved MRD negativity. Current therapies lead to unprecedented frequency and depth of response, and next-generation flow and sequencing methods to measure MRD in bone marrow are in use and being developed with sensitivities in the range of 10−5 to 10−6 cells. These technologies may be combined with functional imaging to detect MRD outside of bone marrow. Moreover, immune profiling methods are being developed to better understand the immune environment in myeloma and response to immunomodulatory agents while methods for molecular profiling of myeloma cells and circulating DNA in blood are also emerging. With the continued development and standardization of these methodologies, MRD has high potential for use in gaining new drug approvals in myeloma. The FDA has outlined two pathways by which MRD could be qualified as a surrogate endpoint for clinical studies directed at obtaining accelerated approval for new myeloma drugs. Most importantly, better understanding of MRD should also contribute to better treatment monitoring. Potentially, MRD status could be used as a prognostic factor for making treatment decisions and for informing timing of therapeutic interventions. Clin Cancer Res; 23(15); 3980–93. ©2017 AACR.

Report of the 6th International Workshop on PET in lymphoma

Abstract Two hundred and ten nuclear medicine physicians, radiologists, and hematologists from 26 countries attended the 6th International Workshop on Positron Emission Tomography (PET) in Lymphoma and Myeloma held in Menton, France, in September 2016. The meeting was under the auspices of the European Lymphoma Institute (ELI), the European Association of Nuclear Medicine (EANM) the Lymphoma Study Association (LYSA), the Italian Foundation on Lymphoma (FIL) and the Carnot Institute for Lymphoma (CALYM). Forty scientific posters were presented. For the first time, specialists in the field of multiple myeloma (MM) were involved in the expert session. The aim was to establish from the experience of Italian and French studies new guidelines of FDG-PET/CT reporting for myeloma staging and restaging. The meeting dedicated an entire session to MM imaging followed by a session on the role of PET in Peripheral T cell Lymphoma. An entire session addressed the issues of Deauville scale particularly for end treatment assessment and the challenging consequences of immunomodulatory treatments on PET reporting. A specific session presented the potential role of baseline metabolic tumor measurement to predict outcome and identify different risk categories and the main results obtained in different lymphoma entities were described. Whether it could replace clinical staging has been extensively discussed. The more recent results obtained in the H10 trial have been presented and compared to the published data in early stage Hodgkin lymphoma. Finally, the ongoing studies using PET for guiding therapeutic strategies have been reported by the various lymphoma cooperative groups that participated to the meeting.

Toward a GEP-based PET in myeloma

In this issue of Blood , Rasche et al provide the first evidence of the biological basis underlying the occurrence of false-negative scans with use of 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) in newly diagnosed transplant-eligible multiple myeloma (MM) patients. 1

Role of serum free light chain assay in the detection of early relapse and prediction of prognosis after relapse in multiple myeloma patients treated upfront with novel agents

Monoclonal (M) protein can be detected in the serum and/or urine of patients with multiple myeloma (MM) as either intact immunoglobulins (Ig) or free light chains (FLC). Current guidelines recommend the use of serum and urine electrophoresis plus immunofixation to evaluate and monitor response to therapy in MM patients with measurable M-protein. In addition, measurement of serum FLC (sFLC) ratio (sFLCR) is required to fulfill the definition of stringent complete response and to define response or progressive disease (PD) in oligosecretory or non-secretory MM. Nonetheless, sFLC assay might be an appropriate tool also in secretory MM, since an imbalance in sFLCR can be detected in approximately 90% of patients with Ig-secretory MM (Ig-MM) and in almost all patients with light chain MM (LC-MM). Moreover, it is well recognized that sFLC escape might occur before, or at the time of, relapse and increasing levels of sFLC at progression have been reported to predict a worse prognosis. However, most of these studies are biased by the lack of serial assay measurements. Furthermore, the prognostic significance of increased levels of sFLC in the absence of any additional parameter defining PD or clinical relapse (Rel) remains an area of investigation. To address this issue, we analyzed a cohort of 100 MM patients at our center who received first-line, fixed-duration, novel agent-based therapies and for whom sFLCR measurements after treatment were available every 3-4 months until relapse. sFLC assay was performed by BN II nephelometer as part of routine clinical care. International Myeloma Working Group (IMWG) criteria were used for the definition of measurable disease, PD and Rel. Criteria defining PD in oligo/non-secretory MM according to sFLC levels were used to identify patients with secretory MM who showed rising sFLC levels in the absence of any additional parameter consistent with PD or Rel. Time to second progression (2 TTP) and overall survival (OS) after relapse were calculated from the date of first progression to the date of second progression or death, respectively, or of last follow up. Time to secondline therapy was the interval between the date of first progression and the date when salvage treatment was started. At diagnosis, 80 patients were classified as having IgMM, 15 LC-MM and 5 oligo/non-secretory disease. sFLC measurements were available at baseline in 81 patients, of whom 63 had sFLC measurable disease, as defined by an abnormal sFLCR and involved sFLC levels 100 mg/L or more. First-line treatments included the proteasomeinhibitor (PI) bortezomib in 45 patients, the immunomodulators (IMiDs) thalidomide or lenalidomide in 25 patients, and both bortezomib and IMiDs in the last 30 patients. Fifty patients received a single or double autologous stem cell transplantation. Median follow up was 63 [interquartile range (IQR) 38-83] months from diagnosis and 23 (IQR 13-37) months from progression. Best response rates were: complete response, 32%; very good partial response, 35%; partial response, 27%, and stable disease or PD, 6%. Overall, in 66 patients, sFLCR after up-front therapy was in the normal range. According to IMWG consensus recommendations, 88 patients required a second-line therapy due to Rel (n=72) or paraprotein relapse (n=16). The remaining 12 patients did not receive salvage therapy due to a paraprotein relapse not fulfilling criteria for restarting treatment (n=8) or early death (n=3) or a concomitant solid tumor (n=1). Serial monitoring of serum/urine M-protein and sFLC levels throughout the follow-up phase after first-line treatment allowed 4 different patterns of relapse to be identified. These were characterized by: 1) an increase in both M-protein and sFLC (n=30); 2) an increase in M-protein only (n=42); 3) an increase in sFLC levels only (n=15), as established according to IMWG criteria for oligo/nonsecretory MM; 4) the presence of one or more criteria defining Rel, without any concurrent change in M-protein or sFLC (n=13). Patterns of relapse characterized by an increase in sFLC levels, with or without concomitant rise in M-protein, were observed more frequently in patients with abnormal versus normal sFLCR at baseline (62% vs. 17%; P=0.001). Among the 80 patients with IgMM, patterns of relapse were: 32% both M-protein and sFLC (n=26), 48% M-protein only (n=38), 10% sFLC only (n=8), and 10% Rel without change in M-protein or sFLC (n=8) compared with 27% both M-protein and sFLC (n=4), 27% M-protein only (n=4), 40% sFLC only (n=6) and 6% Rel without change in M-protein or sFLC (n=1) for the 15 patients with LC-MM. Patients with LC-MM had a higher frequency of relapse characterized by isolated sFLC increasing than those with Ig-MM (P=0.043). In the subgroup of 14 patients with secretory-MM (8 IgMM and 6 LC-MM) and an sFLC only pattern of relapse, an increase in sFLCs preceded by 2.3 months (IQR 1.76.1) the onset of any conventional parameter defining PD, including Rel with organ damage in 10 (71%) of them, and by 4.0 (IQR 2.8-9.3) months the start of subsequent salvage therapy. Median increase in the difference between involved and uninvolved sFLC levels was 224.1 mg/L (IQR 138.3-437.9) at the time of escape and 687.5 mg/L (IQR 224.1-1819.8) at the time of PD or Rel. Overall, patients who experienced a relapse with an increase in both M-protein and sFLC or sFLC only had higher creatinine levels than those with an increase in Mprotein only or Rel without change in M-protein or sFLC (P=0.025). Conversely, no differences between these subgroups were seen with respect to the other diseaseand tumor-related characteristics that could potentially influence clinical outcomes. Second-line treatments including IMiDs (47%), PI (23%) or both these agents (30%) were equally distributed among patients with different patterns of relapse. Time to second-line therapy was shorter for patients relapsing with both M-protein and sFLC, sFLC-only or Rel without increase in M-protein or sFLC levels, than for those relapsing with M-protein only (P=0.001, trend P=0.0001). Moreover, patterns of relapse characterized by an increase in sFLC, with or without a concomitant rise in M-protein levels, correlated with worse 2 TTP and OS after relapse as compared to the other patterns. In particular, patients relapsing with both M-protein and sFLC or sFLC only had a 2-fold increase in

Therapy assessment in multiple myeloma with PET

Multiple myeloma is a plasma cell dyscrasia producing bone lytic lesions. In recent years, a wide spectrum of therapeutic approaches are available to treat the disease: an accurate therapy assessment has, therefore, become of utmost importance.xa0In this field, imaging is becoming a cornerstone, especially in association with clinical parameters. Among imaging procedures, FDG PET/CT is recognized to provide reliable information, achieved in a very safe and fast procedure.xa0xa0The literature has produced very concordant results from different groups assessing the value of FDG PET/CT as a prognostic factor in general and in therapy assessment, but some issues remain regarding a standardization of image interpretation especially in borderline cases.xa0So far, no data regarding nor other imaging compounds and the use of hybrid tomographs PET/MR are available to define therapy assessment in PET.

MRD in multiple myeloma: more questions than answers?

The growing interest in minimal residual disease (MRD) assessment in multiple myeloma (MM) is related to the high quality of responses achieved with novel agents and to the development of reliable techniques to evaluate MRD both within the bone marrow using next-generation sequencing (NGS) or next-generation flow cytometry (NGF), and outside the bone marrow using imaging techniques, such as positron emission tomographycomputed tomography (PET-CT). A consensus paper by the International Myeloma Working Group (IMWG), published in 2016, represents the reference document on MRD in MM. However, since its publication, new data have become available, and it is of interest to discuss what other information beyond that included in the IMWG criteria should be captured in ongoing clinical trials (Table 1). Minimal residual disease certainly matters in MM. Munshi et al. recently published a meta-analysis on 496 patients in complete response (CR), in whom an MRDnegative status was associated with a significant improvement in both progression-free survival (PFS) and overall survival (OS). These findings were recently confirmed by the Spanish group in a pooled analysis of three PETHEMA/GEM clinical trials involving 609 patients, showing that MRD-negative status surpassed the prognostic value of CR achievement for PFS and OS. In the paper by the Spanish group and in the majority of the trials included in the meta-analysis by Munshi et al. MRD was mostly assessed by flow cytometry, with a sensivity level of 10 on average. In the IMWG consensus paper, the definition of MRD negativity requires a minimum sensitivity of 1 in 10 nucleated cells or higher both for flow and sequencing technology. The NGS technology, which is quite well standardized, routinely reaches a sensitivity level of 10. The NGF technology, may easily reach a sensitivity level of 10, if not 10, when using the standardized EuroFlow approach . Therefore, an interesting question is whether a higher level of sensitivity will result in a better predictability, and whether we should try to routinely increase the depth of MRD detection to 10. In the French IFM 2009 study, which compared RVD versus RVD plus autologous stem cell transplantation (ASCT), MRD was evaluated both by 7-color flow cytometry in all patients and by NGS where possible. Minimal residual disease negativity evaluated by flow was associated with a PFS and OS benefit (sensitivity level of 10). Of note, among flow-negative cases, the NGS technology was associated with a higher sensitivity (10) and allowed the segregation of patients into two groups: flow-negative, NGS-negative and flownegative, NGS-positive, with a significantly worse PFS outcome in the latter population. These results indicate that 10 might be the ideal cut-off for the definition of MRD negativity. This is even more plausible when the number of patients reaching 10 in this study was 80 out of 131 evaluable patients. A sensitivity threshold is informative and meaningful when it can be reached by a significant number of patients in a specific therapeutic strategy. The next question is: NGS or NGF? NGS is now standardized, but the EuroFlow consortium recently described a novel NGF approach using an optimized 2-tube 8-color antibody panel for highly sensitive (close to 10) and standardized MRD detection that could be implemented in routine diagnostic procedures. In a small number of samples, a comparison of the two techniques showed a good correlation in the percentage of residual abnormal plasma cells detected, with a similar sensitivity. In addition, the EuroFlow technology was recently evaluated in the prospective EMN02 trial, which compared ASCT to bortezomib-based conventional therapy without ASCT and showed a significant impact of flow negative MRD on

A Comparison of Different Staging Systems for Multiple Myeloma: Can the MRI Pattern Play a Prognostic Role?

OBJECTIVEnThe objective of this study is to compare the most recent systems for the staging of multiple myeloma (MM), the Durie-Salmon PLUS system and the International Staging System, according to patients survival rates and response to therapy. Another objective is to verify whether patterns of bone marrow alteration on MRI (i.e., focal, diffuse, or variegated patterns) can provide prognostic information for patients with MM.nnnMATERIALS AND METHODSnWe retrospectively enrolled 85 patients with MM who were monitored for a minimum of 6 years and who underwent contrast-enhanced spinal and pelvic MRI at 1.5 T and whole-body FDG PET/CT at the time of diagnosis. Patients underwent MM staging performed using both staging systems and were divided into groups on the basis of their MRI patterns. These patient groups were then compared in terms of survival, response to therapy, and duration of response.nnnRESULTSnBoth staging systems showed great capability in differentiating patients with a worse prognosis from patients with a better outcome, with the capability of both systems found to be statistically significant, albeit less statistically significant for the Durie-Salmon PLUS system (p = 0.010 vs p = 0.046, respectively). Patients with a focal pattern on MRI had a worse survival rate than did the patients with other MRI patterns (p = 0.032).nnnCONCLUSIONnThese data indicate that both the International Staging System and the Durie-Salmon PLUS system have great potential for characterizing and stratifying MM to determine the survival outcome and therapy response of patients. Observation of a focal pattern on MRI seems to be associated with poorer survival.

Interpretation criteria for FDG PET/CT in multiple myeloma (IMPeTUs): final results. IMPeTUs (Italian myeloma criteria for PET USe)

AbstractᅟFDG PET/CT (18F-fluoro-deoxy-glucose positron emission tomography/computed tomography) is a useful tool to image multiple myeloma (MM). However, simple and reproducible reporting criteria are still lacking and there is the need for harmonization. Recently, a group of Italian nuclear medicine experts defined new visual descriptive criteria (Italian Myeloma criteria for Pet Use: IMPeTUs) to standardize FDG PET/CT evaluation in MM patients. The aim of this study was to assess IMPeTUs reproducibility on a large prospective cohort of MM patients.Materials and methodsPatients affected by symptomatic MM who had performed an FDG PET/CT at baseline (PET0), after induction (PET-AI), and the end of treatment (PET-EoT) were prospectively enrolled in a multicenter trial (EMN02)(NCT01910987; MMY3033). After anonymization, PET images were uploaded in the web platform WIDEN® and hence distributed to five expert nuclear medicine reviewers for a blinded independent central review according to the IMPeTUs criteria. Consensus among reviewers was measured by the percentage of agreement and the Krippendorff’s alpha. Furthermore, on a patient-based analysis, the concordance among all the reviewers in terms of positivity or negativity of the FDG PET/CT scan was tested for different thresholds of positivity (Deauville score (DS 2, 3, 4, 5) for the main parameters (bone marrow, focal score, extra-medullary disease).ResultsEighty-six patients (211 FDG PET/CT scans) were included in this analysis. Median patient age was 58xa0years (range, 35–66xa0years), 45% were male, 15% of them were in stage ISS (International Staging System) III, and 42% had high-risk cytogenetics. The percentage agreement was superior to 75% for all the time points, reaching 100% of agreement in assessing the presence skull lesions after therapy. Comparable results were obtained when the agreement analysis was performed using the Krippendorff’s alpha coefficient, either in every single time point of scanning (PET0, PET-AI or PET-EoT) or overall for all the scans together. DS proved highly reproducible with the highest reproducibility for score 4.ConclusionsIMPeTUs criteria proved highly reproducible and could therefore be considered as a base for harmonizing PET interpretation in multiple myeloma. A prospective clinical validation of IMPeTUs criteria is underway.

Diagnosis, treatment, and response assessment in solitary plasmacytoma: updated recommendations from a European Expert Panel

Solitary plasmacytoma is an infrequent form of plasma cell dyscrasia that presents as a single mass of monoclonal plasma cells, located either extramedullary or intraosseous. In some patients, a bone marrow aspiration can detect a low monoclonal plasma cell infiltration which indicates a high risk of early progression to an overt myeloma disease. Before treatment initiation, whole body positron emission tomography–computed tomography or magnetic resonance imaging should be performed to exclude the presence of additional malignant lesions. For decades, treatment has been based on high-dose radiation, but studies exploring the potential benefit of systemic therapies for high-risk patients are urgently needed. In this review, a panel of expert European hematologists updates the recommendations on the diagnosis and management of patients with solitary plasmacytoma.