Citations

The treatment of multiple myeloma has evolved markedly in the last decade, but mortality remains high, emphasizing the need for more effective therapies. Daratumumab, a fully human monoclonal antibody targeting CD38, has shown clinical efficacy in relapsed/refractory multiple myeloma both as monotherapy and in combination with other drugs, including novel agents. More recently, promising results have been reported in patients with untreated newly diagnosed multiple myeloma (NDMM). Clinical trials thus far have shown enhanced efficacy and tolerability of several daratumumab-based combinations in both transplant ineligible and eligible patients, without compromising transplant ability. However, benefit in high-risk subpopulations is still unclear. A subcutaneous formulation of daratumumab has been introduced to decrease the risk of infusion reactions, with preliminary results showing non-inferior efficacy. The antimyeloma activity of daratumumab is achieved through multiple mechanisms including direct, Fc-dependent, and immunomodulatory mechanisms. Enhanced efficacy of daratumumab in combination with immunomodulatory drugs and proteasome inhibitors is supported by preclinical data showing synergism. This review will focus on the role of daratumumab in untreated NDMM patients, highlighting the results of major clinical trials, and listing ongoing trials that are evaluating various daratumumab-based combinations in this setting.

AbstractIntroductionConventional Z‐scores are generated by subtracting the mean and dividing by the standard deviation. More recent methods linearly correct for age, sex, and education, so that these “adjusted” Z‐scores better represent whether an individual's cognitive performance is abnormal. Extreme negative Z‐scores for individuals relative to this normative distribution are considered indicative of cognitive deficiency.MethodsIn this article, we consider nonlinear shape constrained additive models accounting for age, sex, and education (correcting for nonlinearity). Additional shape constrained additive models account for varying standard deviation of the cognitive scores with age (correcting for heterogeneity of variance).ResultsCorrected Z‐scores based on nonlinear shape constrained additive models provide improved adjustment for age, sex, and education, as indicated by higher adjusted‐R2.DiscussionNonlinearly corrected Z‐scores with respect to age, sex, and education with age‐varying residual standard deviation allow for improved detection of non‐normative extreme cognitive scores.

AbstractIntroductionThe Advancing Research and Treatment in Frontotemporal Lobar Degeneration and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects longitudinal studies were designed to describe the natural history of familial‐frontotemporal lobar degeneration due to autosomal dominant mutations.MethodsWe examined cognitive performance, behavioral ratings, and brain volumes from the first time point in 320 MAPT, GRN, and C9orf72 family members, including 102 non–mutation carriers, 103 asymptomatic carriers, 43 mildly/questionably symptomatic carriers, and 72 carriers with dementia.ResultsAsymptomatic carriers showed similar scores on all clinical measures compared with noncarriers but reduced frontal and temporal volumes. Those with mild/questionable impairment showed decreased verbal recall, fluency, and Trail Making Test performance and impaired mood and self‐monitoring. Dementia was associated with impairment in all measures. All MAPT carriers with dementia showed temporal atrophy, but otherwise, there was no single cognitive test or brain region that was abnormal in all subjects.DiscussionImaging changes appear to precede clinical changes in familial‐frontotemporal lobar degeneration, but specific early clinical and imaging changes vary across individuals.

AbstractPurpose:Patients with HER2+ breast cancer benefit from trastuzumab-containing regimens with improved survival. Adaptive immunity, including cytotoxic T-cell and antibody immunity, is critical to clinical efficacy of trastuzumab. Because Th cells are central to the activation of these antitumor effectors, we reason that HER2 patients treated with trastuzumab may benefit by administering vaccines that are designed to stimulate Th-cell immunity.Patients and Methods:We developed a degenerate HER2 epitope–based vaccine consisting of four HLA class II–restricted epitopes mixed with GM-CSF that should immunize most (≥84%) patients. The vaccine was tested in a phase I trial. Eligible women had resectable HER2+ breast cancer and had completed standard treatment prior to enrollment and were disease free. Patients were vaccinated monthly for six doses and monitored for safety and immunogenicity.Results:Twenty-two subjects were enrolled and 20 completed all six vaccines. The vaccine was well tolerated. All patients were alive at analysis with a median follow-up of 2.3 years and only two experienced disease recurrence. The percent of patients that responded with augmented T-cell immunity was high for each peptide ranging from 68% to 88%, which led to 90% of the patients generating T cells that recognized naturally processed HER2 antigen. The vaccine also augmented HER2-specific antibody. Immunity was sustained in patients with little sign of diminishing at 2 years following the vaccination.Conclusions:Degenerate HLA-DR–based HER2 vaccines induce sustainable HER2-specific T cells and antibodies. Future studies, could evaluate whether vaccination during adjuvant treatment with trastuzumab-containing regimens improves patient outcomes.

Background: The treatment of Multiple Myeloma (MM) has evolved significantly in the past decade with the introduction of novel agents and drug combinations, thus enhancing treatment efficacy and allowing more patients to achieve complete response (CR). This has created a need to identify surrogates for depth of treatment response. Serum free light chain (sFLC) ratio normalization has been shown to be prognostic for progression free survival as well as overall survival in patients achieving a complete response to therapy. Consequently, it has been incorporated as a defining feature for stringent CR, along with lack of clonal plasma cells by immunohistochemistry (IHC) or low sensitivity flow cytometry. The routine use of multiparametric flow cytometry with higher sensitivity to detect residual disease than IHC or the older 4-color flow cytometry, has raised the question as to whether sFLC ratio is still a valid indicator of response depth. Moreover, in nearly half of the patients with an abnormal sFLC ratio after treatment, the abnormality is secondary to suppression of one or both serum light chains. Therefore, we designed a retrospective study to address these issues. Patients and Methods: This is a retrospective study using the Multiple Myeloma Database at Mayo Clinic, Rochester. We included patients who, after any line of therapy, had negative serum and urine immunofixation and absence of clonal bone marrow plasma cells by flow cytometry (PC-PRO), which has a sensitivity of >10-4. Simultaneous sFLC data was also extracted. Patients were grouped into three categories based on their sFLC ratios: 1) normal ratio (normal), 2) abnormal ratio due to suppression of the uninvolved light chain (LC), involved LC, or both (Abn-suppressed) and 3) abnormal ratio due to elevation of the involved LC (Abn-inv elevated). The primary endpoint was the median time to next treatment (TTNT), defined as the time from sample collection to the time of initiation of the subsequent therapy or time of last follow up if a subsequent line of treatment was not initiated. Results: The cohort consisted of 510 patients. 285 (56%) were males and 225 (44%) females. Median age was 61 years (IQR: 55-67). Median Follow-up was 41 months. The last treatments administered prior to data collection included stem cell transplant (SCT) (with or without maintenance) in 290 (57%) patients, and non-SCT regimens in the others. The sFLC ratio was normal in 337 (66%) and abnormal in 173 (34%) patients. Among the patients with abnormal sFLC ratios, 81 had elevated involved LC, 25 had suppression of the involved LC, 45 had suppression of the uninvolved LC and 22 had suppression of both LCs. We first examined the TTNT for the three groups and found that the TTNT was identical for those with a normal ratio and those with an abnormal ratio due to suppression of one or both light chains (Figure 1). So, we combined these two groups (Normal-Abn suppressed) and compared their outcomes to the patients with abnormal sFLC ratio due to elevated involved LC. The Abn-inv elevated group had a shorter TTNT as shown in Figure 2 (log-rank 0.06, Wilcoxon <0.01). The Abn-inv elevated group also had decreased overall survival compared to the other group (log-rank: 0.05, Wilcoxon: 0.01) (Figure 3). Conclusion: This study provides 2 important observations. First, patients with an abnormal ratio due to suppression of one or both LCs have outcomes similar to those with a normal ratio, suggesting a need to clarify the current definition of stringent CR. Second, the study suggests an important prognostic value for an abnormal sFLC ratio due to elevated involved LC, suggesting this as an important surrogate for depth of response. Disclosures Kapoor: Janssen: Research Funding; Takeda: Honoraria, Research Funding; Cellectar: Consultancy; Celgene: Honoraria; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Glaxo Smith Kline: Research Funding. Dispenzieri:Akcea: Consultancy; Intellia: Consultancy; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Gertz:Ionis: Honoraria; Alnylam: Honoraria; Prothena: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Spectrum: Honoraria, Research Funding. Lacy:Celgene: Research Funding. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; Millenium: Consultancy; Janssen: Consultancy; alexion: Consultancy. Leung:Takeda: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Omeros: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

Abstract Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Abstract Background: Recent reports from the thalassemia literature suggest that serum ferritin may be a poor and possibly misleading measure of total iron store in heavily iron overloaded patients. Moreover, the relationship between plasma ferritin and body iron stores is distorted by ascorbate deficiency, fever, infection, inflammation, and hepatic dysfunction, all of which occur in patients with sickle cell disease (SCD). On the other hand, following the results of multiple studies that demonstrated a high correlation of hepatic iron overload determination by magnetic resonance imaging to the values found in specimens from liver biopsy, R2* liver MRI has emerged as the best noninvasive yet highly sensitive and specific method for measuring the level of iron in the liver. The goal of this study was to determine the correlation of liver iron by liver R2* MRI with serum ferritin and by extrapolation assess whether serum ferritin remains to be a useful clinical marker of iron overload in patients with SCD. We also sought to determine the correlation of liver iron concentration with abnormalities in the liver function tests. Methods: We conducted a retrospective analysis of 31 patients with sickle cell disease and transfusional iron overload who are being followed at the Augusta University Comprehensive Sickle Cell Center. Serum ferritin, hepatic R2* MRI liver iron concentration, hepcidin level, and liver function tests (AST, ALT and total bilirubin) were assessed for correlation. We used the Pearson correlation coefficient to determine the relationship between the various variables with hepatic R2* MRI. Results: Serum ferritin levels showed a statistically significant positive correlation with R2* hepatic MRI (r = 0.479 with p = 0.0085) in the patients with SCD and transfusional iron overload . We also saw a positive correlation, although not statistically significant, between hepcidin level and liver iron concentration by liver MRI(r=0.493 with P= 0.399). This may be due to the small sample size of the patients who had hepcidin levels available. On the other hand, no correlation was detected between abnormalities in liver function tests and liver iron concentration. The correlation between liver iron concentration(LIC) and AST was 0.045 with p = 0.816 and the correlation between LIC and ALT was 0.233 with p = 0.224. Conclusion: While R2* MRI is the the most accurate method to diagnose and monitor response to therapy in SCD patients with transfusional iron overload, we have found a statistically significant positive correlation with serum ferritin values. Thus, where R2* liver MRI is unavailable, serum ferritin remains a clinically useful tool that can be used in the diagnosis and monitoring of iron overload in sickle cell patients, despite its limitations. As previously reported, we did not find any correlation between LIC and liver function abnormalities in this population (Harmatz et al, 2000) These findings suggest that patients with SCD may have a different response to iron overload in comparison to patients with thalassemia or hereditary hemochromatosis. Disclosures Kutlar: Bluebird Bio: Other: DSMB Member; Sancilio: Other: DSMB Chair; Novartis: Consultancy, Honoraria, Other: Personal fees, Research Funding.