Renal injury at onset of newly diagnosed multiple myeloma (NDMM) is associated with poor outcome. Patients with severe renal failure due to MM are excluded from clinical trials with new drugs. The aim of this retrospective study was to describe the clinical characteristics, the treatment choices, the efficacy and the incidence of treatment-related toxicities of NDMM patients with renal insufficiency. We enrolled all NDMM patients with renal failure due to the disease treated at our Centers from 2012 to present. Fifty-one patients with a median age of 75 years were included; 76% had an International Staging System (ISS) of 3; 76% had anemia, 74% bone lesions and 30% had hypercalcemia; 31% had micromolecular myeloma. Thirty seven percent of patients had severe renal failure requiring dialysis treatment. Thirty-five percent of patients received treatment according to a VMP (Bortezomib, Melphalan and Prednisone) scheme, 20% received a triplet including Bortezomib and an immunomodulatory drugs (IMIDs) and 33% received a regimen including Daratumumab. The remaining 12% received a douplet (lenalidomide-dexamethasone or melphalan-prednisone). Thirty one percent of patients underwent an autograft procedure. Overall response rate (ORR) was 94% with a complete response (CR) rate of 17%. In terms of recovery of renal function, 50% achieved at least minimal renal response according to IMWG criteria, with 40% obtain a complete recovery of renal function. Patients who received more innovative treatment (regimens containing Daratumumab or Bortezomib in combination with IMIDs) achieved a response rate superior than very good partial response (≥ VGPR) of 74% with hematologic, neurologic, and infectious toxicities grade ≥ 3 of 22%, 7%, and 26%, respectively. Patients who received therapy with VMP or douplet had response rates ≥ VGPR of 25% with hematologic, neurologic, and infectious toxicity grade ≥ 3 rates of 29%, 4%, and 21%, respectively. Complete renal response rates in these two groups of patients were 45% and 20%, respectively. No death due to toxicity was registered. Patients with NDMM with renal failure at onset had a high burden of disease with unfavorable prognostic features. Although the small numbers of the cohort and the retrospective nature of this study it can be concluded that these patients can received new drugs combinations treatments with excellent response rates and without increased toxicity.

Several new drugs are approved for treatment of patients with multiple myeloma (MM), but no validated biomarkers are available for the prediction of a clinical outcome. We aimed to establish whether pretreatment blood and bone marrow plasma concentrations of major cytokines and angiogenic factors (CAFs) of patients from a phase 3 trial of a MM treatment could have a prognostic and predictive value in terms of response to therapy and progression-free and overall survival and whether these patients could be stratified for their prognosis. Blood and bone marrow plasma levels of Ang-2, FGF-2, HGF, VEGF, PDGF-β, IL-8, TNF-α, TIMP-1, and TIMP-2 were determined at diagnosis in MM patients enrolled in the GIMEMA MM0305 randomized controlled trial by an enzyme-linked immunosorbent assay (ELISA). These levels were correlated both reciprocally and with the type of therapy and patients’ characteristics and with a group of non-MM patients as controls. No significant differences were detected between the blood and bone marrow plasma levels of angiogenic cytokines. A cutoff for each CAF was established. The therapeutic response of patients with blood plasma levels of CAFs lower than the cutoff was better than the response of those with higher levels in terms of percentage of responding patients and quality of response. FGF-2, HGF, VEGF, and PDGF-β plasma levels at diagnosis have predictive significance for response to treatment. The stratification of patients based on the levels of CAFs at diagnosis and their variations after therapy is useful to characterize different risk groups concerning outcome and response to therapy. Clinical trial information can be found at the following link: NCT01063179

Background: Frailty is a common and important geriatric syndrome characterized by age‐associated declines in physiologic reserve and function across multiorgan systems, leading to increased vulnerability for adverse health outcomes. Two major definitions of frailty have emerged over the past years: 1) the frailty phenotype (FP) defined by at least three or five items between weakness, slowness, low physical activity, low energy and weight loss 2) frailty index (FI) based on a comprehensive geriatric assessment (CGA) that evaluates functional status, polypharmacy, comorbidity, emotional and cognitive mental health status, fatigue, socio‐economic condition, nutrition and quality of life. In patients with cancer, the identification of frailty might be relevant to choose the most appropriate therapy for each patient. In hematology the CGA is not routinely performed because it is complex and time‐consuming. Hand Grip strength (HGS) is a general indicator of muscle strength and low HGS has been linked with premature mortality. Aims: The aim of this study was to test HGS as screening tool for frailty in older patients with hematologic malignancies. Methods: Patients ≥ 70 years on treatment for Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), Multiple Myeloma (MM), Chronic Linfocytic Leukemia (CLL) and Non Hodgkin Lymphoma (NHL) who were referred to the hematology department of two centers were included in the study. HGS was evaluated with a Jamar dynamometer and CGA was performed with a set of four questionnaires: Activities of Daily Living (ADL), Instrumental Activities of Daily Living (IADL), G8 screening questionnaire, Cumulative Illness Rating Scale (CIRS). Frailty was defined according to the following cut‐off: ADL (>4 ≤4), IADL (>5 ≤5),G8 (>14 ≤14), CIRS ≥1 score 3–4 or > 8 score 2. Spearman's Rank coefficient was used to evaluate the correlation between HGS and questionnaires score. Age and sex‐adjusted logistic regression model was used to evaluate the association between HGS and frailty. The performance of the HGS screening tool was evaluated using Receiver Operating Curve (ROC) analysis and the area under the ROC curve (AUC). Sensitivity and specificity with 95% confidence interval were calculated. Analysis were performed using the software R version 3.5.0. Results: One hundred and eleven patients were included in the study (12 AML 10.8%, 6 MDS 5,4%, 39 MM 35.1%, 11 CLL 9.9% and 43 NHL 38.7%). Median age was 78 ± 4.7 with 42 patients ≥ 80 years (37.8%). The male/female ratio was 66 (59.5%)/45 (40.5%). Overall, HGS significantly correlated with ADL score (r = 0.45 p < 0.001 for men and r = 0.49 p < 0.001 for women), IADL score (r = 0.5 p < 0.001 for men and r = 0.4 p < 0.001 for women), G8 score (r = 0.57 p < 0.05 for men and r = 0.051 p < 0.001 for women) but not with CIRS score. Age and sex‐adjusted logistic regression analysis demonstrated an association between low HGS and frailty in patients with 2 additive scores in ADL, IADL or G8 but not CIRS (OR = 0.021, p = 0.003). In these patients ROC curves of HGS as screening tool for frailty evidenced AUC 87.4% (95%CI: 77.4%>97.4%) in women and 84% (95%CI 72.2%>96.1%) in men. Moreover, the ROC curves revealed an HGS score ≤14 Kg in women (82.1% sensitivity and 70.6% specificity) and ≤25 Kg in men (91.8% sensitivity and 70.6% specificity) as the optimal cut‐off point according to the best Youden index. Summary/Conclusion: HGS is a valid, reliable, rapid and sensible clinical measure of frailty.

Background: Continuous lenalidomide‐dexamethasone (Rd) is an effective and safe treatment for elderly newly diagnosed multiple myeloma (NDMM) patients. However, the outcome of patients >75 years is still inferior to younger patients, and not only advanced age but also the occurrence of severe adverse events (AEs) may negatively affect duration of treatment and survival. Aims: In order to further optimize Rd treatment, we investigated the efficacy and feasibility of sparing continuous dexamethasone in a dose/schedule‐adjusted Rd therapy followed by lenalidomide maintenance (Rd‐R) compared with standard continuous Rd in intermediate‐fit NDMM patients. Methods: The IMWG frailty score combines age, functional status (ADL and IADL), and comorbidities (Charlson index, CCI), and it identifies fit, intermediate‐fit and frail patients, with different risk of toxicity, treatment discontinuation and mortality (Palumbo A et al. Blood 2015) . Intermediate‐fit NDMM patients (Age 76–80 years or ADL≤4 or IADL≤5 or CCI≥2), with a frailty score = 1 ( http://www.myelomafrailtyscorecalculator.net/ ) were randomized to receive Rd‐R or continuous Rd. Rd‐R treatment consisted of nine 28‐day cycles of lenalidomide 25 mg/day for 21 days and dexamethasone 20 mg on days 1,8,15,22, followed by lenalidomide maintenance 10 mg/day (21 days), until progression. Continuous Rd consisted of lenalidomide 25 mg/day for 21 days and dexamethasone 20 mg on days 1,8,15,22, until progression. The dose and schedule of continuous Rd was the one adopted in patients >75 years in the FIRST trial (Hulin C et al. JCO 2016) . The primary endpoint was event‐free survival (EFS), defined as progression or death for any cause or discontinuation of lenalidomide or occurrence of any hematological grade 4 or non‐hematological grade 3–4 AEs, including Secondary Primary Malignancies, whichever comes first. Results: Of 199 evaluable patients, 98 were randomized to Rd‐R and 101 to continuous Rd. Median age was 75 and 76 years (p = 0.06); 47% in Rd‐R vs 57% in continuous Rd were defined intermediate‐fit for age (≥76 years), 53% vs 43% due to an impairment in CCI, ADL or IADL (p = ns). The median follow‐up was 25 months. Best response rates were comparable between the 2 groups: ≥PR rates were 73% vs 63%, and ≥VGPR rates were 43% vs 35% in the Rd‐R vs Rd continuous group, respectively. EFS was 9.3 vs 6.6 months (HR 0.72, 95% CI 0.52–0.99, p = 0.04), in Rd‐R versus continuous Rd, respectively. No difference in progression‐free survival (PFS) and overall survival (OS) was observed. 20‐month PFS was 43% vs 42% (HR 0.93, 95% CI 0.64–1.34, p = 0.681), 20 month‐OS was 84% versus 79% (HR 0.73, 95% CI 0.40–1.33, p = 0.306; Figure 1). At least 1 non‐hematologic grade 3–4 AE rate was 31% vs 39%. The most frequent grade3–4 AEs were neutropenia (17% vs 14%), infections (9% vs 11%) and skin rash (3% vs 7%). Lenalidomide dose reduction was required in 33% of Rd‐R patients and 43% of continuous Rd patients, and lenalidomide was discontinued in 19% vs 23% of patients, respectively. Lenalidomide median relative dose intensity was 100% in Rd‐R and 90% in continuous Rd group. Summary/Conclusion: Switching to lenalidomide maintenance after 9 cycles of Rd – thus sparing steroid in this dose/schedule‐adjusted Rd‐R treatment ‐ was feasible, without a negative impact but with outcome comparable to standard continuous Rd. This is the first prospective randomized phase III trial specifically designed for intermediate‐fit NDMM patients in which a frailty‐adjusted treatment approach to balance efficacy and safety was investigated. image

Event Abstract Back to Event Mandibular and cheek swelling revealing the diagnosis of localized amyloidosis Matteo Val1*, Roberto Marino1, Tommasina Guglielmelli2, Ubaldo Familiari2 and Monica Pentenero1 1 University of Turin, Department of Oncology, Italy 2 Ospedale San Luigi Gonzaga, Hematology Division, Italy Aim. Amyloidosis is a progressive metabolic disease characterized by abnormal deposits of the amyloid protein in one or more organs. The term was coined by Virchow in 1854 in order to describe abnormal extracellular material seen in the liver during an autopsy. The amyloidogenic protein is the basic component of about 25 different protein structures that can misfold and aggregate in insoluble beta-pleated-sheet structures, which are deposited in the extracellular space of different tissues and finally cause functional impairment.This disease may be acquired or hereditary. Also, it can be restricted to a single organ, where the amyloid is both produced and deposited, such as the lungs, the brain, or the skin (localized form) with an excellent prognosis, or may affect many organs of the body, leading to significant morbidity and mortality (systemic form). Amyloidosis can be classified according to its cause: primary, secondary and familial. Primary systemic amyloidosis, also known as amyloid light-chain (AL) amyloidosis, is thought to be related with monoclonal gammopathies, in which amyloid-forming immunoglobulin light chains are produced. AL amyloidosis is associated with plasma cell dyscrasia and multiple myeloma; the most commonly affected organs are the kidneys, the liver, the heart and the nerves [2]. Familial transthyretin-associated (ATTR) amyloidosis derives from a group of autosomal-dominant diseases where the onset of mutations in protein coding genes leads to deposition of amyloid fibrils in adult age. In this case, the aberrant protein is transthyretin, a transport protein for thyroxine able to bind retinol. Other hereditary forms of amyloidosis involve mutations in other serum proteins, such as apolipoprotein A1, fibrinogen, and gelsolin. Secondary amyloidosis due to chronic diseases (e.g. rheumatoid arthritis and chronic infections) is due deposition of serum amyloid A, an acute-phase protein produced in response to inflammation. Another type of secondary amyloidosis may occur in patients undergoing dialysis. In these patients, β-2 microglobulin, which is part of the Class I major histocompatibility complex antigen, fails to pass the dialysis membrane, resulting in the formation of amyloid fibrils Localized amyloidosis in the head and neck is a rare and generally benign condition. The most common sites of involvement are the thyroid, the larynx and subglottis, whereas in the oral cavity, amyloidosis usually tends to involve the tongue or buccal mucosa. The particularity of our case is linked to the anatomical subsite of onset that coincides with the mandibular bone marrow in just one month and in a team approach to reach the correct diagnosis. Materials and Methods. A 81 year-old male no smoker suffering for hypertension and carotid vasculopathy, diabetes complicated by severe renal failure and lower limb vasculopathy in pharmacological treatment, was admitted to our Oral Medicine and Oral Oncology Clinic on January 2018 with a chief complaint of swelling at the left mandible. The patient referred the onset of a fast-growing asymptomatic swelling from one month, he already assumed an antibiotic therapy (clarithromycin 250 mg), without any improvement. At the clinical observation a large swelling involving the left cheek and submandibular region was observed. On palpation a firm enlargement of the posterior vestibular side of the left mandible was perceived. The intraoral examination revealed a huge submucosal mass partially ulcerated involving the mandible, the mucobuccal fold and the cheek. Incisional biopsy and imaging were performed in the diagnostic process. The pathological assessment revealed the presence of protein infiltrate with few inflammatory cells and no alteration of the overlying mucosa. Due to allergy and poor general conditions of the patient computer tomography (CT) magnetic resonance (MR) imaging were acquired without contrast medium. They showed a large mass of 56x32x58 mm, with a massive mandibular bone involvement, while the masticatory muscles and the parotid did not show evident involvement. Laterocervical lymphadenopathies were not appreciated. Still lacking a complete definitive diagnosis a fine needle aspiration biopsy (FNAB) under ultrasound guidance was performed in order to have deeper tissue sampling from the mandibular mass. Results. The pathological assessment showed the presence of plasmacells (CD20-, CD3-, CD138+) with secretory capacity mainly formed of kappa chains, moreover the red Congo staining highlighted the deposition of amyloid. The joint assessment of such results allowed the diagnosis of plasmacellular kappa dyscrasia with amyloid deposition. The following hematological evaluation included a total body CT and a bone marrow biopsy (BMB). The BMB ruled out an involvement by clonal plasma cells; while the CT showed a multifocal involvement with osteolytic lesions of the left humeral metaphysis, the right humeral condyle and a pathological fracture of the eighth costal arch. Even in absence of further FNABs such findings were diagnoses as multiple amyloid bone involvement. Velcade and cyclophosphamide were administered at a lower dosage than usual due to the systemic conditions of the patient. On May 2018, after administration of the second cycle of chemotherapy, the patient had spontaneous suppuration from the intraoral mass in absence of systemic signs or symptoms of infection. Such feature jointly to the lack of response in mass reduction, suggested a potential mandibular pathological fracture. Chemotherapy was temporarily stopped and an antibiotic therapy was performed. Due to the known renal failure, amoxicillin clavulanate 875 + 125 mg (3 times daily) and metronidazole 250mg (twice daily) were administered. The CT of the facial bones ruled out the mandibular fracture, highlighting multiple colliquative areas, likely related to chemotherapy. The antibiotic therapy gave an improvement of local sign of infection and chemotherapy was restarted. Discussion. A diagnosis of amyloidosis is usually made on the basis of clinical presentation; a tissue biopsy is then performed to confirm the diagnostic hypothesis and to obtain a definitive diagnosis. Bennhold introduced the Congo red stain in 1922, and showed the characteristic red staining of amyloid in normal light. Apple-green birefringence with polarized light microscopy, however, is now the gold standard for diagnosis. The nature of amyloid deposition in the oral cavity has long been the subject of controversy. In presence of systemic amyloidosis, the tongue is the most frequently reported intraoral location of amyloid deposition. Moreover, when systemic amyloidosis is suspected, even in absence of oral signs of amyloid deposition, an incisional biopsy aiming to find out amyloid deposition in minor salivary glands can be performed. Local amyloidosis of the jaws’s bone is an extremely rare condition that can present as an unspecific nodular mass. Dentists, oral surgeons, radiologist, haematologist, pathologists as well as general practitioners should be able to cooperate for the diagnosis, treatment and follow-up. Histologic examination is the first step towards diagnosis, integrated by immunohistochemistry test. The diagnosis of localized amyloidosis should always be followed by blood tests, a bone marrow biopsy, echocardiography and digestive endoscopy to rule out systemic amyloidosis or any other haematological/immunological disorder or organ dysfunction. There is no consensus on the management of local amyloidosis due to their lack of morbidity. Surgical treatment of localized forms is indicated in case of functional impairment due to the presence of the mass. References 1. Virchow VR. Ueber einem Gehirn und Rueckenmark des Menschen auf gefundene Substanz mit chemischen reaction der Cellulose. Virchows Arch Pathol Anat. 1854;6:135–138. 2. Mollee P, Renaut P, Gottlieb D, Goodman H. How to diagnose amyloidosis. Intern Med J. 2014;44(1):7–17 3. Pentenero M, Davico Bonino L, Tomasini C, Conrotto D, Gandolfo S. Localized oral amyloidosis of the palate. Amyloid. 2006 Mar;13(1):42-6. Keywords: Amyloidosis, Mandible, Localised oral amyloid, Fine needle aspiration biopsy, Hematological disorder Conference: 5th National and 1st International Symposium of Italian Society of Oral Pathology and Medicine., Ancona, Italy, 19 Oct - 20 Oct, 2018. Presentation Type: Poster Presentation Topic: Oral Diseases Citation: Val M, Marino R, Guglielmelli T, Familiari U and Pentenero M (2019). Mandibular and cheek swelling revealing the diagnosis of localized amyloidosis. Front. Physiol. Conference Abstract: 5th National and 1st International Symposium of Italian Society of Oral Pathology and Medicine.. doi: 10.3389/conf.fphys.2019.27.00061 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 05 Nov 2018; Published Online: 09 Dec 2019. * Correspondence: Dr. Matteo Val, University of Turin, Department of Oncology, Turin, Piedmont, 10124, Italy, matteo.val@outlook.it Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Matteo Val Roberto Marino Tommasina Guglielmelli Ubaldo Familiari Monica Pentenero Google Matteo Val Roberto Marino Tommasina Guglielmelli Ubaldo Familiari Monica Pentenero Google Scholar Matteo Val Roberto Marino Tommasina Guglielmelli Ubaldo Familiari Monica Pentenero PubMed Matteo Val Roberto Marino Tommasina Guglielmelli Ubaldo Familiari Monica Pentenero Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

In patients with a complete response (CR), high-dose therapy with autologous stem cell transplantation (HDT-ASCT) consolidation improved progression-free survival (PFS), second PFS (PFS2), and overall survival (OS) versus R-Alk (lenalidomide, alkylator) consolidation. Also, lenalidomide maintenance therapy enhanced PFS compared with no maintenance therapy. The survival advantage with HDT-ASCT compared with R-Alk in CR patients can be attributed to the greater minimal residual disease negativity rate induced by HDT-ASCT. Background: High-dose therapy with autologous stem cell transplantation (HDT-ASCT) and maintenance treatment with novel agents are the best options for patients with newly diagnosed multiple myeloma, increasing the rate of complete response (CR) and prolonging progression-free survival (PFS) and overall survival (OS). Indeed, the achievement of a CR is a predictor of long-term survival among transplant-eligible patients. However, it is unclear whether patients reaching a CR after induction treatment could receive less intense consolidation or avoid maintenance therapy. Patients and Methods: We analyzed CR patients treated in 2 phase III trials, GIMEMA-RV-MM-PI-209 and RV-MM-EMN-441, to compare HDT-ASCT with an R-Alk (lenalidomide, alkylator) regimen as consolidation, and lenalidomide (R) maintenance with no maintenance. The primary endpoints were PFS, second PFS (PFS2), and OS from consolidation and maintenance (_m). Results: Overall, the data from 166 patients in CR were analyzed, 95 in the HDT-ASCT group and 71 in the R-Alk group. The CR patients who received HDT-ASCT had a better PFS (hazard ratio [HR], 0.55; P = .01), PFS2 (HR, 0.46; P = .02), and OS (HR, 0.42; P = .03) compared with patients randomized to R-Alk. The survival benefit with HDT-ASCT was confirmed among all the subgroups, according to age, International Staging System (ISS stage, cytogenetic profile, and receipt of maintenance therapy. CR patients who received lenalidomide maintenance had a better PFS_m (4 years: 54% vs. 19%; HR, 0.43; P = .02) compared with those who received no maintenance. However, no difference was observed in terms of PFS2_m (4 years: 72% vs. 58%; HR, 0.83; P = .67) and OS_m (4 years: 79% vs. 72%; HR, 0.82; P = .73) with maintenance therapy. Conclusion: Even in CR patients, outcomes were improved by an intensified approach with HDT-ASCT consolidation and lenalidomide-based maintenance therapy. (C) 2018 Elsevier Inc. All rights reserved.

Maintenance demonstrated to improve survival in newly diagnosed multiple myeloma (NDMM) patients and the achievement of complete response (CR) is a strong predictor of survival. Nevertheless, the role of maintenance according to response after induction/consolidation has not been investigated so far. To evaluate the impact of maintenance according to response, we pooled together and retrospectively analyzed data from 955 NDMM patients enrolled in two trials (GIMEMA-MM-03-05 and RV-MM-PI-209). Primary endpoints were progression-free survival (PFS)1, PFS2 and overall survival (OS) of CR patients randomized to maintenance and no maintenance. Secondary endpoints were PFS1, PFS2 and OS in very good partial response/partial response (VGPR/PR) patients. Overall, 213 patients obtained CR after induction/consolidation, 118 received maintenance and 95 no maintenance. In patients achieving CR, maintenance significantly improved PFS1 (HR 0.50, P < 0.001), PFS2 (HR 0.58, P 0.02) and OS (HR 0.51, P 0.02) compared with no maintenance; the advantage was maintained across all the analyzed subgroups according to age, International Staging System (ISS) stage, cytogenetic profile and treatment. Similar features were seen in VGPR/PR patients. Maintenance prolonged survival in CR and in VGPR/PR patients. The benefit in CR patients suggests the importance of continuing treatment in patients with chemo-sensitive disease. The two source studies are registered at ClinicalTrials.gov: identification numbers NCT01063179 and NCT00551928.

Background: Risk-adapted therapy is a common strategy in curable hematologic malignancies: standard-risk patients receive less intensive treatment, whereas high-risk patients require a more intensive approach. This model cannot be applied in multiple myeloma (MM), which is still incurable. Continuous treatment (CT) is a key strategy for MM treatment, since it improves duration of remission. However, the role of CT according to standard- or high-risk baseline prognosis remains an open question. Patients and methods: We performed a pooled analysis of 2 phase III trials (GIMEMA-MM-03-05 and RV-MM-PI-209) that randomized patients to CT vs fixed-duration therapy (FDT). Results: In the overall patient population (n = 550), CT improved progression-free survival1 (PFS1) (HR 0.54), PFS2 (HR 0.61) and overall survival (OS) (HR 0.71) vs FDT. CT improved PFS1 both in R-ISS I (HR 0.49) and R-ISS II/III patients (HR 0.55). Four-year PFS1 was 38% in R-ISS II/III patients receiving CT and 25% in R-ISS I patients receiving FDT, with similar trends for PFS2 and OS. High-risk patients benefited more from proteasome-inhibitor plus immunomodulatory-based CT than immunomodulatory alone. Conclusion: Good prognosis patients receiving FDT lose their prognostic advantage over high-risk patients receiving CT and high-risk patients may benefit from more intensive maintenance including proteasome inhibitors and immunomodulators.

Abstract Introduction : Cytogenetic abnormalities by fluorescence in situ hybridization (FISH) are clinically relevant prognostic factors in MM. Data in transplant ineligible patients treated with bortezomib or lenalidomide in first-line therapy for high-risk (HiR) patients is limited. Careful analysis of cytogenetic subgroups in trials comparing different treatments remains an important goal. This sub-analysis evaluates the impact of cytogenetics on outcomes in transplant-ineligible patients with newly diagnosed MM (NDMM) treated with bortezomib-based induction (BORT) or lenalidomide-based (LEN) treatment. Methods : In the GIMEMA-MM-03-05-trial, patients were randomized to bortezomib-melphalan-prednisone-thalidomide for 9 cycles followed by maintenance with bortezomib-thalidomide (VMPT-VT) vs VMP for 9 cycles, without maintenance. In the EMN01-trial, patients were randomized to melphalan-prednisone-lenalidomide (MPR) or cyclophosphamide-prednisone-lenalidomide (CPR) or lenalidomide plus low-dose dexamethasone (Rd) for 9 cycles, followed by maintenance with lenalidomide alone or plus prednisone continuously. Results of these studies have previously been reported (Palumbo A et al JCO 2010 and 2014; Magarotto V et al Blood 2016 127(9)). Cytogenetics were assessed using FISH. Patients were categorized into cytogenetic risk groups according to International Myeloma Working Group criteria. HiR cytogenetics included del(17p), t(4;14), and t(14;16); all other patients were categorized as standard risk (StR). Subgroup analyses were performed to determine the consistency of treatment effects of BOR vs LEN in the different subgroups using interaction terms between treatment and FISH, ISS, age, sex, Karnofsky PS and LDH. The different effect of BORT vs LEN in cytogenetic subgroups was confirmed by one sensitivity analysis where the follow-up of the BORT study was reduced to make the follow-up times similar; and by another sensitivity analysis with multiple imputation method for missing cytogenetic value. Results : 902 of 1165 patients from the intent-to-treat population had available cytogenetic profiles, with 243 (27%) patients in the HiR group and 659 (73%) in the StR group. In the BORT vs LEN groups, median age was 71 vs 73 years (p<0.001), ISS3 20% vs 27% (P=0.65), HiR patients were 29% vs 26%, StR patients were 71% vs 74% (p=0.32) and the median follow-up was 72.3 and 63.6 months, respectively. In the subgroup analysis, a significant difference was found in the cytogenetic subgroup with a superior advantage of BORT versus LEN in HiR group, whereas no significant difference was found between BORT and LEN in the other subgroups analyzed (ISS, age, sex, Karnofsky PS and LDH) (interaction-p=0.01) (Fig. 1 B). BORT treatment resulted in a reduced risk of death or progression compared with LEN in patients with HiR. In HiR patients, median PFS was 30.8 with BORT compared with 14.8 months with LEN (HR: 0.54; 95% CI: 0.41-0.72); in StR, median PFS was 29.1 with BORT compared with 22.1 months with LEN (HR: 0.87; 95%; CI: 0.72-1.05) (Fig. 1 A). Considering the standard of care VMP and Rd, in the HiR group (n=95) VMP resulted in a 48% reduced risk of death or progression compared with Rd (HR: 0.53; 95% CI: 0.34-0.83), whereas no significant difference in PFS was found in the StR group (n=273) (HR: 1.00; 95% CI: 0.75-1.33), interaction-p=0.02. BORT treatment resulted in a reduced risk of death in patients with HiR cytogenetics: median OS was 62.4 months with BORT compared with 43.2 months with LEN (HR: 0.68; 95% CI: 0.47-0.96); in StR, median OS was 78.1 months with BORT and was not reached with LEN (HR: 1.06; 95% CI: 0.82-1.36), interaction-p=0.04 (Fig. 1 A). In patients with del(17p) (n=131) median PFS was 18.0 vs 12.9 months for BORT vs LEN (HR: 0.71; 95% CI: 0.49-1.04), interaction-p=0.73. In patients with t(4;14) (n=118) median PFS was 31.5 vs 15.2 months for BORT vs LEN (HR: 0.41; 95% CI: 0.27-0.62) interaction-p=0.002. In patients with t(14;16) (n=31) median PFS was 36.2 vs 9.8 months for BORT vs LEN treated patients (HR: 0.34; 95% CI: 0.16-0.76), interaction-p=0.045. Conclusions : BORT treatment resulted in a PFS and OS benefit vs LEN in patients with HiR cytogenetics. Treatment with VMP led to a significant reduction of the risk of death or progression vs Rd in HiR patients. These results support VMP induction as a standard treatment option for patients with NDMM who are ineligible for transplant with HiR cytogenetics. Disclosures Larocca: Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria. Offidani: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Musto: Janssen: Honoraria; Celgene: Honoraria. Patriarca: MSD Italia: Honoraria; Janssen: Honoraria. Corradini: Gilead: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Bosi: Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Petrucci: Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Boccadoro: Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Mundipharma: Research Funding; AbbVie: Honoraria.

This phase 2 trial evaluated three low-dose intensity subcutaneous bortezomib-based treatments in patients ⩾75 years with newly diagnosed multiple myeloma (MM). Patients received subcutaneous bortezomib plus oral prednisone (VP, N= 51) or VP plus cyclophosphamide (VCP, N= 51) or VP plus melphalan (VMP, N= 50), followed by bortezomib maintenance, and half of the patients were frail. Response rate was 64% with VP, 67% with VCP and 86% with VMP, and very good partial response rate or better was 26%, 28.5% and 49%, respectively. Median progression-free survival was 14.0, 15.2 and 17.1 months, and 2-year OS was 60%, 70% and 76% in VP, VCP, VMP, respectively. At least one drug-related grade ⩾3 non-hematologic adverse event (AE) occurred in 22% of VP, 37% of VCP and 33% of VMP patients; the discontinuation rate for AEs was 12%, 14% and 20%, and the 6-month rate of toxicity-related deaths was 4%, 4% and 8%, respectively. The most common grade ⩾3 AEs included infections (8–20%), and constitutional (10–14%) and cardiovascular events (4–12%); peripheral neuropathy was limited (4–6%). Bortezomib maintenance was effective and feasible. VP, VCP and VMP regimens demonstrated no substantial difference. Yet, toxicity was higher with VMP, suggesting that a two-drug combination followed by maintenance should be preferred in frail patients.

Lenalidomide-dexamethasone improved outcome in newly diagnosed elderly multiple myeloma patients. We randomly assigned 662 patients who were age ≥65 years or transplantation-ineligible to receive induction with melphalan-prednisone-lenalidomide (MPR) or cyclophosphamide-prednisone-lenalidomide (CPR) or lenalidomide plus low-dose dexamethasone (Rd). The primary end point was progression-free survival (PFS) in triplet (MPR and CPR) vs doublet (Rd) lenalidomide-containing regimens. After a median follow-up of 39 months, the median PFS was 22 months for the triplet combinations and 21 months for the doublet (P = .284). The median overall survival (OS) was not reached in either arms, and the 4-year OS was 67% for the triplet and 58% for the doublet arms (P = .709). By considering the 3 treatment arms separately, no difference in outcome was detected among MPR, CPR, and Rd. The most common grade ≥3 toxicity was neutropenia: 64% in MPR, 29% in CPR, and 25% in Rd patients (P < .0001). Grade ≥3 nonhematologic toxicities were similar among arms and were mainly infections (6.5% to 11%), constitutional (3.5% to 9.5%), and cardiac (4.5% to 6%), with no difference among the arms. In conclusion, in the overall population, the alkylator-containing triplets MPR and CPR were not superior to the alkylator-free doublet Rd, which was associated with lower toxicity. This study was registered at www.clinicaltrials.gov as #NCT01093196.

Introduction : Risk-adapted therapy in curable hematologic malignancies is commonly applied: low-risk patients (pts) may be cured with less intensive treatment, avoiding excessive toxicity, whereas high-riskpts require more intensive and toxic regimens. In multiple myeloma (MM), this model may not apply, since the disease is incurable. In recent years, there has been a marked improvement in patient outcome, due to the introduction of novel agents and optimized treatment strategies, including the use of transplant and maintenance. A better evaluation ofpts prognosis based on the new revised international staging system (R-ISS) has been also introduced in clinical practice. The objective of this analysis was to evaluate the impact of treatment intensification (specifically autologous stem cell transplantation [ASCT] and maintenance) inpts with different prognostic features. Methods : Data from 3 phase III randomized trials in newly diagnosed MMpts (RV-MM-209; EMN441; GIMEMA-MM0305) were pooled together and analyzed. Baseline patient risk assessment was estimated using R-ISS. We evaluated: 1) the impact of treatment intensification with high-dose therapy followed by ASCTvs no-ASCT inpts with R-ISS Stage Ivs Stage II/III; 2) the impact of treatment intensification with maintenancevs no maintenance inpts with R-ISS Stage Ivs Stage II/III. RV-MM-209 and EMN441 studies randomizedpts to ASCTvs no-ASCT; allpts in the GIMEMA-MM0305 trial did not receive ASCT and were excluded from the first comparison; RV-MM-209 and GIMEMA-MM0305 studies randomizedpts to maintenance or no maintenance after induction/consolidation; allpts in the EMN441 trial received maintenance and were excluded from the second comparison. We evaluated progression free survival-1 (PFS1), PFS2 and overall survival (OS). Cox proportional hazards models were used to estimate hazard ratios (HRs). To account for potential confounders, the comparisons between ASCTvs no-ASCT and maintenancevs no maintenance were adjusted for the trial effect and the main prognostic features. Results: Overall, 1302 pts were enrolled in the 3 trials. Median follow-up was 4 years.Comparison ASCTvs no-ASCT: 791pts were enrolled in the 2 trials, 529 were eligible for the ASCTvs no ASCT comparison. R-ISS Stage data were available for 419 pts. There was an overall advantage for ASCTvs no-ASCT in PFS1 (0.53; p Conclusions: Both ASCT and maintenance improved PFS1, PFS2 and OS in MM pts. The highest survival was reported in patients with R-ISS Stage I receiving ASCT and/or maintenance. Low-riskpts (R-ISS Stage I) not undergoing intensification with ASCT or maintenance lose their prognostic advantage over high-risk patients receiving the same intensification. Disclosures Gay: Janssen-Cilag: Other: Advisory Board; Celgene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria, Other: Advisory Board; Mundipharma: Other: Advisory Board. Hajek: Novartis: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Bringhen: Mundipharma: Other: Advisory Board; Karyopharm: Other: Advisory Board; BMS: Honoraria; Janssen-Cilag: Honoraria; Amgen: Other: Advisory Board; Celgene: Honoraria. Gaidano: Gilead: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Caravita: Janssen-Cilag: Honoraria. Cavo: Millennium: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Foa: Pfizer: Speakers Bureau; Ariad: Speakers Bureau; BMS: Consultancy; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Janssen-Cilag: Consultancy, Speakers Bureau; Genetech: Consultancy; Roche: Consultancy, Speakers Bureau. Patriarca: Bristol-Myers Squibb: Other: Advisory board; Mundipharma: Other: Advisory board; Janssen-Cilag: Other: Advisory board; MSD: Consultancy; Celgene: Consultancy. Ria: Italfarmaco: Consultancy, Speakers Bureau; Janssen-Cilag: Other: Advisory Board, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Binding Site: Speakers Bureau; BMS: Speakers Bureau; BMS: Speakers Bureau. Palumbo: Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Boccadoro: Novartis: Honoraria, Research Funding; Mundipharma: Research Funding; SANOFI: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Abbivie: Honoraria; Amgen: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding; BMS: Honoraria, Research Funding.

mTOR is a protein kinase that plays a central role in regulating critical cellular processes. We evaluated the activation and cellular localization of the mTOR pathway in multiple myeloma (MM) and analyzed the role of pomalidomide in regulating mTOR. By immunohistochemistry cytoplasmic p-mTOR stained positive in 57 out 101 (57.6%) cases with a nuclear p-mTOR localization in 14 out 101 samples (13.8%). In the 70 MM samples analyzed for the entire pathway, p-mTOR expression significantly correlated with p-AKT, p-P70S6K, and p-4E-BP1 suggesting that the AKT/mTOR pathway is activated in a subset of MM patients. Immunofluorescence assays demonstrated that mTOR protein is distributed throughout the cytoplasm and the nucleus at baseline in MM cell lines and in plasma cells of 13 MM patients and that pomalidomide facilitated the shift of the mTOR protein in the nucleus. By western blotting, treatment with pomalidomide increased nuclear mTOR and p-mTOR expression levels in the nucleus with a concomitant decrease of the cytoplasmic fractions while does not seem to affect significantly AKT phosphorylation status. In MM cells the anti-myeloma activity of pomalidomide may be mediated by the regulation of the mTOR pathway.

Multiple myeloma (MM) accounts for 1% of all cancers and 13% of all hematologic malignancies. Melphalan-prednisone plus melphalan-prednisone-thalidomide or melphalan-prednisone-bortezomib are considered the standards of care for newly diagnosed, transplant-ineligible patients with MM (older than 65 years). In newly diagnosed, transplant-eligible patients with MM (younger than 65 years), a novel agent-based induction followed by high-dose therapy and autologous stem cell transplantation, is the standard approach. The availability of novel agents has considerably increased the treatment options of this disease, but almost all patients relapse after achieving a maximal response to first-line therapy. New drugs and new treatment approaches are urgently needed to improve outcome in MM patients Continuous therapy can be a valid option to keep the patient symptom-free and to prolong progression-free survival and overall survival.

Introduction Several trials have shown that maintenance therapy prolongs progression-free survival (PFS) in multiple myeloma (MM) patients, eligible and ineligible for autologous stem cell transplantation (ASCT); conflicting data exist about its impact on overall survival (OS). The role of maintenance in patients with a sensitive disease is still unclear. We conducted a retrospective pooled analysis to clarify the impact of continuous treatment in patients achieving a complete response (CR).