Outcomes of anti-CD38 isatuximab plus pomalidomide and dexamethasone in five relapsed myeloma patients with prior exposure to anti-C38 daratumumab: case series

© 2022 The Authors. Published by Taylor & Francis and International Society of Hematology. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1080/16078454.2022.2028978Objectives: Daratumumab is the first anti-CD38 monoclonal antibody (Mab) used to treat myeloma in the newly diagnosed setting and in the relapsed setting. Isatuximab, another Mab targeting a specific epitope on the CD38 receptor, was recently approved in the UK in combination with pomalidomide and dexamethasone (IsaPomDex) to treat myeloma patients who received three prior lines of therapy. However, there is a lack of understanding of whether using a prior anti-CD38 Mab (e.g. daratumumab) can affect the efficacy of another Mab (e.g. isatuximab), when the latter is used to treat a subsequent relapse.Methods: We performed a UK-wide outcomes study of IsaPomDex in the real-world. In this case series, we report a detailed descriptive analysis of the characteristics and clinical outcomes of five IsaPomDex patients in UK routine practice (Patients I to V), with a prior exposure to daratumumab.Results: Age range was 51-77 years with two patients >70 and three patients <70 years. The cytogenetic risk was standard in two patients, high in two patients and not known in one patient. Prior daratumumab regimen were monotherapy (dara-mono) in one patient (II), and daratumumab with bortezomib and dexamethasone (DVd) in four patients. Responses to prior daratumumab were: very good partial response (VGPR) in two patients (I and III), minor response-stable disease (MR-SD) in one patient (II), and progressive disease (PD) in two patients (IV and V). Median (range) number of IsaPomDex cycles received was 2 (1-4). Outcomes of IsaPomDex were PD in three patients (II, IV and V) and a response in two patients. Response categories were: MR-SD in patient I and PR in patient III.Discussion: Despite the limitations of our case series, we described the first UK real-world report of IsaPomDex outcomes in myeloma patients with a prior exposure to daratumumab.Conclusion: Large prospective studies are required to further evaluate myeloma outcomes in this setting.Published versio

A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett's esophagus.

Esophageal adenocarcinoma is a cancer with rising incidence and poor survival. Most such cancers arise in a specialized intestinal metaplastic epithelium, which is diagnostic of Barrett's esophagus. In a genome-wide association study, we compared esophageal adenocarcinoma cases (n = 2,390) and individuals with precancerous Barrett's esophagus (n = 3,175) with 10,120 controls in 2 phases. For the combined case group, we identified three new associations. The first is at 19p13 (rs10419226: P = 3.6 × 10(-10)) in CRTC1 (encoding CREB-regulated transcription coactivator), whose aberrant activation has been associated with oncogenic activity. A second is at 9q22 (rs11789015: P = 1.0 × 10(-9)) in BARX1, which encodes a transcription factor important in esophageal specification. A third is at 3p14 (rs2687201: P = 5.5 × 10(-9)) near the transcription factor FOXP1, which regulates esophageal development. We also refine a previously reported association with Barrett's esophagus near the putative tumor suppressor gene FOXF1 at 16q24 and extend our findings to now include esophageal adenocarcinoma

Maternal Undernutrition Significantly Impacts Ovarian Follicle Number and Increases Ovarian Oxidative Stress in Adult Rat Offspring

BACKGROUND: We have shown recently that maternal undernutrition (UN) advanced female pubertal onset in a manner that is dependent upon the timing of UN. The long-term consequence of this accelerated puberty on ovarian function is unknown. Recent findings suggest that oxidative stress may be one mechanism whereby early life events impact on later physiological functioning. Therefore, using an established rodent model of maternal UN at critical windows of development, we examined maternal UN-induced changes in offspring ovarian function and determined whether these changes were underpinned by ovarian oxidative stress. METHODOLOGY/PRINCIPAL FINDINGS: Our study is the first to show that maternal UN significantly reduced primordial and secondary follicle number in offspring in a manner that was dependent upon the timing of maternal UN. Specifically, a reduction in these early stage follicles was observed in offspring born to mothers undernourished throughout both pregnancy and lactation. Additionally, antral follicle number was reduced in offspring born to all mothers that were UN regardless of whether the period of UN was restricted to pregnancy or lactation or both. These reductions were associated with decreased mRNA levels of genes critical for follicle maturation and ovulation. Increased ovarian protein carbonyls were observed in offspring born to mothers UN during pregnancy and/or lactation and this was associated with peroxiredoxin 3 hyperoxidation and reduced mRNA levels; suggesting compromised antioxidant defence. This was not observed in offspring of mothers UN during lactation alone. CONCLUSIONS: We propose that maternal UN, particularly at a time-point that includes pregnancy, results in reduced offspring ovarian follicle numbers and mRNA levels of regulatory genes and may be mediated by increased ovarian oxidative stress coupled with a decreased ability to repair the resultant oxidative damage. Together these data are suggestive of maternal UN potentially contributing to premature ovarian ageing in offspring

Infections in relapsed myeloma patients treated with isatuximab plus pomalidomide and dexamethasone during the COVID-19 pandemic: Initial results of a UK-wide real-world study

© 2022 The Authors. Published by Taylor & Francis. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1080/16078454.2022.2082725Objectives There are no real-world data describing infection morbidity in relapsed/refractory myeloma (RRMM) patients treated with anti-CD38 isatuximab in combination with pomalidomide and dexamethasone (IsaPomDex). In this UK-wide retrospective study, we set out to evaluate infections experienced by routine care patients who received this novel therapy across 24 cancer centres during the COVID-19 pandemic. Methods The primary endpoint was infection morbidity (incidence, grading, hospitalization) as well as infection-related deaths. Secondary outcomes were clinical predictors of increased incidence of any grade (G2–5) and high grade (≥G3) infections. Results In a total cohort of 107 patients who received a median (IQR) of 4 cycles (2–8), 23.4% of patients experienced ≥1 any grade (G2–5) infections (total of 31 episodes) and 18.7% of patients experienced ≥1 high grade (≥G3) infections (total of 22 episodes). Median time (IQR) from start of therapy to first episode was 29 days (16–75). Six patients experienced COVID-19 infection, of whom 5 were not vaccinated and 1 was fully vaccinated. The cumulative duration of infection-related hospitalizations was 159 days. The multivariate (MVA) Poisson Regression analysis demonstrated that a higher co-morbidity burden with Charlson Co-morbidity Index (CCI) score ≥4 (incidence rate ratio (IRR) = 3, p = 0.012) and sub-optimal myeloma response less than a partial response (<PR) (p = 0.048) are independent predictors of ≥ G3 infections. Conclusion Our study described initial results of infection burden during IsaPomDex treatment. We recommend close monitoring particularly in elderly patients with co-morbidities, the effective use of an-infective prophylaxis, as well as optimal vaccination strategies, to limit infections

Effect of Maternal Undernutrition on the Presence of Ovarian Hyperoxidised Prx 3.

<p>Maternal UN resulted in the increased presence of hyperoxidised ovarian Prx 3 in chow-fed UNP and UNPL, but not UNL, offspring. <b>A</b>) Representative non-reducing Western blot of Prx 3; Prx 3 is visualised as a 42 kDa band, hyperoxidised Prx 3 is visualised as a low molecular weight band (20 kDa); <b>B</b>) Data are presented as % hyperoxidised ovarian Prx 3 (as a ratio of band densities) and graphed as means ± S.E.M.; Two-Way ANOVA Main Effects: maternal diet p<0.001; postnatal diet  = 0.036; interaction p<0.001. Holm-Sidak <i>Post-hoc</i> analyses: * p<0.001 compared to chow-fed Controls. # p<0.001 compared to Cont-HF. + p<0.05, chow vs. HF.</p

Effect of Maternal Undernutrition on Offspring Ovarian ER-β mRNA expression levels.

<p>Maternal undernutrition resulted in a significant reduction in offspring ovarian ER-β mRNA levels. Data were normalised to beta-actin and relative mRNA data were normalised to 100% chow-fed Controls. Data are presented as means ± S.E.M. Two-Way ANOVA Main Effects: maternal diet p<0.001; postnatal diet  = 0.585; interaction p = 0.424. Holm-Sidak <i>Post-hoc</i> analyses: * p<0.005 compared to chow-fed Controls. # p = 0.008 compared to HF-fed Controls.</p

Relative mRNA levels of Genes of Interest Regulating Ovarian Folliculogenesis and Steroidogenesis.

<p>Data are mean ± SEM, relative to controls. <i>Post-hoc</i> analyses:</p><p>*p<0.001 compared to Controls;</p>#<p>p<0.05 compared to Cont-HF;</p>+<p>p<0.001 UNL chow vs. UNL-HF. BMP15, bone-morphogenetic protein 15; FSHR, follicle-stimulating hormone receptor; 3β-HSD, 3beta dehydrogenase; CYP17A1, cytochrome P450 17A1; PR, progesterone receptor. Note: Multiple comparisons within UN groups are detailed in the text.</p

Effect of Maternal Undernutrition on Offspring Ovarian Ob-Rb mRNA expression levels.

<p>Maternal UN resulted in significant alterations in offspring ovarian Ob-Rb mRNA levels. Data were normalised to beta-actin and relative mRNA data were then normalised to 100% Control. Data are presented as means ± S.E.M.; n = 4–9 per group. Two-Way ANOVA Main Effects: maternal diet p<0.001; postnatal diet  = 0.165; interaction p = 0.001. Holm-Sidak <i>Post-hoc</i> analyses: * p<0.05 compared to chow-fed Controls; # p<0.05 compared to Cont-HF. + p<0.05, chow vs. HF.</p

Effect of Maternal Undernutrition on Offspring Ovarian Primordial Follicle Number.

<p>Maternal UN occurring throughout pregnancy and lactation (UNPL) resulted in a significant reduction in offspring primordial follicle number. Data are presented as follicle number per mm3 of ovarian tissue; median ± upper and lower quartiles. Open bars correspond to a postnatal chow diet; closed bars correspond to a postnatal HF diet. Two-Way ANOVA Main Effects: maternal diet p = 0.035; postnatal diet  = 0.610; interaction p = 0.072. Holm-Sidak <i>Post-hoc</i> analyses: * p<0.001 compared to chow-fed Controls.</p