Consensus guidelines and recommendations for the management and response assessment of chimeric antigen receptor T-cell therapy in clinical practice for relapsed and refractory multiple myeloma: a report from the International Myeloma Working Group Immunotherapy Committee.

Chimeric antigen receptor (CAR) T-cell therapy has shown promise in patients with late-line refractory multiple myeloma, with response rates ranging from 73 to 98%. To date, three products have been approved: Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), which are approved by the US Food and Drug Administration, the European Medicines Agency, Health Canada (ide-cel only), and Brazil ANVISA (cilta-cel only); and equecabtagene autoleucel (eque-cel), which was approved by the Chinese National Medical Products Administration. CAR T-cell therapy is different from previous anti-myeloma therapeutics with unique toxic effects that require distinct mitigation strategies. Thus, a panel of experts from the International Myeloma Working Group was assembled to provide guidance for clinical use of CAR T-cell therapy in myeloma. This consensus opinion is from experts in the field of haematopoietic cell transplantation, cell therapy, and multiple myeloma therapeutics.

Comparison of NGS and MFC Methods: Key Metrics in Multiple Myeloma MRD Assessment.

In order to meet the challenges in data evaluation and comparability between studies in multiple myeloma (MM) minimal residual disease (MRD) assessment, the goal of the current study was to provide a step-by-step evaluation of next-generation sequencing (NGS) and multicolor flow cytometry (MFC) data. Bone marrow (BM) sample pairs from 125 MM patients were analyzed by NGS and MFC MM MRD methods. Tumor load (TL) and limit of detection (LOD) and quantification (LOQ) were calculated. The best-fit MRD cut-off was chosen as 1 × 10-5, resulting in an overall 9.6% (n overall = 12 (NGS n = 2, MFC n = 10)) nonassessable cases. The overall concordance rate between NGS and MFC was 68.0% (n = 85); discordant results were found in 22.4% (11.2% (n = 14) of cases in each direction. Overall, 55.1% (n = 60/109) and 49.5% (n = 54/109) of patients with a serological response ≥ very good partial response (VGPR) showed BM MRD negativity by NGS and MFC, respectively. A good correlation in the TL assessed by both techniques was found (correlation coefficient = 0.8, n = 40, p < 0.001). Overall, our study shows good concordance between MM BM MRD status and TL when comparing NGS and MFC at a threshold of 10-5. However, a sufficient number of analyzed events and calculation of MRD key metrics are essential for the comparison of methods and evaluability of data at a specific MRD cut-off.

Implications of SARS-CoV-2 Infection and COVID-19 Crisis on Clinical Cancer Care: Report of the University Cancer Center Hamburg.

With the outbreak of the COVID-19 pandemia, routine clinical work was immediately, deeply, and sustainably impacted in Germany and worldwide. The infrastructure of almost all hospitals is currently redirected to provide a maximum of intensive care resources, including the necessary staff. In parallel, routine as well as emergency clinical care for all patients in need has to be secured. This challenge becomes particularly evident in cancer care. In order to maintain adequate oncological care at all levels of provision and to conduct especially curative and intensive treatments with a maximum of safety, continuous adaption of the oncology care system has to be ensured. Intensive communication with colleagues and patients is needed as is consequent expert networking and continuous reflection of the own developed strategies. In parallel, it is of high importance to actively avoid cessation of innovation in order not to endanger the continuous improvement in prognosis of cancer patients. This includes sustained conduction of clinical trials as well as ongoing translational research. Here, we describe measures taken at the University Cancer Center Hamburg (UCCH) - a recognized comprehensive oncology center of excellence - during the COVID-19 crisis. We aim to provide support and potential perspectives to generate a discussion basis on how to maintain high-end cancer care during such a crisis and how to conduct patients safely into the future.

Critical Appraisal of Published Indirect Comparisons and Network Meta-Analyses of Competing Interventions for Multiple Myeloma.

OBJECTIVES: In the field of relapsed or refractory multiple myeloma (RRMM), between-trial or indirect comparisons are required to estimate relative treatment effects between competing interventions based on the available evidence. Two approaches are frequently used in RRMM: network meta-analysis (NMA) and unanchored matching-adjusted indirect comparison (MAIC). The objective of the current study was to evaluate the relevance and credibility of published NMA and unanchored MAIC studies aiming to estimate the comparative efficacy of treatment options for RRMM. METHODS: Twelve relevant studies were identified in the published literature (n = 7) and from health technology assessment agencies (n = 5). Data from trials were extracted to identify between-trial differences that may have biased results. Credibility of the performed analyses and relevance of the research questions were critically appraised using the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) checklist and feedback based on consultations with clinical experts. RESULTS: The identified studies concerned NMAs of randomized controlled trials (RCTs; n = 7), unanchored MAICs (n = 4), or both types of analyses (n = 1). According to clinical expert consultation, the majority of the identified NMAs did not consider differences in prior therapies or treatment duration across the RCTs included in the analyses, thereby compromising the relevance. CONCLUSION: Based on the results and feedback from clinicians, the majority of NMAs did not consider prior treatment history or treatment duration, which resulted in nonrelevant comparisons. Furthermore, it may have compromised the credibility of the estimates owing to differences in effect-modifiers between the different trials. Pairwise comparisons by means of unanchored MAICs require clear justification given the reliance on non-randomized comparisons.

Health-related quality of life of carfilzomib- and daratumumab-based therapies in patients with relapsed/refractory multiple myeloma, based on German benefit assessment data.

BACKGROUND: Carfilzomib and daratumumab are licensed in relapsed/refractory multiple myeloma (RRMM), but no head-to-head trials have been conducted. METHODS: We used data from dossiers prepared for the German Federal Joint Committee based on two phase III randomized trials of carfilzomib-based therapies (ASPIRE, ENDEAVOR) and two of daratumumab-based therapies (POLLUX, CASTOR) to conduct a descriptive assessment of health-related quality of life (HRQoL). HRQoL was assessed using the European Organisation for Research and Treatment of Cancer 30-item HRQoL Questionnaire, with hazard ratios calculated for carfilzomib- and daratumumab-based therapy versus comparators for time to HRQoL deterioration of ≥ 10 points. Analyses were also conducted on data from the EORTC 20-item myeloma-specific questionnaire, the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity scale, and the visual analog scale of the EuroQoL 5-dimension, 5-level questionnaire, where results for these instruments were available. As the designs and patient population of the four trials were similar but not identical, the analysis included only indirect, descriptive comparisons. RESULTS: Compared with lenalidomide/dexamethasone, median time to deterioration in global health status/QoL was longer for carfilzomib-based therapy versus control, but similar for daratumumab-based therapy and control. Compared with bortezomib/dexamethasone, time to deterioration was significantly longer for carfilzomib-based therapy versus control for global health status/QoL and numerous functional and symptom subscales. HRQoL measurement is feasible in large RRMM populations. CONCLUSION: Descriptive assessment of HRQoL data suggests potential benefits for carfilzomib-based over daratumumab-based therapy.

Prospective target assessment and multimodal prediction of survival for personalized and risk-adapted treatment strategies in multiple myeloma in the GMMG-MM5 multicenter trial.

BACKGROUND: Personalized and risk-adapted treatment strategies in multiple myeloma prerequisite feasibility of prospective assessment, reporting of targets, and prediction of survival probability in clinical routine. Our aim was first to set up and prospectively test our experimental and analysis strategy to perform advanced molecular diagnostics, i.e., interphase fluorescence in-situ hybridization (iFISH) in ≥ 90% and gene expression profiling (GEP) in ≥ 80% of patients within the first cycle of induction chemotherapy in a phase III trial, seen as prerequisite for target expression-based personalized treatment strategies. Secondly, whether the assessment of risk based on the integration of clinical, cytogenetic, and expression-based parameters ("metascoring") is possible in this setting and superior to the use of single prognostic factors. METHODS: We prospectively performed plasma cell purification, GEP using DNA-microarrays, and iFISH within our randomized multicenter GMMG-MM5-trial recruiting 604 patients between July 2010 and November 2013. Patient data were analyzed using our published gene expression report (GEP-R): after quality and identity control, integrated risk assessment (HM metascore) and targets were reported in clinical routine as pdf-document. RESULTS: Bone marrow aspirates were obtained from 573/604 patients (95%) and could be CD138-purified in 559/573 (97.6%). Of these, iFISH-analysis was possible in 556 (99.5%), GEP in 458 (82%). Identity control using predictors for sex, light and heavy chain type allowed the exclusion of potential sample interchanges (none occurred). All samples passed quality control. As exemplary targets, IGF1R-expression was reported expressed in 33.1%, AURKA in 43.2% of patients. Risk stratification using an integrated approach, i.e., HM metascore, delineated 10/77/13% of patients as high/medium/low risk, transmitting into significantly different median progression-free survival (PFS) of 15 vs. 39 months vs. not reached (NR; P < 0.001) and median overall survival (OS) of 41 months vs. NR vs. NR (P < 0.001). Five-year PFS and OS-rates were 5/31/54% and 25/68/98%, respectively. Survival prediction by HM metascore (Brier score 0.132, P < 0.001) is superior compared with the current gold standard, i.e., revised ISS score (0.137, P = 0.005). CONCLUSIONS: Prospective assessment and reporting of targets and risk by GEP-R in clinical routine are feasible in ≥ 80% of patients within the first cycle of induction chemotherapy, simultaneously allowing superior survival prediction.

Development of an Initial Conceptual Model of Multiple Myeloma to Support Clinical and Health Economics Decision Making.

Background. We aimed to develop and validate a conceptual model of multiple myeloma (MM) that characterizes the attributes affecting disease progression and patient outcomes, and the relationships between them. Methods. Systematic and targeted literature reviews identified disease- and patient-specific attributes of MM that affect disease progression and outcomes. These attributes were validated by a Delphi panel of four international MM experts, and a physician-validated model was constructed. Real-world clinical data from the Czech Registry of Monoclonal Gammopathies (RMG) was used to confirm the relationships between attributes using pairwise correlations and multiple Cox regression analysis. Results. The Delphi panel reached consensus that most cytogenetic abnormalities influenced disease activity, which results in symptoms and complications and affects overall survival (OS). Comorbidities and complications also affect OS. The entire panel agreed that quality of life was influenced by comorbidities, age, complications, and symptoms. Consensus was not reached in some cases, in particular, the influence of del(17p) on complications. The relationships between attributes were confirmed using pairwise analysis of real-world data from the Czech RMG; most of the correlations identified were statistically significant and the strength of the correlations changed with successive relapses. Czech RMG data were also used to confirm significant predictors of OS included in the model, such as age, Eastern Cooperative Oncology Group performance status, and extramedullary disease. Conclusions. This validated conceptual model can be used for economic modeling and clinical decision making. It could also inform the development of disease-based models to explore the impact of disease progression and treatment on outcomes in patients with MM.

Dual-energy CT: virtual calcium subtraction for assessment of bone marrow involvement of the spine in multiple myeloma.

OBJECTIVE. Dual-energy CT (DECT) enables subtraction of calcium, facilitating the visualization of bone marrow (BM) in the axial skeleton. The purpose of this study was to assess whether DECT BM images have the potential to improve the detection of multifocal and diffuse BM infiltration in multiple myeloma (MM) in comparison with regular CT with MRI as the reference standard. SUBJECTS AND METHODS. This study included 32 consecutive patients who had known MM or presented with monoclonal gammopathy of unknown significance and underwent DECT and MRI of the axial skeleton. The degrees (none, n = 14; moderate, n = 10; and high, n = 8) and patterns (diffuse, n = 10 or multifocal, n = 8) of infiltration were assessed on MR images. Attenuation in BM and CT images in known uninvolved and involved areas was measured. Cutoff values of attenuation in BM images for infiltration in lytic and nonlytic lesions were established by ROC analysis. At least 120 days later, sensitivity and specificity for reading CT images alone and when using additional BM images were evaluated. RESULTS. ROC analysis revealed larger AUC in BM images than in CT images; cutoff values for marrow invasion in BM images were 4 and -3 HU in lytic and nonlytic lesions, respectively. In the blinded reading session, BM images improved the sensitivity for the detection of diffuse infiltration from 0 to as much as 75% for cases with high-grade infiltration. In multifocal patterns, BM images did not significantly change the detection rate. CONCLUSION. BM images have the potential to improve the sensitivity for detection of diffuse BM involvement in comparison with regular CT.

Response assessment in patients with multiple myeloma during antiangiogenic therapy using arterial spin labeling and diffusion-weighted imaging: a feasibility study.

RATIONALE AND OBJECTIVES: To determine whether response to anti-angiogenic therapy in patients with multiple myeloma can be assessed by noncontrast perfusion magnetic resonance imaging (MRI) (ie, arterial-spin-labeling [ASL]), and diffusion-weighted [DWI] MRI. MATERIALS AND METHODS: The study protocol was approved by the local institutional ethic board. Ten consecutive patients (eight men, two women; mean age 60.5 ± 8.5 years) with Stage III multiple myeloma were prospectively included. MRI was performed at baseline, as well as 3 and 8 weeks after onset of antiangiogenic therapy. Functional MRI data were compared with clinical outcome and conventional lesion size and signal-intensity measurements. Differences between baseline and follow-up values for ASL-MRI and DWI-MRI were assessed using a paired Student t-test. RESULTS: Nine patients responded well to therapy, whereas one patient was classified a nonresponder. Temporary changes in signal intensity between baseline and follow-up examinations were inconsistent on T1-weighted (w) and T2w images. Likewise, determination of lesion size at follow-up proved unreliable. ASL showed a marked decrease in perfusion from baseline (251 ± 159 mL/(min*100g)) to follow-up at 3 weeks (115 ± 85 mL/(min*100g), P = .01) and 8 weeks (101 ± 90 mL/(min*100g, P = .01), respectively. Relative to the baseline examination, mean diffusion increased from 0.68 ± 0.19 × 10(-3) s/mm(2) at baseline to 0.94 ± 0.24 × 10(-3) s/mm(2) after 3 weeks (P = .04), and 0.96 ± 0.40 × 10(-3) s/mm(2) after 8 weeks (P = .049). Both methods were able to correctly classify 9/10 patients as responder or nonresponder. CONCLUSION: ASL perfusion as well as DWI-MRI provide accurate, clinically relevant information regarding tumor viability and can predict response already early after therapy onset, as opposed to classical lesion size and MRI signal-intensity measurements.

Early response assessment in patients with multiple myeloma during anti-angiogenic therapy using arterial spin labelling: first clinical results.

OBJECTIVE: To determine if arterial-spin-labelling (ASL) MRI can reliably detect early response to anti-angiogenic therapy in patients with multiple myeloma by comparison with clinical/haematological response. METHODS: Nineteen consecutive patients (10 men; mean age 63.5 ± 9.1 years) were included in the present study. Inclusion criteria were diagnosis of stage III multiple myeloma and clinical indication for therapeutical administration of bortezomib or lenalidomide. We performed MRI on 3.0T MR in the baseline setting, 3 weeks after onset of therapy and after 8 weeks. Clinical responses were determined on the basis of international uniform response criteria in correlation with haematological parameters and medium-term patient outcome. MRI studies were performed after approval by the local institutional review board. RESULTS: Fifteen patients responded to anti-myeloma therapy; 4/19 patients were non-responders to therapy. Mean tumour perfusion assessed by ASL-MRI in a reference lesion was 220.7 ± 132.5 ml min(-1) 100 g(-1) at baseline, and decreased to 125.7 ± 86.3 (134.5 ± 150.9) ml min(-1) 100 g(-1) 3 (8) weeks after onset of therapy (P < 0.02). The mean decrease in paraproteinaemia at week 3 (8) was 52.3 ± 47.7% (58.2 ± 58.7%), whereas ß2-microglobulinaemia decreased by 20.3 ± 53.1% (23.3 ± 57.0%). Correlation of ASL perfusion with outcome was significant (P = 0.0037). CONCLUSION: ASL tumour perfusion measurements are a valuable surrogate parameter for early assessment of response to novel anti-angiogenic therapy.