Elotuzumab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma: a multicenter, retrospective real-world experience with 200 cases outside of controlled clinical trials

In the ELOQUENT-3 trial, the combination of elotuzumab, pomalidomide and dexamethasone (EloPd) proved a superior clinical benefit over Pd with a manageable toxicity profile, leading to its approval in relapsed/refractory multiple myeloma (RRMM), who had received at least two prior therapies, including lenalidomide and a proteasome inhibitor (PI). We report here a real-world experience of 200 RRMMs treated with EloPd in 35 Italian centers outside of clinical trials. In our dataset, the median number of prior lines of therapy was 2, with 51% of cases undergoing autologous stem cell transplant (ASCT) and 73% exposed to daratumumab. After a median follow-up of 9 months, 126 patients stopped EloPd, most of them (88.9%) because of disease progression. The overall response rate (ORR) was 55.4%, in line with the pivotal trial results. Regarding adverse events, our cohort experienced a toxicity profile similar to the ELOQUENT-3 trial, with no significant differences between younger (<70 years) and older patients. The median progression-free survival (PFS) was 7 months, shorter than that observed in the ELOQUENT-3, probably due to the different clinical characteristics of the two cohorts. Interestingly, the ISS stage III (HR:2.55) was associated with worse PFS. Finally, our series's median overall survival (OS) was shorter than that observed in the ELOQUENT-3 trial (17.5 versus 29.8 months). In conclusion, our real-world study confirms EloPd as a safe and possible therapeutic choice for RRMM who received at least two prior therapies, including lenalidomide and a PI

Safe and Effective Administration of Caplacizumab in COVID-19-Associated Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TTP) is a potentially life-threatening, rare acute thrombotic microangiopathy (TMA), caused by a severe ADAMTS13 deficiency. As the COVID-19 pandemic rapidly spread around the globe, much data about the pathogenicity of this virus were published. Soon after the detection of the first cases of COVID-19, it was clear that there was a wide range of COVID coagulopathy manifestations, such as deep venous thrombosis, pulmonary thromboembolism, and thrombotic microangiopathies. In the literature, little data have been reported about the association between TTP and COVID-19, and the treatment of COVID-19-associated TTP is still under debate. Here we present the case of a 46-year-old woman who developed a COVID-associated TTP, successfully treated with plasma exchange (PEX), steroids, and caplacizumab

Targeting of mitochondrial fission through natural flavanones elicits anti-myeloma activity

Abstract Background Mitochondrial alterations, often dependent on unbalanced mitochondrial dynamics, feature in the pathobiology of human cancers, including multiple myeloma (MM). Flavanones are natural flavonoids endowed with mitochondrial targeting activities. Herein, we investigated the capability of Hesperetin (Hes) and Naringenin (Nar), two aglycones of Hesperidin and Naringin flavanone glycosides, to selectively target Drp1, a pivotal regulator of mitochondrial dynamics, prompting anti-MM activity. Methods Molecular docking analyses were performed on the crystallographic structure of Dynamin-1-like protein (Drp1), using Hes and Nar molecular structures. Cell viability and apoptosis were assessed in MM cell lines, or in co-culture systems with primary bone marrow stromal cells, using Cell Titer Glo and Annexin V-7AAD staining, respectively; clonogenicity was determined using methylcellulose colony assays. Transcriptomic analyses were carried out using the Ion AmpliSeq™ platform; mRNA and protein expression levels were determined by quantitative RT-PCR and western blotting, respectively. Mitochondrial architecture was assessed by transmission electron microscopy. Real time measurement of oxygen consumption was performed by high resolution respirometry in living cells. In vivo anti-tumor activity was evaluated in NOD-SCID mice subcutaneously engrafted with MM cells. Results Hes and Nar were found to accommodate within the GTPase binding site of Drp1, and to inhibit Drp1 expression and activity, leading to hyperfused mitochondria with reduced OXPHOS. In vitro, Hes and Nar reduced MM clonogenicity and viability, even in the presence of patient-derived bone marrow stromal cells, triggering ER stress and apoptosis. Interestingly, Hes and Nar rewired MM cell metabolism through the down-regulation of master transcriptional activators (SREBF-1, c-MYC) of lipogenesis genes. An extract of Tacle, a Citrus variety rich in Hesperidin and Naringin, was capable to recapitulate the phenotypic and molecular perturbations of each flavanone, triggering anti-MM activity in vivo. Conclusion Hes and Nar inhibit proliferation, rewire the metabolism and induce apoptosis of MM cells via antagonism of the mitochondrial fission driver Drp1. These results provide a framework for the development of natural anti-MM therapeutics targeting aberrant mitochondrial dependencies

High surface IgM levels associate with shorter response to ibrutinib and BTK bypass in CLL patients

Chronic lymphocytic leukemia (CLL) cells have variably low surface IgM (sIgM) levels/signaling capacity, influenced by chronic antigen engagement at tissue sites. Within these low levels, CLL with relatively high sIgM (CLLhigh) progress more rapidly than CLL with low sIgM (CLLlow). During ibrutinib therapy, surviving CLL cells redistribute into the peripheral blood and can recover sIgM expression. Return of CLL cells to tissue may eventually recur, where cells with high sIgM could promote tumor growth. We analyzed time to new treatment (TTNT) following ibrutinib in 70 CLL patients (median follow-up of 66 months) and correlated it with pre-treatment sIgM levels and signaling characteristics. Pre-treatment sIgM levels correlated with signaling capacity, as measured by intracellular Ca2+ mobilization (iCa2+), in vitro (r=0.70; p<0.0001). High sIgM levels/signaling strongly correlated with short TTNT (p<0.05), and 36% CLLhigh versus 8% CLLlow progressed to require a new treatment. In vitro, capacity of ibrutinib to inhibit sIgM-mediated signaling inversely correlated with pre-therapy sIgM levels (r=-0.68, p=0.01) or iCa2+ (r=-0.71, p=0.009). In patients, sIgM-mediated iCa2+ and ERK phosphorylation levels were reduced by ibrutinib therapy, but not abolished. The residual signaling capacity downstream of BTK was associated with high expression of sIgM, while it was minimal when sIgM expression was low (p<0.05). These results suggested that high sIgM levels facilitated CLL cell resistance to ibrutinib in patients. The CLL cells, surviving in the periphery with high sIgM expression, include a dangerous fraction, able to migrate to tissue and receive proliferative stimuli, which may require targeting by combined approaches

Insertion of atypical glycans into the tumor antigen-binding site identifies DLBCLs with distinct origin and behavior

Glycosylation of the surface immunoglobulin (Ig) variable region is a remarkable follicular lymphoma–associated feature rarely seen in normal B cells. Here, we define a subset of diffuse large B-cell lymphomas (DLBCLs) that acquire N-glycosylation sites selectively in the Ig complementarity-determining regions (CDRs) of the antigen-binding sites. Mass spectrometry and X-ray crystallography demonstrate how the inserted glycans are stalled at oligomannose-type structures because they are buried in the CDR loops. Acquisition of sites occurs in ∼50% of germinal-center B-cell–like DLBCL (GCB-DLBCL), mainly of the genetic EZB subtype, irrespective of IGHV-D-J use. This markedly contrasts with the activated B-cell–like DLBCL Ig, which rarely has sites in the CDR and does not seem to acquire oligomannose-type structures. Acquisition of CDR-located acceptor sites associates with mutations of epigenetic regulators and BCL2 translocations, indicating an origin shared with follicular lymphoma. Within the EZB subtype, these sites are associated with more rapid disease progression and with significant gene set enrichment of the B-cell receptor, PI3K/AKT/MTORC1 pathway, glucose metabolism, and MYC signaling pathways, particularly in the fraction devoid of MYC translocations. The oligomannose-type glycans on the lymphoma cells interact with the candidate lectin dendritic cell–specific intercellular adhesion molecule 3 grabbing non-integrin (DC-SIGN), mediating low-level signals, and lectin-expressing cells form clusters with lymphoma cells. Both clustering and signaling are inhibited by antibodies specifically targeting the DC-SIGN carbohydrate recognition domain. Oligomannosylation of the tumor Ig is a posttranslational modification that readily identifies a distinct GCB-DLBCL category with more aggressive clinical behavior, and it could be a potential precise therapeutic target via antibody-mediated inhibition of the tumor Ig interaction with DC-SIGN–expressing M2-polarized macrophages.</p

Feasibility, Tolerability and Efficacy of Carfilzomib in Combination with Lenalidomide and Dexamethasone in Relapsed Refractory Myeloma Patients: A Retrospective Real-Life Survey of the Sicilian Myeloma Network

Background: The ASPIRE (NCT01080391) phase 3 trial showed the efficacy of carfilzomib, lenalidomide and dexamethasone (KRd) triplet for relapse and refractory multiple myeloma (RRMM). However, little is known about safety and efficacy of KRd outside a clinical trial context. Methods: Herein we report real life results of KRd given to 130 RRMM patients from 12 Sicilian Centers. Results: Median age was 62 years; patients had received a median of two previous lines of treatment (range 1&ndash;10) and 52% were refractory to previous treatment. Median number of KRd cycles was 12 (2&ndash;29), with a mean duration of treatment of 12 months; 21 patients had received at least 18 cycles. Overall response rate was 61%, including 18% complete response. Median PFS was 22.9 months, median OS was not reached. Creatinine clearance &gt;30 mL/min, quality of the best achieved response and standard Fluorescence In Situ Hybridization (FISH) risk were independent predictors of favorable outcome. Patients who received the full-dosage of carfilzomib in the first two cycles had a better outcome. Conclusions: KRd was effective and well tolerated and in a considerable proportion of patients, therapy continued beyond the 18th cycle. The finding of a better outcome in patients with the higher cumulative dose of carfilzomib in the first two cycle encourages to maintain the maximum tolerated dose

Ibrutinib as first line therapy in chronic lymphocytic leukemia patients over 80 years old: A retrospective real-life multicenter Italian cohort

: Although chronic lymphocytic leukemia (CLL) predominantly affects the elderly, limited data exists about the outcomes of over 80-year-old patients, usually underrepresented in clinical trials. we conducted a multicenter study enrolling 79 consecutive CLL patients ≥80&nbsp;years at the time of frontline therapy, all treated with ibrutinib. nearly 48% of cases exhibited unmutated IGHV genes, 32% 17p deletion, and 39.2% TP53 mutations; 63.3% displayed a cumulative illness rating scale (CIRS)&nbsp;&gt;&nbsp;6. the overall response rate on ibrutinib, computed in 74/79 patients (5 patients excluded for early withdrawal), was 89.9%. after a median follow-up of 28.9&nbsp;months, the median progression-free survival (PFS) and overall survival (OS) were 42.5 and 51.8&nbsp;months, respectively. CIRS&gt;6 and temporary discontinuation of ibrutinib lasting for 7-30&nbsp;days were the only parameters associated with a significantly shorter PFS and were both relevant in predicting a shorter PFS compared to patients with CIRS≤6 and therapy discontinuation ≤7&nbsp;days. The most common grade≥3 adverse events were infections (25.5%), neutropenia (10.1%), and anemia (2.5%). eighteen patients (22.8%) experienced a cardiovascular event, including grade-2 atrial fibrillation (n&nbsp;=&nbsp;9; 11%), grade-2 hypertension (n&nbsp;=&nbsp;5; 6%), heart failure (n&nbsp;=&nbsp;3; 3%), and acute coronary syndrome (n&nbsp;=&nbsp;1; 1%). mild bleeding events were observed in 27 patients (34.2%). Ibrutinib was permanently discontinued in 26 patients due to progressive disease (n&nbsp;=&nbsp;11, including 5 Richter's syndromes), secondary malignancies (n&nbsp;=&nbsp;6), infections (n&nbsp;=&nbsp;3), cardiac failure (n&nbsp;=&nbsp;3), severe bleeding (n&nbsp;=&nbsp;2), and sudden death (n&nbsp;=&nbsp;1). In conclusion, our analyses confirmed the overall effectiveness and favorable safety profile of the ibrutinib-single agent therapeutic approach in CLL patients ≥80&nbsp;years

Carfilzomib combined with lenalidomide and dexamethasone (KRd) as salvage therapy for multiple myeloma patients: Italian, multicenter, retrospective clinical experience with 600 cases outside of controlled clinical trials

In combination with lenalidomide and dexamethasone (KRd), Carfilzomib has been approved for the treatment of relapsed and refractory multiple myeloma (RRMM) on ASPIRE trial. Efficacy and safety of the triplet are stillthe object of investigationby many groupstoconfirmASPIRE results in the setting of RRMM treatedin real-life who don’t meet trial restrictive inclusion criteria.Therefore, we report a retrospective multicenter analysis of 600 RRMM patients treated with KRd between December 2015 and December 2018. The medianage was 64 years (range 33-85),and the median number of previous therapies was 2 (range 1-11). After a median of 11 KRd cycles, the ORR was 79.9%. The median PFS was 22 months,and the 2-year probability of PFS was 47.6%. Creatinine clearance&lt;30 mL/min, &gt;1line of previous therapy, and high-risk FISH were all associated with a poor prognosis in multivariate analysis.The median OS was 34.8 months; the 2-year probability of OS was 63.5%.At multivariate analysis,creatinine clearance&lt;30 ml/min, &gt;1 line of previous therapy,and high-risk FISH were significantly associated with poor prognosis. After a median follow-up of 16 months (range 1-50),259 withdrew from therapy. The main discontinuation reasonwas progressive disease (81.8%). Seventy-four patients (12.3%) discontinued therapy for toxicity. The most frequent side effects were hematological (anemia 49.3%, neutropenia 42.7%, thrombocytopenia 42.5%) and cardiovascular (hypertension 14.5%, heart failure 2.5%, arrhythmias 3.6%).Our studyconfirmsthe safety and efficacy of KRd in the real-life setting of RRMM patients and encourages its use in clinical practice