Background The phase 2 IZALCO study (NCT05704049) demonstrated comparable efficacy, safety, and pharmacokinetics for subcutaneous (SC) isatuximab administered via an on-body injector (Isa SC OBI) vs manual injection in combination with carfilzomib-dexamethasone in relapsed/refractory multiple myeloma. Methods We evaluated patient-reported outcomes (PROs) in 74 adults and experiences of 19 healthcare providers (HCPs) from IZALCO. In part 1, Isa was given via manual injection. In part 2, patients were randomly assigned to manual injection or Isa SC OBI in cycle (C)1-3 and crossed over to the other method for C4-6. From C7, patients could select either method. Patient preference of delivery method at C6 Day (D)15 was a key secondary endpoint (n=47). PROs and HCP experience were assessed using the Patient Expectations Questionnaire, Patient Experience and Satisfaction Questionnaire, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), and HCP questionnaire. Results In part 2, at C6D15, after experiencing both methods, 74.5% (35/47) of patients preferred Isa SC OBI over manual injection, with comfort, convenience, and reduced injection-site pain being the main reasons for preference. Fewer patients reported discomfort, pain, and side effects with Isa SC OBI vs manual injection at most time points. Most patients (90.4%, 47/52) opted for Isa SC OBI from C7 onward. Mean EORTC QLQ-C30 global health status/QoL score was maintained over time. Of 19 HCPs, 78.9% (15/19) preferred Isa SC OBI vs manual injection. Conclusion These findings support Isa SC OBI as the preferred administration method for patients and HCPs.

In the Phase 2 IZALCO study, we evaluated efficacy, patient preference, safety and pharmacokinetics for isatuximab administered SC by an innovative on-body injector (OBI) or manual injection, plus carfilzomib-dexamethasone (Kd) in relapsed/refractory multiple myeloma (RRMM) patients. In Part 1, isatuximab SC was injected manually (cycles 1−6). In Part 2, patients were randomized to isatuximab SC by manual injection (cycles 1−3) followed by OBI administration (cycles 4−6) or to isatuximab OBI (cycles 1−3) followed by manual injection (cycles 4−6). From cycle 7, all patients could choose either treatment method. Overall, 74 RRMM patients received isatuximab SC plus Kd: 8 in Part 1 and 66 in Part 2. The patients had a median age of 65.0 years (44−85) with a median of 1 prior treatment line (1−5). The study met its primary efficacy endpoint with a 79.7

Background Genetic factors have proven to have an impact on multiple myeloma (MM) susceptibility, with genome-wide association studies (GWAS) discovering 23 loci associated with MM risk. However, much of the heritability of MM remains unexplained. The stringent significance threshold used in GWAS (p<5×10-8) accounts for the numerous statistical tests being performed but is prone to the risk of false negatives. One strategy for reducing the number of tests is to consider only SNPs with heightened prior probabilities of association, according to meaningful biological criteria. The best candidate SNPs identified with this approach can then be tested in additional MM cases and controls from independent populations. We aimed at surveying the effect of single nucleotide polymorphisms (SNPs), predicted to have a functional role, on MM risk. Methods The association study consisted of two GWAS as discovery datasets, namely the InterLymph consortium and the German GWAS and a replication dataset, namely the the International Multiple Myeloma rESEarch (IMMEnSE) consortium, for an overall total of 5442 MM cases and 6174 controls. SNPs were first ranked according to p-value and concordance of the association between the two discovery datasets, then ranked by functional annotation, using bioinformatic tools and databases. We considered the following classes of functional SNPs: missense, synonymous and non-sense SNPs, expression quantitative trait loci (eQTLs), splicing quantitative trait loci (sQTLs),), SNPs in SNPs affecting function of long non-coding RNAs (lncRNA), and SNPs modifying transcription factor binding sites. We prioritized the resulting SNPs for replication in IMMEnSE by p-values for association in InterLymph and German GWAS and by evidence for a functional role. Results In the two discovery datasets, 136 SNPs fit the criteria of association with MM risk with p<10-4 and did not map close to known MM risk loci. After pruning for linkage disequilibrium, four SNPs (rs12038685, rs2664188, rs12652920, rs29794) were chosen for replication in IMMEnSE. Among these, rs2664188 showed to be significantly associated also in the replication dataset (OR=1.30, 95% CI = 1.16-1.46, p=0.001). The final meta-analysis including the three datasets, using a random-effect model, confirmed the association (OR=1.18, 95% CI = 1.07-1.30, p=0.0007). Conclusion The G-allele of rs2664188, that showed a consistent association with increased risk of developing MM in all phases of our analysis is an eQTL, according to GTEx., The G-allele is associated with increased expression of the N4BP2 gene in whole blood. N4BP2 encodes a protein which binds to B-cell leukemia/lymphoma 3 (BCL-3), a well-known proto-oncogene, known to play a role in cell proliferation and apoptosis inhibition in myeloma cell lines. Genetic factors have proven to have an impact on multiple myeloma (MM) susceptibility, with genome-wide association studies (GWAS) discovering 23 loci associated with MM risk. However, much of the heritability of MM remains unexplained. The stringent significance threshold used in GWAS (p<5×10-8) accounts for the numerous statistical tests being performed but is prone to the risk of false negatives. One strategy for reducing the number of tests is to consider only SNPs with heightened prior probabilities of association, according to meaningful biological criteria. The best candidate SNPs identified with this approach can then be tested in additional MM cases and controls from independent populations. We aimed at surveying the effect of single nucleotide polymorphisms (SNPs), predicted to have a functional role, on MM risk. The association study consisted of two GWAS as discovery datasets, namely the InterLymph consortium and the German GWAS and a replication dataset, namely the the International Multiple Myeloma rESEarch (IMMEnSE) consortium, for an overall total of 5442 MM cases and 6174 controls. SNPs were first ranked according to p-value and concordance of the association between the two discovery datasets, then ranked by functional annotation, using bioinformatic tools and databases. We considered the following classes of functional SNPs: missense, synonymous and non-sense SNPs, expression quantitative trait loci (eQTLs), splicing quantitative trait loci (sQTLs),), SNPs in SNPs affecting function of long non-coding RNAs (lncRNA), and SNPs modifying transcription factor binding sites. We prioritized the resulting SNPs for replication in IMMEnSE by p-values for association in InterLymph and German GWAS and by evidence for a functional role. In the two discovery datasets, 136 SNPs fit the criteria of association with MM risk with p<10-4 and did not map close to known MM risk loci. After pruning for linkage disequilibrium, four SNPs (rs12038685, rs2664188, rs12652920, rs29794) were chosen for replication in IMMEnSE. Among these, rs2664188 showed to be significantly associated also in the replication dataset (OR=1.30, 95% CI = 1.16-1.46, p=0.001). The final meta-analysis including the three datasets, using a random-effect model, confirmed the association (OR=1.18, 95% CI = 1.07-1.30, p=0.0007). The G-allele of rs2664188, that showed a consistent association with increased risk of developing MM in all phases of our analysis is an eQTL, according to GTEx., The G-allele is associated with increased expression of the N4BP2 gene in whole blood. N4BP2 encodes a protein which binds to B-cell leukemia/lymphoma 3 (BCL-3), a well-known proto-oncogene, known to play a role in cell proliferation and apoptosis inhibition in myeloma cell lines.

Research has been focusing on identifying novel biomarkers to better stratify non-Hodgkin lymphoma patients based on prognosis. Studies have demonstrated that lncRNAs act as miRNA sponges, creating ceRNA networks to regulate mRNA expression, and its deregulation is associated with lymphoma development. This study aimed to identify novel circulating prognostic biomarkers based on miRNA/lncRNA-associated ceRNA network for NHL. Herein, bioinformatic analysis was performed to construct ceRNA networks for hsa-miR-150-5p and hsa-miR335-5p. Then, the prognostic value of the miRNA–lncRNA pairs’ plasma levels was assessed in a cohort of 113 NHL patients. Bioinformatic analysis identified MALAT1 and NEAT1 as hsa-miR-150-5p and has-miR-335-5p sponges, respectively. Plasma hsa-miR-150-5p/MALAT1 and hsa-miR335-5p/NEAT1 levels were significantly associated with more aggressive and advanced disease. The overall survival and progression-free survival analysis indicated that hsa-miR-150-5p/MALAT1 and hsa-miR335-5p/NEAT1 pairs’ plasma levels were remarkably associated with NHL patients’ prognosis, being independent prognostic factors in a multivariate Cox analysis. Low levels of hsa-miR-150-5p and hsa-miR-335-5p combined with high levels of the respective lncRNA pair were associated with poor prognosis of NHL patients. Overall, the analysis of ceRNA network expression levels may be a useful prognostic biomarker for NHL patients and could identify patients who could benefit from more intensive treatments.

Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome‐wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10−8) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4‐rs34517439‐A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13‐1.32, P = 4.81 × 10−7). rs34517439‐A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA‐binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4‐rs34517439 as a potentially novel MM risk locus.

Non-Hodgkin lymphoma (NHL) is characterized by a great variability in patient outcomes, resulting in the critical need for identifying new molecular prognostic biomarkers. This study aimed to identify novel circulating prognostic biomarkers based on an miRNA/lncRNA-associated ceRNA network for NHL. Using bioinformatic analysis, we identified the miRNA-lncRNA pairs, and using RT-qPCR, we analyzed their plasma levels in a cohort of 113 NHL patients to assess their prognostic value. Bioinformatic analysis identified SNHG16 and SNHG6 as hsa-miR-20a-5p and hsa-miR-181a-5p sponges, respectively. Plasma levels of hsa-miR-20a-5p/SNHG16 and hsa-miR-181a-5p/SNG6 were significantly associated with more aggressive disease and IPI/FLIPI scores. Moreover, we found that patients with risk expression profiles of hsa-miR-20a-5p/SNHG16 and hsa-miR-181a-5p/SNHG6 presented a higher risk of positive bone marrow involvement. Moreover, hsa-miR-20a-5p/SNHG16 and hsa-miR-181a-5p/SNHG6 pairs' plasma levels were associated with overall survival and progression-free survival of NHL patients, being independent prognostic factors in a multivariate Cox analysis. The prediction models incorporating the ceRNA network expression analysis improved the predictive capacity compared to the model, which only considered the clinicopathological variables. There are still few studies on using the ceRNA network as a potential prognostic biomarker, particularly in NHL, which may permit the implementation of a more personalized management of these patients.

Non-Hodgkin lymphoma (NHL) is a heterogeneous malignancy with variable patient outcomes. There is still a lack of understanding about the different players involved in lymphomagenesis, and the identification of new diagnostic and prognostic biomarkers is urgent. MicroRNAs and long non-coding RNAs emerged as master regulators of B-cell development, and their deregulation has been associated with the initiation and progression of lymphomagenesis. They can function by acting alone or, as recently proposed, by creating competing endogenous RNA (ceRNA) networks. Most studies have focused on individual miRNAs/lncRNAs function in lymphoma, and there is still limited data regarding their interactions in lymphoma progression. The study of miRNAs’ and lncRNAs’ deregulation in NHL, either alone or as ceRNAs networks, offers new insights into the molecular mechanisms underlying lymphoma pathogenesis and opens a window of opportunity to identify potential diagnostic and prognostic biomarkers. In this review, we summarized the current knowledge regarding the role of miRNAs and lncRNAs in B-cell lymphoma, including their interactions and regulatory networks. Finally, we summarized the studies investigating the potential of miRNAs and lncRNAs as clinical biomarkers, with a special focus on the circulating profiles, to be applied as a non-invasive, easy-to-obtain, and reproducible liquid biopsy for dynamic management of NHL patients.

Increasing evidence has demonstrated the functional roles of miRNAs and lncRNAs in lymphoma onset and progression, either by acting as tumor-promoting ncRNAs or as tumor suppressors, emphasizing their appeal as lymphoma therapeutics. In fact, their intrinsic ability to modulate multiple dysregulated genes and/or signaling pathways makes them an attractive therapeutic approach for a multifactorial pathology like lymphoma. Currently, the clinical application of miRNA- and lncRNA-based therapies still faces obstacles regarding effective delivery systems, off-target effects, and safety, which can be minimized with the appropriate chemical modifications and the development of tumor site-specific delivery approaches. Moreover, miRNA- and lncRNA-based therapeutics are being studied not only as monotherapies but also as complements of standard treatment regimens to provide a synergic effect, improving the overall treatment efficacy and reducing the therapeutic resistance. In this review, we summarize the fundamentals of miRNA- and lncRNA-based therapeutics by discussing the different types of delivery systems, with a focus on those that have been investigated in lymphoma in vitro and in vivo. Moreover, we described the ongoing clinical trials of novel miRNA- and lncRNA-based therapeutics in lymphoma.

Multiple myeloma (MM) is the second most frequent hematological disease and can cause skeletal osteolytic lesions. This study aims to evaluate the expression of circulating microRNAs (miRNAs) in MM patients and to correlate those levels with clinicopathological features, including bone lesions. A panel of miRNAs associated with MM onset and progression, or with bone remodeling, was analyzed in the plasma of 82 subjects (47 MM patients; 35 healthy controls). Results show that miR-16-5p, miR-20a-5p, and miR-21-5p are differently expressed between MM patients and healthy controls. Receiver operating characteristic analyses indicate that their combined expression has potential as a molecular marker (Area Under the Curve, AUC of 0.8249). Furthermore, significant correlations were found between the analyzed miRNAs and disease stage, treatment, β2 microglobulin, serum albumin and creatinine levels, but not with calcium levels or genetic alterations. In this cohort, 65.96% of MM patients had bone lesions, the majority of which were in the vertebrae. Additionally, miR-29c-3p was decreased in patients with osteolytic lesions compared with patients without bone disease. Interestingly, circulating levels of miR-29b-3p correlated with cervical and thoracic vertebral lesions, while miR-195-5p correlated with thoracic lesions. Our findings suggest circulating miRNAs can be promising biomarkers for MM diagnosis and that their levels correlate with myeloma bone disease and osteolytic lesions.

There is overwhelming epidemiologic evidence that the risk of multiple myeloma (MM) has a solid genetic background. Genome-wide association studies (GWAS) have identified 23 risk loci that contribute to the genetic susceptibility of MM, but have low individual penetrance. Combining the SNPs in a polygenic risk score (PRS) is a possible approach to improve their usefulness. Using 2361 MM cases and 1415 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, we computed a weighted and an unweighted PRS. We observed associations with MM risk with OR = 3.44, 95% CI 2.53–4.69, p = 3.55 × 10−15 for the highest vs. lowest quintile of the weighted score, and OR = 3.18, 95% CI 2.1 = 34–4.33, p = 1.62 × 10−13 for the highest vs. lowest quintile of the unweighted score. We found a convincing association of a PRS generated with 23 SNPs and risk of MM. Our work provides additional validation of previously discovered MM risk variants and of their combination into a PRS, which is a first step towards the use of genetics for risk stratification in the general population.

Telomeres are involved in processes like cellular growth, chromosomal stability, and proper segregation to daughter cells. Telomere length measured in leukocytes (LTL) has been investigated in different cancer types, including multiple myeloma (MM). However, LTL measurement is prone to heterogeneity due to sample handling and study design (retrospective vs. prospective). LTL is genetically determined; genome-wide association studies identified 11 SNPs that, combined in a score, can be used as a genetic instrument to measure LTL and evaluate its association with MM risk. This approach has been already successfully attempted in various cancer types but never in MM. We tested the “teloscore” in 2407 MM patients and 1741 controls from the International Multiple Myeloma rESEarch (IMMeNSE) consortium. We observed an increased risk for longer genetically determined telomere length (gdTL) (OR = 1.69; 95% CI 1.36–2.11; P = 2.97 × 10 −6 for highest vs. lowest quintile of the score). Furthermore, in a subset of 1376 MM patients we tested the relationship between the teloscore and MM patients survival, observing a better prognosis for longer gdTL compared with shorter gdTL (HR = 0.93; 95% CI 0.86–0.99; P = 0.049). In conclusion, we report convincing evidence that longer gdTL is a risk marker for MM risk, and that it is potentially involved in increasing MM survival.

Gene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype-tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10-7 either in EBV-transformed B-lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression-free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4-rs1992292, TBRG4-rs2287535 and ENTPD1-rs2153913) showed associations with OS at P < .05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta-analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4-rs1992292 is associated with OS (hazard ratio = 1.14, 95% confidence interval 1.04-1.26, P = .007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients.

We evaluated the association between germline genetic variants located within the 3 '-untranlsated region (polymorphic 3 ' UTR, ie, p3UTR) of candidate genes involved in multiple myeloma (MM). We performed a case-control study within the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 3056 MM patients and 1960 controls recruited from eight countries. We selected p3UTR of six genes known to act in different pathways relevant in MM pathogenesis, namely KRAS (rs12587 and rs7973623), VEGFA (rs10434), SPP1 (rs1126772), IRF4 (rs12211228) and IL10 (rs3024496). We found that IL10-rs3024496 was associated with increased risk of developing MM and with a worse overall survival of MM patients. The variant allele was assayed in a vector expressing eGFP chimerized with the IL10 3 '-UTR and it was found functionally active following transfection in human myeloma cells. In this experiment, the A-allele caused a lower expression of the reporter gene and this was also in agreement with the in vivo expression of mRNA measured in whole blood as reported in the GTEx portal. Overall, these data are suggestive of an effect of the IL10-rs3024496 SNP on the regulation of IL10 mRNA expression and it could have clinical implications for better characterization of MM patients in terms of prognosis.

Genetic variants in genes acting during the maturation process of immature B-cell to differentiated plasma cell could influence the risk of developing multiple myeloma (MM). During B-cell maturation, several programmed genetic rearrangements occur to increase the variation of the immunoglobulin chains. Class switch recombination (CSR) is one of the most important among these mechanisms. Germline polymorphisms altering even subtly this process could play a role in the etiology and outcome of MM. We performed an association study of 30 genetic variants in the key CSR genes, using 2632MM patients and 2848 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the Heidelberg MM Group and the ESTHER cohort. We found an association between LIG4-rs1555902 and decreased MM risk, which approached statistical significance, as well as significant associations between AICDA-rs3794318 and better outcome. Our results add to our knowledge on the genetic component of MM risk and survival.

PurposeIncreased glycolytic activity with accumulation of extracellular lactate is regarded as a hallmark of cancer. In lymphomas, FDG-PET has undeniable diagnostic and prognostic value, corroborating that these tumours are avid for glucose. However, the role of glycolytic metabolism-related molecules in lymphoma is not well known. Here, we aimed to evaluate the clinical and prognostic significance of a panel of glycolytic metabolism-related molecules in primary non-Hodgkin lymphomas (NHL) and to test in vitro the putative therapeutic impact of lactate transport inhibition.MethodsWe assessed, by immunohistochemistry, the expression of the metabolism-related molecules MCT1, MCT2, MCT4, CD147, GLUT1, LDHA and CAIX in both tumour and stroma compartments of tissue sections obtained from 104 NHL patients. In addition, the lymphoma-derived cell lines OZ and DOHH-2 were used to evaluate the effect of AZD3965 on their viability and on apoptosis induction, as well as on extracellular lactate accumulation.ResultsWe found that expression of MCT1 in the NHL tumour compartment was significantly associated with a poor clinicopathological profile. We also found that MCT4 and CAIX were present in the stromal compartment and correlated with an aggressive phenotype, while MCT1 was absent in this compartment. In addition, we found that AZD3965-mediated disruption of MCT1 activity led to inhibited NHL cell viability and extracellular lactate accumulation, while increasing apoptotic cell death.ConclusionsOur results indicate that elevated glycolytic activity is associated with NHL aggressiveness, pointing at metabolic cooperation, mediated by MCT1 and MCT4, between tumour cells and their surrounding stroma. MCT1 may serve as a target to treat NHL (diffuse large B cell lymphoma) patients with high MCT1/low MCT4 expressing tumours. Further (pre-)clinical studies are required to allow the design of novel therapeutic strategies aimed at e.g. reprogramming the tumour microenvironment.

Patient blood management (PBM) is a safe approach aiming to improve a patient’s medical and surgical management in ways that boost and conserve their own blood. Approximately 32% to 60% of oncology patients have iron deficiency – the majority of whom are anaemic – therefore, it is important to discuss strategies to avoid excessive blood usage and the reduction of tumour progression and cancer recurrence. In this position paper experts together with the Anaemia Working Group Portugal discussed a PBM program in haematology and oncology, taking into account several factors that are currently used to approve the applied therapies, based on the latest reviewed information of the National Comprehensive Cancer Network®.

Central nervous system vasculitis is an uncommon disease resulting from inflammation and destruction of the blood vessels of the brain, spinal cord, and meninges, and it constitutes a challenging diagnosis. It is classified as primary when it is confined to the central nervous system. We present a previously healthy 40-year-old man admitted because of a left hemiparesis and one-week history of mild bilateral frontal headache usually in the late afternoon that was relieved by paracetamol. Blood and cerebrospinal fluid workup was normal. Brain imaging showed a right frontoparietal lesion, and an abdominal lymphadenopathy was detected on the abdominal computed tomography. The lymph node and brain lesion histopathologies were compatible with Hodgkin's lymphoma and granulomatous vasculitis, respectively. He was treated with chemotherapy and rituximab as maintenance treatment during 18 months and entered clinical and imaging remission for 33 months.