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Patients who experience extramedullary relapses (EMR) of multiple myeloma (MM) have an adverse prognosis, also in this era of novel agents like proteasome inhibitors and immunomodulatory drugs. We describe the case of an MM patient with EMR at 2 different sites after allogeneic stem cell transplantation. EMR was refractory to bortezomib, anthracycline, and bendamustine, but the patient achieved long-term complete remission (4 years) with pomalidomide and dexamethasone. This supports the hypothesis that this could be due to the graft-versus-myeloma effect during therapy enhanced by pomalidomide.

Background: Chronic Lymphocytic Leukemia (CLL) represents 7% of Non Hodgkin Lymphoma being the most common leukemia. Efficacy and safety data on Ibrutinib used as a single agent for treatment of previously treated CLL comes from RESONATE trial, which showed 6% of Overall incidence of grade 3 atrial fibrillation (AF).Another side effect of Ibrutinib is increased rate of bleeding. The 2019 long term follow-up of RESONATE 2 trial of Ibrutinib in previously untreated CLL reported major hemorrhage and grade 3 AF in 11% and 5% of patients on Ibrutinib arm, respectively; notably, 67% of patients who experienced Grade 3 Major hemorrhage were taking concomitant anticoagulation therapy. The use of Ibrutinib in patients with AF requiring anticoagulation therapy could be challenging, given that both the optimal starting dose of Novel Anti Coagulants (NOACs) and the specific NOAC to be used in patients taking ibrutinib have not been established yet. Here we describe the clinical history of three CLL patients affected by AF treated with ibrutinib associated with NOACs. Cases : 1. The first patient was a 72-year-old male affected by IGHV unmutaded CLL with no TP53 disruption relapsed five years after the achievement of first complete remission through 6 courses R-Bendamustine. He started full dose Ibrutinib on august 2019. When he started ibrutinib there were no bulky lesions, the biggest node diameter was 2.7 cm, spleen longest diameter was 18 cm, Hb was 9.3 g/dL, platelets were 166,000/µL, neutrophils 4,000/µL and ALC 129,000/ µL, b symptoms were absent. Since 2018 he suffered from chronic AF treated with Apixaban at the dose of 5 mg BID. He achieved partial response with no evidence of lymphadenopathy and lymphocytosis after 6 months of treatment with no occurrence of major bleeding. On April 2020 he came to our attention with minor bleeding consisting of small petechial macules. Neither epistaxis nor bruising were reported. Petechiae resolved on May 2020, at last follow-up clinical visit (July 2020) Ibrutinib and Apixaban are still well tolerated and signs and symptoms of both CLL and bleeding are absent. 2. The second patient was a 65-year-old male affected by IGHV unmutated CLL with no TP53 disruption, relapsed three years after a complete response achieved with first line treatment with 6 courses of R-Bendamustine. When he started full dose Ibrutinib (420 mg OD), Hb was 11.8 g/dL, neutrophils 5,100/ µL, lymphocyte 145,000/ µL and platelets 51,000/ µL. He achieved partial remission on May 2020. On April 2020, high rate AF was diagnosed, heart rate was 162 beats per min, systolic and diastolic blood pressure were 125 and 80 mmHg, respectively. The cardiologist prescribed bisoprolole 1.25 mg OD and after 24h heart rate became normal (60 beats per min). An Echocardiography was performed showing ejection fraction of 60% with all other parameters being normal. CHADS-VASc score was 3 and HAS-BLED score was 2, so he started Edoxaban at the dose of 30 mg OD, while Ibrutinib was never stopped. The patient now has neither signs and symptoms of CLL, nor those of AF and bleeding. 3. The last patient was a 81-year-old male affected by previously untreated IGHV mutated CLL with TP53 mutation and absence of del 17p. High rate AF was diagnosed on may 2020 and edoxaban 30 mg OD was started. He started reduced dose Ibrutinib (280 mg OD) on the first days of July 2020 due to risk of bleeding. Hb, neutrophils, lymphocyte and platelets were 10.8 g/dL, neutrophils 2,730/ µL, lymphocyte 195,000/µL and platelets were 116,000/µL. RAI and Binet where 3 and B, respectively. CLL-IPI was 8 (very high risk), neither bulky nodes nor B symptoms were present. After 1 month-follow-up there is no evidence of bleeding and AF is still asymptomatic. Conclusions: In our limited experience and according with literature, Ibrutinib could be safely used in patients with pre-existing or de novo AF in association with NOACs with no or minimal bleeding signs. Therefore, patients affected by AF might completely benefit from this highly effective therapy for CLL. Disclosures No relevant conflicts of interest to declare.

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.

BACKGROUND/AIM The Philadelphia chromosome is found in 30% of acute lymphoblastic leukemia (ALL) patients, a distinct ALL subgroup where the BCR-ABL fusion gene is associated with poor prognosis. Treatment with tyrosine kinase inhibitors (TKIs) often induces complete remission and these patients subsequently undergo an autologous stem cell transplantation (ASCT). However, 20% of subjects experience a relapse associated with the selection of point-mutations in the BCR-ABL kinase domain. We report the clinical evolution of a Philadelphia-positive ALL patient co-expressing the e1a2 and e14a2 BCR-ABL transcript at diagnosis. MATERIALS AND METHODS Multiplex reverse transcriptase (RT)-PCR was used to detect BCR-ABL transcripts and their levels were measured by quantitative Real Time PCR. Clonal sequencing and next-generation sequencing (NGS) were used to identify mutations. RESULTS Although the patient underwent ASCT following treatment with multiple TKIs, he relapsed twice. The first time he exhibited the e1a2 transcript and the second time he presented only the e14a2 variant. Mutation analysis, performed by clonal sequencing and NGS, detected two alterations after the first relapse and a single mutation at the time of the second relapse. CONCLUSION The observed shift from the e1a2 to the e14a2 variant and the selection of TKI-resistant clones heavily contributed to the fatal evolution of the disease.

Background : Allogeneic hemopoietic stem cell transplantation (HSCT) has been widely used in hematologic malignancies for over 4 decades. One important question is the longterm outcome of these patients, in terms of leukemia control and quality of life. Aim of the study. Assess the outcome of patients surviving at least 3000 days post allogeneic HSCT, and identify risk factors for failure. Methods. We used our transplant relational database, in which patients' clinical and laboratory data are prospectively recorded during each outpatient visit or during admission. We identified 673 patients who were seen between 8 and 30 years post-transplant. The median follow up was 17.5 years (range 8.2-36.6), median age was 34 years (range1-65). The diagnosis was AML (n=205), ALL (n=97) CML (n=208), MDS (n=51), Lymphoma (n=45), Myelofibrosis (n=19), other (n=48). The stem cell source was bone marrow (BM)(n= 488), peripheral blood (PB) (n=154), cord blood (CB) (n=31). The disease was in remission (n=553) or in relapse (n=120). Result . The overall actuarial survival at 20 years was 86% (95%CI 83%-89%). The CI of TRM at 20 years was 9.4% and the CI of relapse related death (RRD) was 4.6% . Leading causes of death were second tumours (3.2%), chronic GvHD (2.8%) relapse (2.8%). In univariate analysis negative predictors of survival were the following : severe cGvHD (RR 5.0, p=0.002) compared to n0 cGvHD, the use of PB compared to BM as a stem cells source (RR 2.6, p 40 years was 91% vs 80% (p Multivariate analysis. In a multivariate Cox analysis, negative predictors of survival, were severe cGvHD (RR 5.0, p=0.0003), patients age over 40 (RR 2.4, p=0.001) , PB grafts versus BM (RR 1.8, p=0.002). Conclusions. Patients surviving 8 years post HSCT have a 9% risk of transplant related death and a 4% risk of relapse related death. Chronic GvHD remains the strongest negative predictor of survival , together with patients age , and PB as a stem cell source. The impact of cGvHD 10-20 years post transplant strongly calls for preventing meaures to be adopted early in the transplant course, and or with a preferential use of BM as a stem cell source. Disclosures Angelucci: Novartis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Participation in DMC; BlueBirdBio: Other: Local advisory board; Jazz Pharmaceuticals: Other: Local advisory board; Roche: Other: Local advisory board; Vertex Pharmaceuticals Incorp., and CRISPR Therapeutics: Other: Participation in DMC.

In Multiple Myeloma (MM) relapse can be defined according to disease aggressiveness and the presence of clinical symptoms. Aggressive relapse can occur even at biochemical level, characterized by a rapid and relevant increase of monoclonal component or LDH, or at clinical level, defined by the presence of extramedullary disease, acute renal injury or progression to secondary plasma cell leukemia. To identify the clinical outcome upon treatment with second generation novel agents (pomalidomide, carfilzomib) and monoclonal antibodies (elotuzumab, daratumumab), we collected evidence of the best timing in providing early salvage treatment to RRMM. We reviewed files of 128 R/R MM (58% males, median age 64 years, range 43-83), treated at biochemical (N=54, 42%) or clinical relapse (N=74, 58%) between January 2017 and December 2019 in our single Institution. Median number of previous lines was 2 (1-9), including autologous stem cell transplantation (ASCT) in half of cases. FISH was repeated before to start the second-generation drugs, and it was available in 53 cases: 11 carried on high-risk (del 17p, t4;14 or t14;16) and 42 standard-risk cytogenetics, without any additional marker compared to the matched sample at diagnosis. Our series included patients who received IMiD-s based treatments, alone (pomalidomide, N= 76, 59%) or in combination with proteasome inhibitors (carfilzomib, lenalidomide and dexamethasone, KRd, N= 43, 33%) or monoclonal antibodies (daratumumab-lenalidomide, N= 3 elotuzumab-lenalidomide, N 12); 16 patients (%) received Daratumumab in monotherapy, and N=16 associated to bortezomib. After a median follow-up of 19.2 months, 66 (52%) patients were alive and 33 (25%) received a further line of therapy due to progression. In multivariable analysis only the type of relapse (biochemical versus clinical) and refractory status were independent predictors of overall survival (p In 20/33 individuals who further progressed under novel agents treatment we found second biochemical relapse was anticipated by doubling sFLC ratio one month before. In 5 patients who developed extramedullary lesions (EMD) an increase of sFLC always preceded the diagnosis ofEMD relapse irrespective of M-spike measurement. Taken together, our findings suggest that using second generation novel agents can improve outcome even in heavily pretreated patients. Earlier treatment at biochemical asymptomatic relapse is associated with longer OS. Longitudinal monitoring of sFLC assay ratio can anticipateearly detection of aggressive and/or EMD relapse in the RRMM setting in real life. Disclosures Del Fabro: Janssen: Consultancy. Di Raimondo:Takeda: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Conticello:Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

Background : The role of aminoacid substitution at position 116 of class I HLA antigens, has been the subject of several contributions, suggesting the possibility of permissive or non permissive mismatches. Hypothesis. Permissive mismatched at position AA116, yield outcomes comparable to 10/10 matched grafts and superior to AA116 non permissive mismatches. Patients: We have analyzed 358 unrelated donor transplants (UD) to test this hypothesis. All donors were matched at class II for DRB1 and DQ alleles; 226 were also matched at high resolution for A,B and C alleles; 84 had 1 permissive AA116 mismatch (Pmm), and 48 had 1 non permissive mismatch (NPmm). The 3 groups were comparable for patients age (p=0.5), donors age (p=0.9), diagnosis (p=0.2) and intensity of the conditioning regimen (p=0.4); both NPmm and Pmm had more patients with advanced disease, as compared to matched patients. The stem cell source was peripjheral blood for the large majority of patients. Results. The cumulative incidence (CI) of acute GvHD grade II-IV (p=0.01) and III-IV (p=0.001) was greater in patients with 1 allele mismatch, compared to matched patients, irrespective of AA116 permissive substitution. The CI of non relapse mortality (NRM) at 5 years 29%, 35%, 50% respectively in patients grafted from 10/10 matched donors, 1 allele Pmm donors and 1 allele NPmm donors (p=0.005). GvHD with or without infections, as a cause of death was recorded in 19%, 23% and 33% of the three groups respectively (p=0.1). The CI of relapse was respectively 18%, 30%, 20% (p=0.1). The actuarial survival at 5 years was 68% for 10/10 matched patients, 63% for 1 allele Pmm patients and 47% for 1 allele NPmm patients. Conclusions. We confirm that aminoacid substitution at position 116 of class I HLA antigens, is a risk factor for non relapse mortality and survival. Patients with permissive mismatched AA116 donors have outcome comparable to patients grafted from matched donors. Figure Disclosures Angelucci: Novatis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Participation in DMC; BlueBirdBio: Other: Local advisory board; Jazz Pharmaceuticals: Other: Local advisory board; Roche: Other: Local advisory board; Vertex Pharmaceuticals Incorp., and CRISPR Therapeutics: Other: Participation in DMC.

Background: Triplet-based lenalidomide plus dexamethasone (Rd) combinations have become the new standard of care for early relapse and refractory multiple myeloma (RRMM). Carfilzomib is a novel selective proteasome inhibitor (PI) with high efficacy in RRMM. The ASPIRE phase 3 trial showed the superiority of carfilzomib-based triplet (KRd compared to Rd), leading to approval of K for RRMM. However, little is known about safety and efficacy of KRd outside a clinical trial context. Experimental design and aims: In 11 Sicilian Centers belonging to the Sicilian Myeloma Network, from November 2016, when KRd regimen was approved in Italy, to June 2018, 103 consecutive RRMM patients (previous lines 1-10) have received KRd regimen, according to ASPIRE schedule. Lenalidomide dosage was reduced in patients with a low count of platelet and/or renal failure according to manufacturer guidelines. Since previous studies have demonstrated that increased cumulative dose of first generation PI bortezomib significantly improved overall survival of patients treated with VMP regimen, we studied the effect of cumulative dose of Carfilzomib in RRMM patients receiving KRd. Results: Clinical and demographic characteristics of patients included in the study are summarized in Table 1. Median age was 65 years (range 33-86), most patients were males (54%). About half of the patients included in the survey were refractory to previous treatment (54%); Sixty-five (63%) patients received at least 5 cycles of KRd and 38 (36%) received at least 10 cycles. Overall response rate was 34% (35 patients); 18 patients (17%) achieved a complete response (CR), 6 patients minimal response (MR), 13 (12%) patients achieved PR, 16 patients achieved MR and then progressed; progression occurred in 20 patients, among them 3 did not reached any response. Delays due to adverse events were 33%, mainly due to febrile neutropenia (22%), thromboembolic events (4.5%), heart failure (3%), or thrombocytopenia (4.5%). To prevent hematological toxicities, 24% of patients received granulocyte growth factors, 15% erythropoietin. In 30 patients treatment was reduced (mainly due to lenalidomide toxicity) and in 5 patients discontinued for toxicity. Thus, median cumulative carfizomib doses at 2, 3, 4 and 6 cycles were respectively 480 mg (282 mg/m2), 735 mg (435 mg/m2), 995 mg (589 mg/m2) and 1522mg (890 mg/m2). After a median follow up of 16.2 months, PFS at 12 months was 67.3%. We found that median PFS was significantly longer in patients who received at least 480 mg (282 mg/m2) within first two months of treatment compared to those that could not receive full-dose KRd (respectively, undefined vs 11 months p=0.04). To identify patients that could obtain the most advantage by KRd treatment, 65 patients who had received at least six cycles were distinguished in two groups, based on previous treatments. In group A, 27 patients were heavily pretreated (median previous lines 4, range 2-10) and had previously received lenalidomide while 38 patients included in group B were less pretreated (median previous lines 3, range 1-5) and lenalidomide- naïve. We found that group A had lower PFS than group B although duration of PFS from the previous treatment was similar in both groups. Conclusions: In our cohort of patients rate of VGPR or better obtained with KRd combination was high with an overall response rate of 34%, with an acceptable safety profile. It is therefore reasonable that approaches to achieve a higher cumulative dose, such as continuing therapy in responding patients and/or proactive adverse events management, influence efficacy. In addition, it is likely that patients not previously exposed to several lines of treatment including lenalidomide are the best candidate for a favorable outcome with KRd regimen. Disclosures Di Raimondo: Celgene: Honoraria; Takeda: Honoraria, Research Funding.

In both monoclonal gammopathy of uncertain significance (MGUS) and multiple myeloma (MM) patients, immune functions are variably impaired, and there is a high risk of bacterial infections. Neutrophils are the most abundant circulating leukocytes and constitute the first line of host defense. Since little is known about the contribution of autophagy in the neutrophil function of MGUS and MM patients, we investigated the basal autophagy flux in freshly sorted neutrophils of patients and tested the plastic response of healthy neutrophils to soluble factors of MM. In freshly sorted high-density neutrophils obtained from patients with MGUS and MM or healthy subjects, we found a progressive autophagy trigger associated with soluble factors circulating in both peripheral blood and bone marrow, associated with increased IFN&gamma, and pSTAT3S727. In normal high-density neutrophils, the formation of acidic vesicular organelles, a morphological characteristic of autophagy, could be induced after exposure for three hours with myeloma conditioned media or MM sera, an effect associated with increased phosphorylation of STAT3-pS727 and reverted by treatment with pan-JAK2 inhibitor ruxolitinib. Taken together, our data suggest that soluble factors in MM can trigger contemporary JAK2 signaling and autophagy in neutrophils, targetable with ruxolitinib.

Background and Objective : There is an increasing interest about the role of amino acid degrading enzymes in cancer immunotherapy.In multiple myeloma (MM) disease progression depends on the ability of malignant plasma cells (PC) to subvert the local microenvironment and reshape host immunity to support tumor growth. Our previous work showed that i) MM cells have metabolic plasticity due to availability of external nutrients; ii) aminoacid shortage due to the tryptohan (trp) degrading enzyme IDO-1 was associated to clinical MM progression. Thus, we tested bio-energetic changes in MM upon trp deprivation. Experimental design : We evaluated the trascriptome changes in the adaptive response in four human MM cell lines (MM1.s, H929, U266, OPM2), chosen for their cytogenetic alterations and previously characterized for differential expression of CD38 and c-myc and primary BM samples of MGUS and MM to trp shortage. The pathway was confirmed looked at the expression levels of key metabolic genes in a large series of highly purified BM PC samples from healthy donors (4N), 129 MM, 24 primary plasma cell leukemia (pPCL), 12 secondary PCL (sPCL) cases from a proprietary dataset (GSE66293). Results Trp deprivation induced an adaptive response through increased expression, time and dose-dependent, of ATF4-ASNS-CHOP-GADD34, part of GCN2 signaling, associated to increased expression of p62 (the main autophagic receptor in MM) followed by autophagy flux induction, as shown by flow cytometry and immunofluorescence evaluations. In MM cell lines, trp deprivation altered the cellular dependence on mitochondrial ATP generation via oxidative phosphorylation, inducing in vitro increase of lactate dehydrogenase (LDH) and intracellular lactate and NAD/NADH with down-regulation of surface expression of the NAD-ase CD38. Similarly, short-term trp deprivation in CD138+ plasma cells isolated by magnetic sorting from MM patients, downregulated surface expression of CD38 and intra-cellular amount of c-myc, as detected by flow cytometry. This phenomenon was associated to increased isocitrate dehydrogenase (IDH-1), enolase-1 (ENO-1), phosphoglycerate kinase 1 (PGK-1), and dihydrolipoamide dehydrogenase (DLD), suggesting that branched chain amino acids with tolerogenic meaning like trp are used in MM to sustain NADH availability and energy production. In the GSE66293 MM progression was associated to increased expression of ENO-1, PGK-1, and DLD, suggesting that changes in transcription of genes involved in bioenergetics could be clinically relevant. Conclusion Overall, our study reveals that trp deprivation promotes an adaptive response of MM offering new putative targets in the bio-energetic pathway for synthetic lethality. Disclosures Palumbo: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Di Raimondo:Takeda: Honoraria, Research Funding; Celgene: Honoraria.