ALBERT

Description: Introduction Multiple Myeloma (MM) is a hematologic malignancy characterized by proliferation of clonal plasmacells in the bone marrow and sometimes extramedullary sites which inevitably tend to relapse. Patients with relapsed/refractory MM (R/R MM) who are treated with conventional drugs as immunomodulating agents (IMiDs) and proteasoma inhibitors (PIs) have a poor survival. Based on the results of MM 003 phase III randomised trial, pomalidomide in association with dexamethasone has shown to improve R/R MM outcome. We conducted a single-center real life-based observational and pharmacological analysis to investigate the efficacy and tolerability of pomalidomide in a group of patients with R/R MM previously exposed to IMiDs and PIs. Method and Materials We included 34 patients (females 21) treated with pomalidomide (POMA) from January 2015 to May 2018 at the Hematology Department of "Santo Spirito" Hospital in Pescara, Italy. All patients were diagnosed by R/R MM according to IMWG guidelines and were classificated using ISS criteria. Prognostic cytogenetic value was identified by FISH analysis. POMA was administred at the oral daily dose of 3-4 mg (days 1-21) in combination with oral dexamethasone (days 1,8,15,22) at the dosage of 20 mg/day. Adverse events were evaluated according to the common terminology criteria for adverse reactions (CTCAE version 4.0). Overall survival (OS) and progression free survival (PFS) were designed according to Kaplan-Myer method. The adherence to therapy was determined using 'received daily dose/prescribed daily dose' method (RDD/PDD). Statistic analysis were conducted with GraphPad Prism 7.0; p values ≤ 0.05 were considered statistically significant. Results The clinical and biological characteristics of 34 patients are described in Tab.1. The median follow up after POMA therapy was 5 months (range, 1-32); at the end of this period 12 patients had completed at least 6 cycles of therapy (range, 1-21). Overall response rate (ORR) was 24%: 4 complete remission (CR), 3 very good partial response (VGPR), 1 partial response (PR); moreover 6 patients (18%) achieved a minimal response (MR). Clinical benefit rate (CBR) was 74%: ORR plus 6 MR and 11 stable disease (SD). At time of this report 12 patients (35%) are living. Among living patients, 4 are now receiving other treatments and 8 are still under POMA treatment: 4 are in CR, 1 is in PR, 1 in MR and 2 in SD. Median OS of all patients was 10 months, whereas median PFS was 6 months (Fig.1,A-B). Median PFS was notably lower in high cytogenetic risk patients (4 months) as compared to the PFS of standard cytogenetic risk patients (16 months) (p= 0.02) (Fig.1,D). Patients treated with at least 4 previous lines of therapy had a median PFS of 5 months, while those receiving until 3 previous lines of therapy had a median PFS of 24 months (p= 0.01) (Fig.1,C). Patients receiving a drug regimen lenalidomide-based as last treatment before starting POMA didn't show significant difference in PFS from those receiving other treatments (4 months vs 6 months) (p=NS). During treatment with POMA, 22 patients (65%) showed adverse drug reactions (ADRs) for a total of 77. Seventy-four ADRs were ≥ 2 grade. Forty nine ADRs (63%) were hematological and 43 ADRs (56%) occurred in the first 3 months of therapy. In particular Twenty-two of them occurred within the first month of therapy. Thirty two cases of ADRs (41%) were successfully managed with simple delay of treatment. As consequence, the adherence to therapy was not optimal (78%). However only 9 (12%) of the total ADRs were cause of end of treatment. Conclusions Despite the low sample size and short follow-up, our real life analysis contributes to show that pomalidomide therapy is a favorable option for patients with R/R MM, leading to good responses in terms of OS and PFS. The best results were obtained when POMA treatment was utilized at first relapses and in particular in patients with favorable genetic profile. About the safety, despite the frequent hematological toxicity, ADRs can be quite easily managed to allow few interruptions of the treatment and improve the adherence. Disclosures No relevant conflicts of interest to declare.

Description: Introduction Lenalidomide (Len) and low-dose Dexamethasone (dex) (Rd) in continuous is a new standard of care for elderly newly-diagnosed multiple myeloma (NDMM) patients (pts), as established by FIRST trial (Facon et al, Blood 2018). Methods and results This is a retrospective, multicentric study conducted in Italy with the aim of evaluating efficacy and tolerability of Rd in a real-life population. Thirty-seven centers were involved and data of 429 pts are available. Pts were considered eligible for the study when completing at least 2 cycles of Rd regimen. Table 1 summarizes the characteristics of pts at time of MM diagnosis. Median age was 78 years (range 57-92), 36.6% had an ECOG PS≥2, creatinine clearance (ClCr) was ULN (P=0.01) and ClCr2 still impact on OS (p

Description: Abstract 4959 Introduction Notwithstanding recent findings, multiple myeloma (MM) remains an incurable disease and almost all treated patients invariably relapse. The clinical presentation of recurrent MM is heterogeneous. Extramedullary relapses (EMRs) are rare, but recently an increased frequence has been reported, probably favoured by the new diagnostic imaging techniques, and maybe caused by the induction chemotherapeutic regimens. Patients We report 6 cases of EMRs, occurring after a median time of 3 years (yrs) from stem cell transplantation (SCT). Five (A,B,C,D,E) male and one (F) female patients (pts), median age 50 yrs (39-63), were affected by IgGk (5 pts) and IgAk (1 pt) MM, all in stage IIIA. At diagnosis one pt (E) had an EM sternal extrapleural plasmocytoma, which was successfully irradiated. Three pts were treated with total therapy II (B,D,E), 2 pts with VAD and autologous-SCT (ASCT) (A,F) or ASCT followed by mini allogeneic-SCT (AlloSCT) (C). The patient F showed an orbital localization after VAD, before ASCT. After SCT all 5 patients resulted in complete remission (CR). Results A systemic relapse occurred after 3 yrs in pt A, who was treated according to EDAP chemotherapy (etoposide-dexamethasone-cytarabine-carboplatin); after 2 yrs in pt B, treated with combination of bortezomib-thalidomide-dexamethasone (VTD). Both pts reached a second CR and a maintenance with thalidomide was started. However, after one yr, pt A had a lumbar paravertebral EMR, and pt B lumbosacral extradural and dorsal endocanalar EMRs, besides a tumour mass in the pelvic bone, jutting in abdominal cavity. As regarding the other 4 pts, C had a pulmonary embolism 4 yrs after first CR and an EMR was demonstrated, looking as a 6 cm long lumbar mass, infiltrating the inferior vena cava and determining thrombosis of it. In pt D the EMRs occurred 2 yrs after ASCT: one lumbar 3 cm long mass and another of 9 cm of diameter in the pelvic bone. Finally patient E and F had a dorsal 7 × 5 cm paravertebral and a femoral mass, respectively, 1 and 4 yrs after ASCT. Only in pt B elevated lactate dehydrogenase levels were present when EMR was diagnosed. Therapeutic approaches to EMRs were represented by radiotherapy; in addition pts B,C,E,F were treated with EDAP, without response; AlloSCT was performed in pt A; PAD plus lenalidomide in pt D. The latter (D) reached a third CR, so an AlloSCT was performed, but unfortunately the patient died because of hepatic acute GVHD. The other patient firstly treated with AlloSCT (pt A) was refractory and was treated with VTD chemotherapy, but he recently showed nodular lesions in the liver, showing hypercaptation at PET. Chemotherapy with lenalidomide, dexamethasone and cyclophosphamide (LDC) was started, but after 2 cycles a progressive hepatic EM disease (lesion of 7 cm) is now present. As we mentioned 4 patients (B,C,E,F) has been treated with EDAP, which resulted ineffective. Patient C, after EDAP, started bortezomib-dexamethasone therapy (VD), with initial clinical and radiological response (PET negative); however shortly after, he showed other scapular and axillary PET positive EMRs; radiotherapy, thalidomide-dexamethasone (TD) and then donor lymphocyte infusions (DLI) from the allogeneic donor were performed; as results the previous hypercaptant scapular regions resulted negative at PET, but various new lesions appeared, so a salvage therapy with LDC has been recently started. Femoral and humeral radiotherapy has been simultaneously started. Patient F died soon after EDAP because of renal failure. The other 2 pts, refractory to EDAP chemotherapy, showed successive EMRs. The patient B died after progressive cranial, orbital, encephalic EMRs, complicated by CD56 negative plasma cell leukaemic meningitis. Patient E developed maxillary, cranial, orbital, zygomatic MM masses, pelvic, humeral and radial fracture and died. Discussion From the initial diagnosis of MM one pt died after 3 and three patients died after 4.5 yrs respectively; 2 patients are still long survivors after 7 and 9 yrs. EMRs could be the consequence of a clonal selection after high dose chemotherapy, with the persistence of a plasmacellular clone after induction therapy before ASCT. In spite of the small number of patients, our experience shows that EMRs appear refractory to radiotherapy and to conventional and even high dose chemotherapy. Instead it seems that regimens including new drugs (thalidomide, bortezomib, lenalidomide) could be useful, prolonging survival, as demonstrated for patient A and C, still surviving, and for patient D, who died in CR for acute GVHD. Disclosures No relevant conflicts of interest to declare.

Description: Polycythemia vera (PV) is associated with high morbidity and mortality for thrombosis. We hypothesized that in PV altered sensitivity to aspirin might be related to dysfunction of the endothelial repair and/or of the nitric oxide (NO) system. Urinary thromboxane (TX) A2 metabolite (TXM), endothelial colony-forming cells (ECFCs), plasma asymmetric dimethylarginine (ADMA) and von Willebrand factor (VWF) were measured in 37 PV patients on low-dose aspirin and 12 healthy controls. Patients showed an approximately 2-fold increase in median TXM and plasma ADMA levels (P 〈 .001), while ECFC numbers were reduced by approximately 7-fold (P 〈 .001) as compared with nonaspirinated control. These differences were more pronounced in patients with previous thrombosis. An 8-week course of aspirin did not affect ECFCs in 6 controls. VWF and TXM correlated directly with ADMA, and inversely with ECFCs. By multiple regression analysis, lower ECFC quartiles (beta = −0.39; SE = 0.17; P = .028) and higher VWF levels (beta = 0.338, SE = 0.002, P = .034) were independent predictors of higher TXM quartiles (R2 = 0.39). Serum TXB2, measured in 22 patients, was approximat-ly 10-fold higher than aspirin-treated controls. PV patients appear to have an unbalanced ECFC/NO axis, and an apparent altered sensitivity of platelet TXA2 production, all potentially contributing to aspirin-insensitive TXM formation. Thus, additional antithrombotic strategies may be beneficial in PV.

Description: Background: Most patients (pts) with HL can be cured today. Nevertheless, 10 to 40% of pts fail to respond to front-line treatment or relapse both early and late. Pts who do not achieve complete remission with conventional treatment or who present early relapse have poor prognosis compared with pts who develop late relapse. The treatment of choice for refractory or early relapsed pts is high-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT), while late relapsed pts may be treated with either conventional therapy or HDC plus ASCT. The purpose of this study is to evaluate the results of our experience in the treatment of refractory or relapsed HL pts. Methods: From January 1999 to December 2007, 179 untreated pts with HL have been admitted in our institution and 176 completed treatment today. Front-line treatment included 4–6 courses of ABVD polychemotherapy in combination with involved field radiotherapy (IFRT) (36 Gy) in clinical stage (CS) I–IIA, and 6 courses of ABVD, COPPEBVCAD (cyclophosphamide, lomustine, vindesine, melphalan, prednison, epidoxorubicin, vincristine, procarbazine, bleomycin, vinblastine) or BEACOPP in CS IIB–IV. Overall, 157 pts (89%) obtained a complete response (CR) and 9 (6%) of them relapsed. In particular, 4 pts relapsed within 12 months after diagnosis of HL, while 5 pts experienced late relapse. The remaining 19 pts (11%), who obtained a minor response or failed to respond, were classified as having a refractory disease after front-line therapy. Twenty-six pts received, as salvage treatment, 3–6 courses of IGEV (iphosphamide, gemcitabine, vinorelbine). The other 2 pts received 6 courses of COPPEBVCAD and 6 courses of ABVD, respectively. Nineteen pts (11 with refractory disease and 8 with relapsed disease) have been submitted also to ASCT with BEAM conditioning regimen. Retrospectively, we evaluated the response rate, overall survival (OS) and disease free survival (DFS) in our 28 refractory-relapsed pts. Results: 15 pts were male and 13 female (M/F ratio: 1,15); median age was 34 years (range: 16–59). At the time of diagnosis 5 pts presented CS I–IIA and 23 CS IIB–IV. B symptoms and bulky disease were present in 18 (64%) and 15 (54%) pts respectively. Twenty-seven pts completed salvage treatment today. Seventeen pts (63%) obtained a CR, while 10 pts (37%) had progressive disease (PD). In particular, CR and PD in refractory pts were 56% and 44%, in comparison to 78% and 22% in relapsed pts. With a median follow-up of 23 months (range 3–80), OS was 53%. Ten pts dead of progressive HL; another patient dead in CR of BEAM toxicity prior to ASCT. DFS of the CR pts was 85%. Only 2 refractory pts, who obtained a CR after salvage treatment, relapsed after 5 and 23 months respectively. Conclusion: Our data confirm that HDC plus ASCT is useful both in relapsed and in refractory pts with HL. Nevertheless, nearly half of refractory pts fail to respond to salvage treatment and die of progressive lymphoma. The selection of these latter pts is very difficult today. An advanced disease with a high international prognostic score could be an effective risk indicator at the time of diagnosis. Moreover, an early PET/CT, during salvage treatment, could select the pts who remain unresponsive. Anyway, new treatment modalities are required for these pts.

Description: Background: PMBCL accounts for nearly 2% of all non Hodgkin lymphoma. The most effective treatment of this disease is unknown. In retrospective studies third generation chemotherapy regimens, namely MACOP-B or VACOP-B, plus radiotherapy achieved better results in comparison with conventional CHOP. Moreover, the value of the addition of rituximab (R) to CHOP or MACOP-B in PMBCL is not well-known today. The purpose of this study is to evaluate the results of our experience in the treatment of PMBCL. Methods: Between 1/2000 and 1/2008, 25 untreated patients (pts) with PMBCL have been admitted in our institution. Disease evaluation was performed with whole-body computed tomography at diagnosis, after 3–4 courses or after 2 months of chemotherapy and at the conclusion of treatment. At early restaging, pts who obtained at least a partial remission (PR) completed planned treatment, while unresponsive pts started high dose sequential chemotherapy (HDSC) (2 courses of APO, 2 courses of DHAP, cyclophosphamide 7gr/m2, methotrexate 8gr/m2, etoposide 2gr/m2) followed by autologous stem cells transplantation (ASCT). In a first time, the planned treatment generally consisted of third generation chemotherapy (PROMACE-CYTABOM in 5 pts and MACOP-B in 1 pt) plus involved field radiotherapy (IFRT) (36 Gy). Another patient with high risk disease (stage IVB, aaIPI 3) received front-line HDSC plus ASCT. One patient aged 16 years was treated according NHL97-AIEOP pediatric protocol (drugs total dose mg/m2, course A: iphosphamide 4000, methotrexate 5000, cytarabin 300, etoposide 200, vincristine 1,5. Course B: cyclophosphamide 1000, methotrexate 5000, daunomycin 50, vincristine 1,5. Course C: cytarabin 12000, etoposide 500, vindesine 3) plus IFRT (36 Gy). Subsequently, for the remaining 17 pts, planned treatment consisted of R-CHOP chemo-immunotherapy (CHOP21 in 4 cases and CHOP14 in 13 cases) plus IFRT (36 Gy). Retrospectively, we evaluated the response rate, overall survival (OS) and disease free survival (DFS). Results: 5 pts were male and 20 female (M/F ratio: 0,25); median age was 32 years. Stage I–II was present in 20 pts and stage III–IV in 5; aa-IPI was 0–1 in 20 pts and 2–3 in the remaining 5. Fifteen pts (60%) had B symptoms at the time of diagnosis. After early restaging, 21 pts (84%) showed at least a PR. The other 4 pts, who were treated with third generation chemotherapy (1/6, 17%) or R-CHOP (3/17, 18%) and who were early unresponsive, received treatment intensification with HDSC followed by ASCT in 2 cases. At present, 1 patient died of sepsis during MACOP-B, 2 pts are still under treatment and 22 pts completed treatment. We obtained a complete remission (CR) in 19 pts (86%) and a PR in 2 pts (9%). One of the last 2 pts achieved CR after HDSC plus ASCT. Overall, 5 pts received treatment intensification (4 after early restaging and 1 after treatment completion). With a median follow-up of 44 months, OS was 87% and DFS of the 20 CR pts was 100%. Two pts (1 with PR, 1 with unresponsive disease) died of progressive lymphoma. No difference in response and outcome was seen between third generation chemotherapy and R-CHOP. Conclusions: various chemo-radiotherapic combinations have been used successfully in the treatment of PMBCL. Waiting for prospective studies aimed to define a gold standard treatment, we think that our response-adapted treatment modality is an effective approach for inducing durable response in the majority of pts with PMBCL.

Description: Background The role of consolidation treatment for newly diagnosed, transplant eligible MM (NDMM) patients has never been prospectively addressed in a randomised trial. Methods The EMN02/HOVON95 trial was designed to compare intensification therapy using 4 cycles of bortezomib-melphalan-prednisone (VMP) vs high-dose melphalan (HDM) plus single or double autologous stem cell transplantation (ASCT), after induction with VCD (R1) (M. Cavo et al. Lancet Haemat 2020, 7, e456-68). A second randomisation was performed after intensification for consolidation treatment with 2 cycles of bortezomib-lenalidomide-dexamethasone (VRD) vs no consolidation (R2), in both arms followed by lenalidomide (10 mg) maintenance until progression or unacceptable toxicity. Patients assigned to consolidation treatment received two 28-day cycles of VRD, each comprising bortezomib (1·3 mg/m2 either i.v. or s.c., on days 1, 4, 8, and 11) combined with lenalidomide (25 mg orally, on days 1 through 21), and dexamethasone (20 mg orally, on days 1, 2, 4, 5, 8, 9, 11, and 12). Primary study end points were progression-free survival (PFS) from R1 and PFS from R2. Secondary endpoints included response and survival. Here we report the final analysis for R2 which was performed in July 2020. Results From February 2011 to April 2014, 1503 pts aged ≤ 65 years with symptomatic MM were enrolled in 172 EMN centres, of whom 1500 were eligible. Of these, 1212 were randomised (stratification by ISS stage) to VMP (495 pts) or HDM (1 or 2 ASCT) (702 pts). For R2 894 patients were eligible, of whom 878 had also been included in R1. These 878 patients were randomised to consolidation (451 pts) or no consolidation (427 pts). Median follow-up from R2 was 71.3 months (IQR 63-80). Response status at time of R2 was equal in both arms, ie ≥ CR (20%), ≥ VGPR (67%), ≥ PR (92%). At the time of this final analysis, 512 events for PFS after R2 had been reported. 5-year PFS from R2 was 50% (95% confidence interval (CI) 45-55) with consolidation and 42% (95% CI 37-46) without, while median PFS from R2 was 59 vs 43 months, respectively. PFS from R2 with adjustment for R1 was prolonged in pts randomised to VRD consolidation (hazard ratio (HR)=0.80; 95% CI=0.67-0.95; P=0.013), which is consistent with the results of the first and second interim analyses (P. Sonneveld et al. ASH 2016, abstract #242; EHA 2018, abstract #1525). With Cox regression analysis revised ISS3 stage (HR 2.05, 95%CI 1.43-2.92) and ampl1q (HR 1.68, 95%CI 1.38-2.06) were adverse prognostic factors at diagnosis. The PFS benefit was observed across most predefined subgroups, including revised ISS stage I-III, standard-risk cytogenetics and both treatment arms of the first randomisation (VMP or HDM treatment). The median duration of maintenance treatment was 33 months (0-97+ months), with 32% of patients still on treatment at 5 years after start of lenalidomide. The secondary endpoint response 〉=CR after consolidation vs no consolidation before start of maintenance was 34% vs 18%, respectively (p=CR on protocol was 59% with consolidation and 45% without, respectively (p