Daratumumab, carfilzomib, lenalidomide, and dexamethasone with tandem transplant for high-risk newly diagnosed myeloma.

ABSTRACT: High-risk (HR) cytogenetics are associated with poor outcomes in newly diagnosed multiple myeloma (NDMM), and dedicated studies should address this difficult-to-treat population. The phase 2 study 2018-04 from the Intergroupe Francophone du Myelome evaluated feasibility of an intensive strategy with quadruplet induction and consolidation plus tandem transplant in HR transplant-eligible (TE) NDMM. HR cytogenetics were defined by presence of del(17p), t(4;14), and/or t(14;16). Treatment consisted of daratumumab-carfilzomib-lenalidomide-dexamethasone (D-KRd) induction, autologous stem cell transplantation (ASCT), D-KRd consolidation, second ASCT, and daratumumab-lenalidomide maintenance. The primary end point was feasibility. Fifty patients with previously untreated NDMM were included. Median age was 57. Del(17p), t(4;14), and t(14;16) were found in 40%, 52%, and 20% of patients, respectively. At data cutoff, the study met the primary end point with 36 patients completing second transplant. Twenty patients discontinued the study due to stem cell collection failure (n = 8), disease progression (n = 7), adverse event (n = 4), or consent withdrawal (n = 1). Grade 3 to 4 D-KRd induction/consolidation-related adverse events (>5% of patients) were neutropenia (39%), anemia (12%), thrombocytopenia (7%), and infection (6%). The overall response rate was 100% for patients completing second transplant, including 81% complete response. Premaintenance minimal residual disease (MRD) negativity rate (10-6) was 94%. After a median follow-up of 33 months, the 30-month progression-free survival (PFS) and overall survival were 80% and 91%, respectively. In conclusion, D-KRd with tandem transplant is feasible in patients with HR TE-NDMM and resulted in high response rates and PFS. This trial was registered at www.clinicaltrials.gov as #NCT03606577.

RAS/RAF landscape in monoclonal plasma cell conditions.

ABSTRACT: Multiple myeloma is characterized by a huge heterogeneity at the molecular level. The RAS/RAF pathway is the most frequently mutated, in ∼50% of the patients. However, these mutations are frequently subclonal, suggesting a secondary event. Because these genes are part of our routine next-generation sequencing panel, we analyzed >10 000 patients with different plasma cell disorders to describe the RAS/RAF landscape. In this large cohort of patients, almost 61% of the patients presented a RAS/RAF mutation at diagnosis or relapse, but much lower frequencies occurred in presymptomatic cases. Of note, the mutations were different from that observed in solid tumors (higher proportions of Q61 mutations). In 29 patients with 2 different mutations, we were able to perform single-cell sequencing, showing that in most cases, mutations occurred in different subclones, suggesting an ongoing mutational process. These findings suggest that the RAS/RAF pathway is not an attractive target, both on therapeutic and residual disease assessment points of view.

High efficacy of CD19 CAR T cells in patients with transformed Waldenström macroglobulinemia.

ABSTRACT: Histologic transformation of Waldenström macroglobulinemia (HT-WM) carries a poor prognosis with standard treatments. Here, we report the first series of HT-WM treated with chimeric antigen receptor T cells showing a high efficacy and no unexpected toxicity.

Cerebellum/liver index on baseline 18F-FDG PET/CT to improve prognostication in post-transplant lymphoproliferative disorders: a multicenter retrospective study.

BACKGROUND: Besides International Prognostic Index (IPI) score, baseline prognostic factors of post-transplant lymphoproliferative disorders (PTLD) are poorly identified due to the rarity of the disease. New indexes derived from healthy organ uptake in baseline 18F-FDG PET/CT have been studied in immunocompetent lymphoma patients. The aim of this study is to evaluate the performances of the cerebellum-to-liver uptake ratio (denoted as CLIP) as a prognostic factor for PFS and OS. This retrospective multicenter study is based on patients with PTLD included in the K-VIROGREF cohort. The previously published threshold of 3.24 was used for CLIP in these analyses. RESULTS: A total of 97 patients was included with a majority of monomorphic diffuse large B-cell lymphoma subtype (78.3%). Both IPI score (≥ 3) and CLIP (< 3.24) were significant risk factors of PFS with corresponding hazard ratios of 2.0 (1.0-4.0) and 2.4 (1.3-4.5) respectively. For OS, CLIP was not significant and resulted in a hazard ratio of 2.6 (p = 0.059). Neither IPI score or Total Metabolic Tumor Volume reached significance for OS. CONCLUSION: CLIP is a promising predictor of PFS and perhaps OS in PTLD. Further prospective studies are needed to confirm these results.

Preclinical in vivo assessment of the activity of AZD7442 anti-SARS-CoV-2 monoclonal antibodies against Omicron sublineages.

Therapeutic monoclonal antibodies have been successful in protecting vulnerable populations against SARS-CoV-2. However, their effectiveness has been hampered by the emergence of new variants. To adapt the therapeutic landscape, health authorities have based their recommendations mostly on in vitro neutralization tests. However, these do not provide a reliable understanding of the changes in the dose-effect relationship and how they may translate into clinical efficacy. Taking the example of EvusheldTM (AZD7442), we aimed to investigate how in vivo data can provide critical quantitative results and project clinical effectiveness. We used the Golden Syrian hamster model to estimate 90 % effective concentrations (EC90) of AZD7442 in vivo against SARS-CoV-2 Omicron BA.1, BA.2 and BA.5 variants. While our in vivo results confirmed the partial loss of AZD7442 activity for BA.1 and BA.2, they showed a much greater loss of efficacy against BA.5 than that obtained in vitro. We analyzed in vivo EC90s in perspective with antibody levels measured in a cohort of immunocompromised patients who received 300 mg of AZD7442. We found that a substantial proportion of patients had serum levels of anti-SARS-CoV-2 spike protein IgG above the estimated in vivo EC90 for BA.1 and BA.2 (21 % and 92 % after 1 month, respectively), but not for BA.5. These findings suggest that AZD7442 is likely to retain clinical efficacy against BA.2 and BA.1, but not against BA.5. Overall, the present study illustrates the importance of complementing in vitro investigations by preclinical studies in animal models to help predict the efficacy of monoclonal antibodies in humans.

Baseline 18F-FDG Metabolic Tumor Volume Predicts Response to Rituximab Induction in Post-transplant Lymphoproliferative Disorders: A Multi-institutional Retrospective Study.

Post-transplant lymphoproliferative disorder (PTLD) is a rare complication of immunosuppression. Sequential treatment is commonly proposed, combining induction with rituximab (R-induction) followed by either continuation of treatment or addition of chemotherapy depending on response. Response to R-induction, often assessed by CT scan, is a major predictor of overall survival (OS). The aim of the study was to analyze predictive factors of R-induction response, including total metabolic tumor volume (TMTV), and investigate the role of 18F-FDG PET/CT in response assessment. This retrospective multicenter study is based on patients with PTLD included in the K-VIROGREF cohort. Only patients treated by R-induction with a baseline 18F-FDG PET/CT were included. Response to R-induction was assessed by 18F-FDG PET/CT. The optimal threshold of TMTV for rituximab response was determined using receiver operating characteristic curves. Univariate and multivariate analyses were conducted to identify predictive factors of response. A total of 67 patients were included. Survival characteristics were similar to those previously reported: the complete response rate to R-induction was 30%, the 3-year OS estimate was 66%, and the treatment-related mortality was 4%. The optimal threshold for TMTV to predict R-induction response was 135 cm3. The response rate to R-induction was 38% in the 21 patients with TMTV ≥ 135 cm3 and 72% in the 46 patients with TMTV < 135 cm3. TMTV was a significant predictor of response, both at univariate and multivariate analyses (odd ratios = 3.71, P = 0.022). Baseline TMTV is predictive of response to R-induction. Early assessment of patient response is feasible with 18F-FDG PET/CT.

Filling the Gap: The Immune Therapeutic Armamentarium for Relapsed/Refractory Hodgkin Lymphoma.

Despite years of clinical progress which made Hodgkin lymphoma (HL) one of the most curable malignancies with conventional chemotherapy, refractoriness and recurrence may still affect up to 20-30% of patients. The revolution brought by the advent of immunotherapy in all kinds of neoplastic disorders is more than evident in this disease because anti-CD30 antibodies and checkpoint inhibitors have been able to rescue patients previously remaining without therapeutic options. Autologous hematopoietic cell transplantation still represents a significant step in the treatment algorithm for chemosensitive HL; however, the possibility to induce complete responses after allogeneic transplant procedures in patients receiving reduced-intensity conditioning regimens informs on its sensitivity to immunological control. Furthermore, the investigational application of adoptive T cell transfer therapies paves the way for future indications in this setting. Here, we seek to provide a fresh and up-to-date overview of the new immunotherapeutic agents dominating the scene of relapsed/refractory HL. In this optic, we will also review all the potential molecular mechanisms of tumor resistance, theoretically responsible for treatment failures, and we will discuss the place of allogeneic stem cell transplantation in the era of novel therapies.

A case report of Guillain Barré syndrome revealing underlying infective endocarditis due to Cardiobacterium hominis.

RATIONALE: Guillain-Barré syndrome (GBS) is an acute inflammatory polyradiculoneuropathy presumed to result from an infection-triggered autoimmune reaction. PATIENT CONCERNS: This paper describes a 53-year-old man admitted to hospital for deterioration of his general condition. DIAGNOSIS: He developed GBS, confirmed by lumbar puncture and electromyogram, which recovered after intravenous immunoglobulins. A grade 2 aortic regurgitation was detected by transthoracic echocardiography upon diagnosis of GBS, but in the absence of fever, no further investigations were conducted. A few weeks later, the patient presented with fever and infective endocarditis (IE) was diagnosed after the identification of vegetation on the aortic valve with transesophageal echocardiography. The etiologic agent was identified as Cardiobacterium hominis based on 3 positive blood cultures and DNA detection in valvular material. INTERVENTIONS: IE was cured with a 6-week course of antibiotics and aortic valve replacement. OUTCOMES: The patient completely recovered from Guillain-Baré syndrome and IE. LESSONS: This case of GBS associated with C hominis endocarditis, emphasizes the importance of blood cultures and transesophageal echocardiography for the detection of IE and highlights the insidious nature of C hominis endocarditis which is often diagnosed late.

Vaccine Education of Medical Students: A Nationwide Cross-sectional Survey.

Physicians play a primary role in vaccination of the population. Strong initial training of medical students is therefore essential to enable them to fulfill this role. This cross-sectional nationwide online survey conducted between September 2015 and January 2016 obtained 2,118 completed surveys from 6,690 eligible respondents (response rate, 32%) at 27 of 32 medical schools in France regarding their education about vaccination. The data were analyzed in April-June 2016. The survey covered their knowledge, attitudes, practices, and perceptions, and assessed their level of perceived preparedness for their future practice as interns. Around a third of the students (n=708, 34%) felt insufficiently prepared for questions about vaccination, especially for communicating with patients on side effects (n=1,381, 66%) and strategies to respond to vaccine hesitancy (n=1,217, 58%). The mean knowledge score was 26/45 (SD=7.9). Lecture courses, which are the main education method used in French medical schools (1,891/5,660 responses, 33%), were considered effective by only 11% of students (693/6,155 responses), whereas practical training was significantly associated with better perceived preparedness (p<0.001). In conclusion, education about vaccination during medical school in France is not optimal. Methods based on practical learning methods (case-based learning, clinical placements, and other hands-on methods) appear to produce the best results and must be favored for improving students' preparedness.