Tumor Reduction in Multiple Myeloma: New Concepts for New Therapeutics

The development of new resources for a more accurate diagnosis and response assessment in multiple myeloma has been a long process for decades, mainly since the middle of the 20th century. During this time, the succession of technical advances has run parallel to the better knowledge of disease biology and the availability of novel therapeutic strategies. The cornerstone of standardized criteria to uniformly evaluate the disease response in myeloma dates back to the 1990s when the key role of complete remission was established. Since then, different updates have been implemented according to available scientific evidences not always without certain controversies. The progressive improvements in survival results of myeloma patients and the growing quality of responses due to the novel therapies have led to the need of developing new tools for better monitoring of tumor burden. In this way, the concept of minimal residual disease and its key value based on the prognostic significance and the clinical relevance has been consolidated during the last years, overcoming the value of conventional response criteria or classical adverse prognosis markers. Nevertheless, its precise role in the clinical management of myeloma patients to detect early treatment failure and trigger early rescue strategies is still pending to be defined. In this review, we revisit the major milestones in the understanding of tumor reduction in multiple myeloma until the most recent imaging techniques or liquid biopsy approaches, including a critical view of conventional response criteria, whose backbone has remained unchanged during the last 20 years.

Time for an individualized approach to first-line management of follicular lymphoma

Follicular lymphoma is a heterogeneous B-cell lymphoma both in presentation and at progression. For most patients it is a chronic, relapsing indolent disease with overall survival expectations now potentially beyond 20 years. However, in a significant minority (~20%) who experience early progression or histological transformation after treatment, the disease no longer has an indolent behavior. This review looks at the development of prognostic indices, staging and therapies for follicular lymphoma, identifying where the data can, and cannot, guide the multidisciplinary team to determine an individualized approach to first-line therapy. A nuanced patient- and disease-specific approach is necessary to maximize disease response and survival while minimizing therapeutic toxicity.

Safety And Efficacy of Terlipressin In Acute-On-Chronic Liver Failure With Acute Kidney Injury – A Prospective Cohort Study

Background: Terlipressin with albumin, the recommended treatment for hepatorenal syndrome-acute kidney injury (HRS-AKI), is associated with adverse events. Furthermore, the course of AKI in patients with acute-on-chronic liver failure (ACLF) is unknown. We aimed to analyze the safety and efficacy of terlipressin infusion and AKI course in patients with ACLF.Methods: We prospectively enrolled consecutive adult patients with ACLF with HRS-AKI (satisfying either EASL or APASL criteria) treated with terlipressin infusion between 14 October 2019 and 24 July 2020. The objectives were to assess the incidence of adverse events, response to terlipressin, and differential treatment response in EASL and APASL subgroups. Results: Of the 116 patients, 51 satisfied EASL criteria, and 65 satisfied APASL criteria. Twenty-one percent of patients developed adverse effects. Only 1/3rd of patients who developed adverse events were alive at day 90. Sixty-five percent of the patients responded to terlipressin. Nearly 22% developed recurrence of HRS, and 5.2% progressed to HRS-chronic kidney disease. Response to terlipressin was higher in EASL (78.43%) than APASL subgroup (53.84%;P=0.006). Terlipressin non-response predicted mortality in EASL (aHR,6.35[1.15-35.13];P=0.03) and APASL subgroups (aHR,3.07[1.47-6.4];P=0.003).Conclusion: ACLF patients who develop terlipressin adverse events have dismal prognoses. Terlipressin non-response predicts mortality in patients with ACLF and HRS-AKI.

Adjunctive Thymosin Beta-4 Treatment Influences PMN Effector Cell Function during Pseudomonas aeruginosa-Induced Corneal Infection

Previous work examining the therapeutic efficacy of adjunct thymosin beta 4 (Tβ4) to ciprofloxacin for ocular infectious disease has revealed markedly reduced inflammation (inflammatory mediators and innate immune cells) with increased activation of wound healing pathways. Understanding the therapeutic mechanisms of action have further revealed a synergistic effect with ciprofloxacin to enhance bacterial killing along with a regulatory influence over macrophage effector cell function. As a natural extension of the aforementioned work, the current study uses an experimental model of P. aeruginosa-induced keratitis to examine the influence of Tβ4 regarding polymorphonuclear leukocyte (PMN/neutrophil) cellular function, contributing to improved disease response. Flow cytometry was utilized to phenotypically profile infiltrating PMNs after infection. The generation of reactive oxygen species (ROS), neutrophil extracellular traps (NETs), and PMN apoptosis were investigated to assess the functional activities of PMNs in response to Tβ4 therapy. In vitro work using peritoneal-derived PMNs was similarly carried out to verify and extend our in vivo findings. The results indicate that the numbers of infiltrated PMNs into infected corneas were significantly reduced with adjunctive Tβ4 treatment. This was paired with the downregulated expression of proinflammatory markers on these cells, as well. Data generated from PMN functional studies suggested that the corneas of adjunctive Tβ4 treated B6 mice exhibit a well-regulated production of ROS, NETs, and limited PMN apoptosis. In addition to confirming the in vivo results, the in vitro findings also demonstrated that neutrophil elastase (NE) was unnecessary for NETosis. Collectively, these data provide additional evidence that adjunctive Tβ4 + ciprofloxacin treatment is a promising option for bacterial keratitis that addresses both the infectious pathogen and cellular-mediated immune response, as revealed by the current study.

Measurable Residual Disease Response and Prognosis in Treatment-Naïve Acute Myeloid Leukemia With Venetoclax and Azacitidine

PURPOSE There is limited evidence on the clinical utility of monitoring measurable residual disease (MRD) in patients with acute myeloid leukemia treated with lower-intensity therapy. Herein, we explored the outcomes of patients treated with venetoclax and azacitidine who achieved composite complete remission (CRc; complete remission + complete remission with incomplete hematologic recovery) and MRD < 10–3 in the VIALE-A trial. METHODS The patients included in this report were treated with venetoclax and azacitidine. Bone marrow aspirate samples for multiparametric flow cytometry assessments were collected for central analysis at baseline, end of cycle 1, and every three cycles thereafter. MRD-negative response was defined as < 1 residual blast per 1,000 leukocytes (< 10–3 or 0.1%) with an estimated analytic sensitivity of 0.0037%-0.0027%. CRc, duration of remission (DoR), event-free survival (EFS), and overall survival (OS) were assessed. A multivariate Cox regression analysis identified prognostic factors associated with OS. RESULTS One hundred sixty-four of one hundred ninety (86%) patients with CRc were evaluable for MRD. MRD < 10–3 was achieved by 67 of 164 (41%), and 97 of 164 (59%) had MRD ≥ 10–3. The median DoR, EFS, and OS were not reached in patients with CRc and MRD < 10–3, and the 12-month estimates for DoR, EFS, and OS in this group were 81.2%, 83.2%, and 94.0%. Among patients with CRc and MRD ≥ 10–3, the median DoR, EFS, and OS were 9.7, 10.6, and 18.7 months. Multivariate analysis showed that CRc with MRD < 10–3 was a strong predictor of OS (adjusted hazard ratio = 0.285; 95% CI, 0.159 to 0.510; P < .001). CONCLUSION Patients who achieved CRc and MRD < 10–3 with venetoclax and azacitidine had longer DoR, EFS, and OS, than responding patients with MRD ≥ 10–3.

Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone With Minimal Residual Disease Response-Adapted Therapy in Newly Diagnosed Multiple Myeloma

PURPOSE The MASTER trial combined daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) in newly diagnosed multiple myeloma (NDMM), using minimal residual disease (MRD) by next-generation sequencing (NGS) to inform the use and duration of Dara-KRd post-autologous hematopoietic cell transplantation (AHCT) and treatment cessation in patients with two consecutive MRD-negative assessments. METHODS This multicenter, single-arm, phase II trial enrolled patients with NDMM with planed enrichment for high-risk cytogenetic abnormalities (HRCAs). Patients received Dara-KRd induction, AHCT, and Dara-KRd consolidation, according to MRD status. MRD was evaluated by NGS at the end of induction, post-AHCT, and every four cycles (maximum of eight cycles) of consolidation. Primary end point was achievement of MRD negativity (< 10–5). Patients with two consecutive MRD-negative assessments entered treatment-free MRD surveillance. RESULTS Among 123 participants, 43% had none, 37% had 1, and 20% had 2+ HRCA. Median age was 60 years (range, 36-79 years), and 96% had MRD trackable by NGS. Median follow-up was 25.1 months. Overall, 80% of patients reached MRD negativity (78%, 82%, and 79% for patients with 0, 1, and 2+ HRCA, respectively), 66% reached MRD < 10–6, and 71% reached two consecutive MRD-negative assessments during therapy, entering treatment-free surveillance. Two-year progression-free survival was 87% (91%, 97%, and 58% for patients with 0, 1, and 2+ HRCA, respectively). Cumulative incidence of MRD resurgence or progression 12 months after cessation of therapy was 4%, 0%, and 27% for patients with 0, 1, or 2+ HRCA, respectively. Most common serious adverse events were pneumonia (6%) and venous thromboembolism (3%). CONCLUSION Dara-KRd, AHCT, and MRD response-adapted consolidation leads to high rate of MRD negativity in NDMM. For patients with 0 or 1 HRCA, this strategy creates the opportunity of MRD surveillance as an alternative to indefinite maintenance.

Genome-Wide Identification of the Thaumatin-like Protein Family Genes in Gossypium barbadense and Analysis of Their Responses to Verticillium dahliae Infection

(1) Background: Plants respond to pathogen challenge by activating a defense system involving pathogenesis-related (PR) proteins. The PR-5 family includes thaumatin, thaumatin-like proteins (TLPs), and other related proteins. TLPs play an important role in response to biotic and abiotic stresses. Many TLP-encoding genes have been identified and functionally characterized in the model plant species. (2) Results: We identified a total of 90 TLP genes in the G. barbadense genome. They were phylogenetically classified into 10 subfamilies and distributed across 19 chromosomes and nine scaffolds. The genes were characterized by examining their exon–intron structures, promoter cis-elements, conserved domains, synteny and collinearity, gene family evolution, and gene duplications. Several TLP genes were predicted to be targets of miRNAs. Investigation of expression changes of 21 GbTLPs in a G. barbadense cultivar (Hai7124) resistance to Verticillium dahliae revealed 13 GbTLPs being upregulated in response to V. dahliae infection, suggesting a potential role of these GbTLP genes in disease response. (3) Conclusions: The results of this study allow insight into the GbTLP gene family, identify GbTLP genes responsive to V. dahliae infection, and provide candidate genes for future studies of their roles in disease resistance.

Real-world outcomes of pomalidomide therapy after lenalidomide induction in relapsed/refractory multiple myeloma

Aim: To demonstrate the efficacy of pomalidomide for relapsed/refractory multiple myeloma (RRMM) following treatment in real-world, community practice using retrospective database analysis. Materials & methods: US-based community oncologists identified patients with RRMM treated with or without pomalidomide following first-line lenalidomide. Disease response (≥ very good partial response) and progression-free survival were compared. Results: Disease response was 78.6 and 51.7% for pomalidomide (n = 126) and nonpomalidomide cohorts (n = 174), respectively (p < 0.0001). Multivariate adjusted odds of response were 4.5-times greater for pomalidomide cohort (p < 0.0001). Median progression-free survival was not reached for pomalidomide cohort and 16.7 months for nonpomalidomide cohort (log-rank p < 0.01). Conclusion: Following lenalidomide induction in RRMM, pomalidomide is an effective treatment.

Reviewing the Efficacy of Pollen Substitutes as a Management Tool for Improving the Health and Productivity of Western Honey Bee (Apis mellifera) Colonies

Western honey bees (Apis mellifera L.) collect pollen from flowers as their source of protein, fat, vitamins, and minerals. Beekeepers feed pollen substitutes to their honey bee colonies to mitigate a lack of natural pollen resources in the environment. Despite their widespread use, it is unclear if pollen substitutes are beneficial to colony health and productivity. Herein, we review the literature regarding pollen substitute efficacy in four major categories: (1) consumption/palatability of pollen substitutes, (2) colony productivity, (3) pest and disease response, and (4) physiological response. Collectively, the literature shows a mix of positive, neutral, and negative impacts of pollen substitutes on honey bee colony health. Additionally, we recommend areas for improvement in pollen substitute research. We hope this review will lead to more research on pollen substitutes given nutrition is a key factor impacting the health of managed honey bees globally.