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Lymphoma represents a heterogeneous hematological malignancy (HM), which is characterized by severe immunosuppression. Patients diagnosed of coronavirus disease 2019 (COVID-19) during the course of HM have been described to have poor outcome, with only few reports specifically addressing lymphoma patients. Here, we investigated the clinical behavior and clinical parameters of a large multicenter cohort of adult patients with different lymphoma subtypes, with the aim of identifying predictors of death. The study included 856 patients, of whom 619 were enrolled prospectively in a 1-year frame and were followed-up for a median of 66 days (range 1-395). Patients were managed as outpatient (not-admitted cohort, n = 388) or required hospitalization (n = 468), and median age was 63 years (range 19-94). Overall, the 30- and 100-days mortality was 13% (95% confidence interval (CI), 11% to 15%) and 23% (95% CI, 20% to 27%), respectively. Antilymphoma treatment, including anti-CD20 containing regimens, did not impact survival. Patients with Hodgkin’s lymphoma had the more favorable survival, but this was partly related to significantly younger age. The time interval between lymphoma diagnosis and COVID-19 was inversely related to mortality. Multivariable analysis recognized 4 easy-to-use factors (age, gender, lymphocyte, and platelet count) that were associated with risk of death, both in the admitted and in the not-admitted cohort (HR 3.79 and 8.85 for the intermediate- and high-risk group, respectively). Overall, our study shows that patients should not be deprived of the best available treatment of their underlying disease and indicates which patients are at higher risk of death. This study was registered with ClinicalTrials.gov, NCT04352556.

Background. Given the good penetration of systemic high-dose cytarabine (HDara-C) into the cerebrospinal fluid (CSF), this approach was used to treat patients with central nervous system (CNS) leukemia, either isolated or with concurrent extraneurologic disease (END). Methods. From 1983 to 1991, 46 adults with CNS involvement were treated with systemic HDara-C: 25 had acute lymphoblastic leukemia (ALL), 15 had high-grade non-Hodgkin lymphoma (NHL), 5 had acute myelogenous leukemia (AML), and 1 had lymphoid blast crisis of chronic myelogenous leukemia. Induction consisted of HDara-C 3 g/[m.sup.2] every 12 hours, by 3-hour infusion, for 8 doses (30 patients), or 6 doses (16 patients), followed by 4 doses at day 21. Results. Of 46 patients, 29 (63%) achieved complete remission (CR): 15/15 with isolated CNS leukemia, and 14/31 (45%) with CNS and concurrent marrow or lymph node disease. Of 17 patients not meeting CR criteria because of persistent END, 11 showed complete CNS response. The first 10 remitters were consolidated with monthly 4-dose courses of HDara-C. The remaining 19 received postinduction multidrug chemotherapy (including vincristine, doxorubicin, cyclophosphamide, Lasparaginase, etoposide plus intermediate-dose ara-C, mitoxantrone plus HDara-C) and intrathecal methotrexate (MTX) [+ or -] cranial radiation therapy. One patient underwent autologous and one allogeneic bone marrow transplant. Median CR duration was 7 months (range, 2-56+): 8 months for patients with isolated CNS leukemia, and 4 months for those with concurrent END. In only two patients was CNS the primary site of relapse. Three patients with isolated CNS leukemia are disease-free at 23, 40, and 56 months. The main toxicity was myelosuppression. No patient showed dose-limiting neurologic toxicity. Conclusions. Systemic HDara-C appears effective therapy for CNS leukemia, maximally in cases with isolated CNS involvement. HDara-C may be combined safely with cranial radiation therapy and intrathecal MTX. This approach for CNS leukemia, however, needs to be combined with additional treatments to eradicate residual disease in extraneurologic compartments.

In the phase 3 OPTIMISMM trial, pomalidomide, bortezomib, and dexamethasone (PVd) demonstrated superior efficacy vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma previously treated with lenalidomide, including those refractory to lenalidomide. This analysis evaluated outcomes in patients at first relapse (N= 226) by lenalidomide-refractory status, prior bortezomib exposure, and prior stem cell transplant (SCT). Second-line PVd significantly improved PFS vs Vd in lenalidomide-refractory (17.8 vs 9.5 months; P= 0.0276) and lenalidomide-nonrefractory patients (22.0 vs 12.0 months; P= 0.0491), patients with prior bortezomib (17.8 vs 12.0 months; P= 0.0068), and patients with (22.0 vs 13.8 months; P= 0.0241) or without (16.5 vs 9.5 months; P= 0.0454) prior SCT. In patients without prior bortezomib, median PFS was 20.7 vs 9.5 months (P= 0.1055). Significant improvement in overall response rate was also observed with PVd vs Vd in lenalidomide-refractory (85.9% vs 50.8%; P< 0.001) and lenalidomide-nonrefractory (95.7% vs 60.0%; P< 0.001) patients, with similar results regardless of prior bortezomib or SCT. No new safety signals were observed. These data demonstrate the benefit of PVd at first relapse, including immediately after upfront lenalidomide treatment failure and other common first-line treatments.

Several small studies on patients with COVID-19 and haematological malignancies are available showing a high mortality in this population. The Italian Hematology Alliance on COVID-19 aimed to collect data from adult patients with haematological malignancies who required hospitalisation for COVID-19.

Improving real‐life functioning is the main goal of the most advanced integrated treatment programs in people with schizophrenia. The Italian Network for Research on Psychoses previously explored, by using network analysis, the interplay among illness‐related variables, personal resources, context‐related factors and real‐life functioning in a large sample of patients with schizophrenia. The same research network has now completed a 4‐year follow‐up of the original sample. In the present study, we used network analysis to test whether the pattern of relationships among all variables investigated at baseline was similar at follow‐up. In addition, we compared the network structure of patients who were classified as recovered at follow‐up versus those who did not recover. Six hundred eighteen subjects recruited at baseline could be assessed in the follow‐up study. The network structure did not change significantly from baseline to follow‐up, and the overall strength of the connections among variables increased slightly, but not significantly. Functional capacity and everyday life skills had a high betweenness and closeness in the network at follow‐up, as they had at baseline, while psychopathological variables remained more peripheral. The network structure and connectivity of non‐recovered patients were similar to those observed in the whole sample, but very different from those in recovered subjects, in which we found few connections only. These data strongly suggest that tightly coupled symptoms/dysfunctions tend to maintain each other's activation, contributing to poor outcome in schizophrenia. Early and integrated treatment plans, targeting variables with high centrality, might prevent the emergence of self‐reinforcing networks of symptoms and dysfunctions in people with schizophrenia.

Maintenance therapy following autologous stem cell transplantation (ASCT) can delay disease progression and prolong survival in patients with multiple myeloma. Ixazomib is ideally suited for maintenance therapy given its convenient once-weekly oral dosing and low toxicity profile. In this study, we aimed to determine the safety and efficacy of ixazomib as maintenance therapy following ASCT.

Transparent objects require acquisition modalities that are very different from the ones used for objects with more diffuse reflectance properties. Digitizing a scene where objects must be acquired with different modalities requires scene reassembly after reconstruction of the object surfaces. This reassembly of a scene that was picked apart for scanning seems unexplored. We contribute with a multimodal digitization pipeline for scenes that require this step of reassembly. Our pipeline includes measurement of bidirectional reflectance distribution functions and high dynamic range imaging of the lighting environment. This enables pixelwise comparison of photographs of the real scene with renderings of the digital version of the scene. Such quantitative evaluation is useful for verifying acquired material appearance and reconstructed surface geometry, which is an important aspect of digital content creation. It is also useful for identifying and improving issues in the different steps of the pipeline. In this work, we use it to improve reconstruction, apply analysis by synthesis to estimate optical properties, and to develop our method for scene reassembly.

Systemic light chain (AL) amyloidosis is caused by the clonal production of an unstable immunoglobulin light chain (LC), which affects organ function systemically. Although pathogenic LCs have been characterized biochemically, little is known about the biology of amyloidogenic plasma cells (PCs). Intrigued by the unique response rates of AL amyloidosis patients to the first-in-class proteasome inhibitor (PI) bortezomib, we purified and investigated patient-derived AL PCs, in comparison with primary multiple myeloma (MM) PCs, the prototypical PI-responsive cells. Functional, biochemical, and morphological characterization revealed an unprecedented intrinsic sensitivity of AL PCs to PIs, even higher than that of MM PCs, associated with distinctive organellar features and expression patterns indicative of cellular stress. These consisted of expanded endoplasmic reticulum (ER), perinuclear mitochondria, and a higher abundance of stress-related transcripts, and were consistent with reduced autophagic control of organelle homeostasis. To test whether PI sensitivity stems from AL LC production, we engineered PC lines that can be induced to express amyloidogenic and nonamyloidogenic LCs, and found that AL LC expression alters cell growth and proteostasis and confers PI sensitivity. Our study discloses amyloidogenic LC production as an intrinsic PC stressor, and identifies stress-responsive pathways as novel potential therapeutic targets. Moreover, we contribute a cellular disease model to dissect the biology of AL PCs.

A study has shown that MYD88(L265P) is a recurring somatic mutation in Waldenström's macroglobulinemia (WM). We developed an allele-specific polymerase chain reaction (PCR) for this mutation, and analyzed bone marrow or peripheral blood samples from 58 patients with WM, 77 with IgM monoclonal gammopathy of undetermined significance (IgM-MGUS), 84 with splenic marginal zone lymphoma (SMZL), and 52 with B-cell chronic lymphoproliferative disorders (B-CLPD). MYD88(L265P) was detected in 58/58 (100%) patients with WM, 36/77 (47%) with IgM-MGUS, 5/84 (6%) with SMZL, and 3/52 (4%) with B-CLPD. Compared to IgM-MGUS patients with wild-type MYD88, those carrying MYD88(L265P) showed significantly higher levels of IgM (P< .0001) and presented Bence-Jones proteinuria more frequently at diagnosis (P= .002). During follow-up, 9 patients with IgM-MGUS progressed to WM or to marginal zone lymphoma. Using a case-control approach, the risk of evolution of patients carrying MYD88(L265P) was significantly higher than that of patients with wild-type MYD88(odds ratio 4.7, 95% confidence interval 0.8 to 48.7, P= .047). These findings indicate that the allele-specific PCR we developed is a useful diagnostic tool for patients with WM or IgM-MGUS. In this latter condition, MYD88(L265P) is associated with greater disease burden and higher risk of disease progression, and the mutation may therefore also represent a useful prognostic marker.

A study has shown that MYD88 (L265P) is a recurring somatic mutation in Waldenström's macroglobulinemia (WM). We developed an allele-specific polymerase chain reaction (PCR) for this mutation, and analyzed bone marrow or peripheral blood samples from 58 patients with WM, 77 with IgM monoclonal gammopathy of undetermined significance (IgM-MGUS), 84 with splenic marginal zone lymphoma (SMZL), and 52 with B-cell chronic lymphoproliferative disorders (B-CLPD). MYD88 (L265P) was detected in 58/58 (100%) patients with WM, 36/77 (47%) with IgM-MGUS, 5/84 (6%) with SMZL, and 3/52 (4%) with B-CLPD. Compared to IgM-MGUS patients with wild-type MYD88, those carrying MYD88 (L265P) showed significantly higher levels of IgM (P < .0001) and presented Bence-Jones proteinuria more frequently at diagnosis (P = .002). During follow-up, 9 patients with IgM-MGUS progressed to WM or to marginal zone lymphoma. Using a case-control approach, the risk of evolution of patients carrying MYD88 (L265P) was significantly higher than that of patients with wild-type MYD88 (odds ratio 4.7, 95% confidence interval 0.8 to 48.7, P = .047). These findings indicate that the allele-specific PCR we developed is a useful diagnostic tool for patients with WM or IgM-MGUS. In this latter condition, MYD88 (L265P) is associated with greater disease burden and higher risk of disease progression, and the mutation may therefore also represent a useful prognostic marker.

Abstract: Thalidomide represents the first attempt in multiple myeloma (MM) patients to overcome resistance to chemotherapy through a biological agent. The exciting results reported in the first study by Singhal et al. in 1999 [1] led to several other studies which aimed to evaluate its efficacy in different settings and disease phases, to define its toxicity, and to establish the optimal dose. Some of these questions have already been answered while others, such as the best dosage or the best schedule to obtain the highest efficacy with the lowest toxicity, still remain. Thalidomide has been studied as a single agent or in association with other drugs (dexamethasone, chemotherapy and new drugs) showing a synergic activity. We review the results of the main studies on the efficacy and toxicity of thalidomide used as a single agent or in association with other drugs, reflect on its present role, and consider its future contribution to the treatment of MM.

High-dose therapy with the rescue of autologous stem cells represents today the standard approach for multiple myeloma patients aged <65 years. Several studies, in fact, have demonstrated the superiority of high-dose therapy with respect to conventional chemotherapy in younger patients. Peripheral blood stem cells (PBSCs) provide a rapid and effective hematopoietic recovery after the administration of supra maximal chemotherapy and mainly for this reason have become the preferred source of stem cells for autologous transplantation. Recently, however, a number of new drugs have appeared in the armamentarium of the hematologist. Among these, thalidomide has been the first antiangiogenetic drug effectively adopted firstly in refractory-relapsed patients and now also as first line treatment with better results respect to VAD or VAD-like regimens. Inhibitors of proteasome, such as bortezomib, and other immunomodulatory agents, such as lenalidomide, have been also studied more recently in myeloma patients. In particular, bortezomib has shown to be very effective as single agent or in combination with high-dose dexamethasone. In this review, we try to define the potential role of these new drugs, how and when they can be included in the therapeutic program designed for younger and older patients, and mostly if and how these new agents could jeopardize the central role of autologous stem cell transplantation in the treatment of multiple myeloma.

CA 125 is a glycoprotein produced by epithelial ovarian tumors and by mesothelial cells; its levels also have been shown to be elevated in patients with non-Hodgkin's lymphoma (NHL). The authors evaluated serum CA 125 levels in patients with NHL to elucidate the frequency of this finding, its relationship with other presenting features, and its potential role as tumor marker. One hundred and fifty-seven patients underwent the first CA 125 assessment at onset, 54 at disease recurrence or progression, and 62 during complete remission (CR). Of the 157 patients evaluated at diagnosis (median CA 125: 26 U/mL; range, 2-1400 U/mL), 63 (40%) had increased CA 125 values. Higher CA 125 levels were associated with advanced disease, aggressive histology, mediastinal and/or abdominal involvement, bulky tumor, high tumor burden, effusions, contiguous extranodal extension, high serum lactate dehydrogenase (LDH) activity, and elevated β2-microglobulin (β2-M) levels. Parameters identified by multivariate analysis to be independently associated with high CA 125 were: aggressive histology, mediastinal and/or abdominal disease, bulky tumor, high serum LDH activity and β2-M serum levels, and the presence of effusion (P = 0.0000; explained variation = 0.64). Of the patients presenting with abnormal CA 125 levels, all those who achieved a CR (35) and 3 of the 6 who achieved a partial response had normalization of CA 125 values by the end of treatment. Conversely, CA 125 remained above normal values in 18 nonresponders. All 62 patients evaluated during CR showed normal CA 125 levels. Among patients first evaluated at disease recurrence or progression, 22 of 54 (41%) showed increased CA 125 levels, which were associated with the same parameters of disease found in patients examined at diagnosis. High serum CA 125 levels were found to correlate with mediastinal and/or abdominal involvement, high tumor mass, and effusions, reflecting the reaction of mesothelial cells to the tumor. Serum CA 125 is a reliable biologic marker for the staging and restaging of patients with lymphoma. Serial measurements are useful, in conjunction with other markers, for monitoring response to treatment. Cancer 1998;82:576-82. © 1998 American Cancer Society.

Acute promyelocytic leukemia (APL) is uniquely sensitive to treatment with all-trans retinoic acid (ATRA) which exerts its action via a well-documented cytodifferentiating mechanism. The combination of this retinoid with anthracyclines gives high percentages of complete remission and is now considered the optimal induction treatment for APL patients. Continuous treatment with ATRA, however, induces accelerated drug catabolism, with progressive decline in plasma drug concentrations potentially to below the levels required to maintain differentiation of leukemic cells. This process, which occurs rapidly and consistently has led to the hypothesis that the development of acquired clinical resistance to ATRA in APL has a pharmacologic basis. The rapid autoinduction of the hypercatabolic state precludes maintenance with continuous ATRA oral dosing, and is a limitation of better use of the drug both in APL and in other disorders in which it could be beneficial. Here we briefly review the pharmacologic alterations of ATRA metabolism induced by continuous oral administration, the clinical implications of this phenomenon, and the strategies currently under investigation to prevent or overcome the induced catabolism of this retinoid.

Dimopoulos: Sanofi Oncology: Research Funding. Weisel:GSK: Honoraria; Juno: Consultancy; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Moreau:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Anderson:Amgen, Janssen, Takeda, Celgene: Consultancy, Speakers Bureau. White:Sanofi: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria. Sonneveld:SkylineDx: Research Funding; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dürig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Celgene: Consultancy, Other: Travel or accommodations, Speakers Bureau. Pavic:Celgene, Janssen, Takeda, Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Casal:Celgene Corporation: Employment. Srinivasan:Celgene: Employment, Equity Ownership. Nguyen:Celgene Corporation: Employment, Equity Ownership. Biyukov:Celgene: Employment, Equity Ownership. Peluso:Celgene Corporation: Employment. Richardson:Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees.Yes. The triplet combination is not currently approved in the US for the treatment of multiple myeloma.

Dimopoulos: Celgene: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria. Weisel:Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moreau:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Anderson:Celgene: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau. White:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. San-Miguel:Celgene: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Roche: Honoraria; BMS: Honoraria; Novartis: Honoraria. Sonneveld:Amgen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Jenner:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau. Dürig:Janssen: Consultancy, Honoraria; Celgene: Honoraria; Roche: Honoraria, Speakers Bureau. Pavic:AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Salomo:Cilag: Consultancy; Janssen: Consultancy. Yu:Celgene: Employment, Equity Ownership. Nguyen:Celgene Corporation: Employment. Bensmaine:Celgene: Equity Ownership. Peluso:Celgene Corporation: Employment, Equity Ownership. Zaki:Celgene Corporation: Employment, Equity Ownership. Richardson:BMS: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees.

Bakground.The association of light chain (AL) amyloidosis with lymphoplasmacytic lymphoma/Waldenström's Macroglobulinemia is well established. However, both localized and systemic AL amyloidosis have been also reported in other types of lymphoma, but a detailed description of these cases is still lacking.

Introduction. Bortezomib (Bort) and lenalidomide (Len) are standard treatments for relapsed MM, but, so far, a comparative trial between them has never been conducted. We designed a multicenter, open label, phase III study to compare bortezomib/cyclophosphamide/dexamethasone and lenalidomide/cyclophosphamide/dexamethasone in a fixed duration design protocol. The combination of Bort and Len with chemotherapy was devised to improve efficacy and to allow a fixed duration treatment in patients not heavily pretreated.

Introduction.Despite availability of newer effective therapies, approximately 30% of patients with AL amyloidosis still die within 1 year from diagnosis due to advanced, irreversible cardiac involvement at presentation. In 40% of patients the diagnosis is made more than 1 year after the onset of symptoms, and, once amyloid organ involvement becomes symptomatic, organ dysfunction is often already advanced (Kourelis et al. AJH 2014, Lousada et al. Adv Ther 2015). Biomarkers [(N terminal pro natriuretic peptide (NT-proBNP) for the heart, albuminuria for the kidney, and alkaline phosphatase (ALP) for the liver] can detect organ involvement before symptoms appear and can facilitate early diagnosis. Moreover, increased circulating free light chains (FLC) precede the presentation of AL amyloidosis by 4 years or more (Weiss et al. JCO 2014). Thus, we advocated the screening with biomarkers of amyloid organ involvement of all patients with monoclonal gammopathy of undetermined significance (MGUS) and abnormal FLC ratio (Merlini et al. Hematology Am Soc Hematol Educ Program 2012, Merlini et al. Blood 2013). Here we present the clinical features and outcome of patients with MGUS diagnosed with AL amyloidosis while asymptomatic during biomarker-based screening.

Musto: Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cascavilla:Janssen-Cilag: Honoraria. Falcone:Janssen-Cilag: Honoraria. Petrucci:Janssen-Cilag: Honoraria. Di Raimondo:Janssen-Cilag: Honoraria. Ria:Binding Site: Speakers Bureau; BMS: Speakers Bureau; BMS: Speakers Bureau; Italfarmaco: Consultancy, Speakers Bureau; Janssen-Cilag: Other: Advisory Board, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau. Mastrullo:Janssen-Cilag: Honoraria. D'Arena:Janssen-Cilag: Honoraria. Bringhen:Janssen-Cilag: Honoraria; Celgene: Honoraria; BMS: Honoraria; Amgen: Other: ADVISORY BOARD; Mundipharma: Other: ADVISORY BOARD; Karyopharm: Other: ADVISORY BOARD. Di Renzo:Janssen-Cilag: Honoraria. Caravita:Janssen-Cilag: Honoraria. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Corso:Janssen-Cilag: Honoraria.

Corso: Janssen-Cilag: Honoraria.

Autologous stem cell transplant (ASCT) remains the standard of care for Multiple Myeloma (MM) patients younger than 70 years old. The role of induction therapy is crucial within a program of high-dose therapy since deeper is the response before, higher is the outcome of transplant.

Mohty: Celgene: Honoraria; Janssen: Honoraria. Terpos:Amgen: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Mateos:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Palumbo:Array BioPharma: Consultancy; Onyx Pharmaceuticals: Consultancy; Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Genmab A/S: Consultancy; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy; Sanofi Aventis: Consultancy. Lejniece:Amgen: Honoraria; Sandoz: Honoraria. Beksac:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dimopoulos:Novartis: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Onyx: Honoraria; Celgene: Honoraria; Genesis Pharma: Research Funding. De Stefano:Shire: Speakers Bureau; Roche: Research Funding; Bruno Farmaceutici: Research Funding; Janssen Cilag: Research Funding; Amgen: Speakers Bureau; GlaxoSmithKline: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Celgene: Speakers Bureau. Salwender:Celgene: Honoraria; Janssen Cilag: Honoraria; Bristol Meyer Sqibb: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Pečeliūnas:Johnson & Johnson: Honoraria, Research Funding. Willenbacher:CTI: Consultancy, Other: Travel, Accommodations, Expenses; Gilead: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; Amgen: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Da Silva:Janssen Pharmaceuticals: Research Funding. Louw:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Nemet:Sanofi: Honoraria; Pliva: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Potamianou:Janssen: Employment. Couturier:Janssen-Cilag: Employment. Olie:Johnson & Johnson: Equity Ownership; Janssen-Cilag: Employment. Feys:Janssen Pharmaceutica N.V.: Employment, Equity Ownership. Thoret-Bauchet:Janssen-Cilag: Employment.

No relevant conflicts of interest to declare.

Mantovani: Janssen: Research Funding. Rossi:Janssen: Consultancy.

Rossi: Janssen: Consultancy. Mantovani:Janssen : Research Funding.

Bahlis: Celgene: Honoraria, Research Funding. Off Label Use: Lenalidomide used in newly diagnosed multiple myeloma patients. Stoppa:Celgene, Janssen: Honoraria. Decaux:Celgene and Janssen-Cilag : Consultancy, Honoraria. Marit:Celgene, Janssen: Congress expenses Other. Demuynck:Janssen-Cilag: Honoraria. Ervin-Haynes:Celgene: Employment. Leupin:Celgene: Employment. Marek:Celgene: Employment, Equity Ownership. Chen:Celgene: Employment. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

No relevant conflicts of interest to declare.

The combination of immunomodulatory drugs (IMiDs(r)) and alkylating agents have significantly improved outcomes of patients with relapsed or refractory multiple myeloma (RRMM). Bendamustine, an agent sharing properties of alkylators and purine analogous, and lenalidomide, an immunomodulator drug, are highly effective for the treatment of lymphoprolipherative disorders. Some clinical trials have shown good responses to the combination of bendamustine with steroids and novel agents (thalidomide, lenalidomide and bortezomib) for the treatment of RRMM (Knop S 2005, Lentzsch S 2012, Pönisch W 2013), but further research is needed to confirm the best combination, the optimal schedule of administration, and to better define the safety profile.

Bendamustine, an agent sharing properties of alkylators and purine analogous, showed a strong efficacy and safe toxicity profile in relapsed multiple myeloma (MM) patients (pts), with a maximally tolerated dose (MTD) ranging from 100 mg/m2/die day 1 and 2 as single agent to 60 mg/m2/die in association with thalidomide. In a pooled analysis of two large phase 3 trials Lenalidomide, an analogous of thalidomide with strong activities in MM, significantly improved overall response rate and progression-free survival. Since the role of Lenalidomide in the treatment of naïve and relapsed/refractory pts has been well established, the current research is focused on the combination of Lenalidomide with chemotherapy to further improve patient outcome.This multicenter phase I/II trial was designed to investigate the combination of Bendamustine, Lenalidomide, and Dexamethasone (BdL) in repeating 4-week cycles as treatment for relapsed MM. Pts over 18 years with measurable stage II or III MM who relapsed after 1 to 3 previous lines of therapy, including bone marrow transplantation were considered eligible. Prior Lenalidomide and Bortezomib were allowed.The phase I study was conducted using a 3+3 cohort design beginning at a dose level 0 of intravenous Bendamustine 40 mg/m2/die days 1 and 2, oral Lenalidomide 10 mg/die days 1–21 and oral Dexamethasone 40 mg/die days 1, 8, 15, and 22 (28-day cycle).The dose of Bendamustine and Lenalidomide (from 0 to 5) were increased from one cohort to the next, in a 3+3 dose escalation scheme to reach the MTD (Table 1).The MTD of Bendamustine and Lenalidomide were evaluated during the first treatment course (cycle 1). Enrollment at each subsequent dose level was permitted only if the first 3 patients at the previous level received 1 cycle with an acceptable dose-limiting toxicity (DLT).DLTs were defined as any adverse event (AE) possibly related to the study drug ≥grade 3 CTC. If 1 of the 3 subjects experienced DLT during the first cycle, 3 more subjects were to be recruited and treated at the same dose level of Bendamustine and Lenalidomide.Treatment was given until plateau of best response according to the International Myeloma Working Group uniform response criteria for a maximum of 6 cycles.Herein, we present the results from phase I of the study which established MTD. Fifteen pts with a median age of 69 years (range 49 to 88) were enrolled between October 2011 and February 2012. The number of prior therapies was at maximum 3 as per protocol: Lenalidomide (27% of pts), thalidomide (33% of pts), Bortezomib (67% of pts) and 13% of the pts had a prior autologous stem cell transplant. Because 3 DTL were observed in Phase I, the MTD was set at 40 mg/m2/die for Bendamustine and 10 mg/die for Lenalidomide. DLTs at dose level 1 included: 1 grade 4 cutaneous rash; at dose level 2: 1 grade 4 thrombocytopenia and 1 grade 3 bronchopneumonia with renal dysfunction (Table 2).Among the 15 patients with evaluable data, the grade 3 or 4 AEs observed in ≥10% of patients included neutropenia (20%), thrombocytopenia (13%) and anemia (20%). Two patients died of treatment-related complications: 1 for hematological toxicity and CNS hemorrhage, and 1 for cardiac ischemia.Fifteen patients received at least 2 cycles and were included in the response assessment. The overall response rate was 40% with 1 case achieving complete response and 1 a very good partial response.Until now 7 pts entered the phase II part of the trial.In pretreated patients with relapsed MM, MTD was determined to be Bendamustine 40 mg/m2/die on days 1 and 2, and Lenalidomide 10 mg/m2/die on days 1–21, plus Dexametasone 40 mg/die on days 1, 8, 15, and 22. This BdL schedule was relatively tolerated and showed promising efficacy. Based on the mainly myelosuppressive properties, concomitant treatment with growth factors are recommended for all patients. The toxicity profile of BdL scheme resulted in an acceptable treatment-related toxicity and mortality and induced a good quality responses in a pretreated population of MM pts.No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Abstract 4003

Abstract 3997This icon denotes a clinically relevant abstract

Abstract 2667

The presence of a serum IgM monoclonal component is associated with a spectrum of lymphoid disorders including Waldenström Macroglobulinemia (WM), IgM monoclonal gammopathy of undetermined significance (MGUS) and IgM-related disorders (IgM-RD). Limited information is available on immunoglobulin heavy chain (IGH) gene rearrangement in this setting.The aim of this study was to analyze IGHV-D-J rearrangements in a large series of patients (pts) and to compare the gene usage across different monoclonal IgM disorders.We analyzed 107 pts including 52 WM, 47 IgM MGUS and 8 IgM-RD. Diagnosis was made according to the consensus criteria proposed at the 2nd International Workshop on WM. Mononuclear cells were obtained from bone marrow in all pts. IGHV-D-J rearrangements were amplified and directly sequenced from cDNA using primers specific for each of the leader sequences of HV1-6 subgroups in combination with a joining heavy chain (JH) consensus primer or cμ constant region primer. Sequences were aligned to ImMunoGeneTics sequence directory using the IMGT V-QUEST analysis software.A complete productive monoclonal IGHV-D-J rearrangement was obtained in 84/107 cases (78%). Using a homology cut-off value of 98% to the nearest germline gene, we observed mutated IGHV in 79/84 pts (94%) and unmutated IGHV in 5 (6%). The frequency of IGHV, IGHD and IGHJ gene usage is shown in the table. The most common IGHV subgroup was IGHV3, which was found in 69/84 cases (82%). The individual IGHV genes most frequently used were IGHV3-23 (20/84, 24%) and IGHV3-7 (10/84, 12%). IGHD segments were assignable in 83 out of 84 rearrangements. The most represented IGHD subgroups were IGHD3 (23/83, 28%), IGHD6 (16/83, 19%) and IGHD2 (15/83, 18%). The most common individual IGHD genes were IGHD6-19 (10/83, 12%) and IGHD2-2 (8/83, 10%). The analysis of IGHJ genes showed a preferential usage of IGHJ4 gene (56/84, 67%) and IGHJ4*02 allele (54/84, 64%). The median HCDR3 length was 13 amino acids (range: 5–29). We found an association between IGHV3 and IGHJ4 subgroups (p=0.01), while no association was found between IGHV and IGHD (p=0.8), and between IGHD and IGHJ subgroups (p=0.8).We compared IGH rearrangement features in pts with WM, MGUS and IgM-RD. A complete productive monoclonal IGHV-D-J rearrangement was detected in a higher percentage of WM pts (47/52, 90%) as compared to MGUS (31/47, 66%) and IgM-RD pts (6/8, 75%) (p=0.01). The proportion of mutated IGHV cases was similar in the three groups (p=0.6). Regarding specific gene usage, there was a trend toward a higher usage of IGHV3-23 gene in WM (14/47, 30%) as compared to MGUS (4/31, 13%) (p=0.07). On the contrary, there was no difference in distribution of IGHD subgroups (p=0.13) and IGHJ genes (p=0.5). The median HCDR3 length was similar in WM, MGUS and IgM-RD (p=0.6).We also compared IGHV usage with clinical characteristics of pts. Interestingly, we found that autoimmune manifestations were more frequently observed in pts carrying IGHV4-34 gene (3/4, 75%) as compared to pts using alternative genes (8/80 pts, 10%) (p=0.006). Autoimmune phenomena associated with IGHV4-34 gene were represented by cold agglutinin haemolytic anemia in 2 pts with IgM-RD and 1 with WM.the identification of a monoclonal IGHV-D-J rearrangement seems more feasible in WM as compared to MGUS and IgM-RD. In all three groups, the majority of cases are mutated, confirming the derivation of the clone from a post-germinal center cell. This study shows a preferential usage of VH3 subgroup and in particular of VH3-23 gene, with a trend for a higher usage in WM as compared to other IgM disorders. A higher prevalence of autoimmune manifestations was observed in pts carrying VH4-34 gene.No relevant conflicts of interest to declare.

Multiple myeloma (MM) accounts for about 14% of all newly diagnosed haematological cancers, and it is estimated that its incidence will rise considerably due to an increasingly aging population in the Western world. Treatment of myeloma has changed in the past decade leading to a possibility of reaching a complete remission (CR) of nearly 50%, a median survival of 5 years, and a 10-year survival rate of 20%. Most of the recent treatment strategies do not require hospitalization so that many patients spend a considerable amount of time at home managing all the difficulties related to the therapies often with little support. Even though this physically disabling and deteriorating condition has a great impact on patients, little is known about their (unmet) needs and quality of life (QOL).The purpose of this qualitative study was to identify dominant themes, links between domains of QoL from the patients' perspective and how these domains influence their expectations regarding QoL in patients with multiple myeloma, trying to identify possible interventional instruments. The sample consisted of 34 patients treated in 9 Italian Centres: 16 women and 18 men; median age 65 years (range 35–77); with a first diagnosis of MM between 1982 and 2009 (median time since diagnosis 3 years ). From July 2009 to Nov 2009, 34 indepth interviews (60 minutes each) were conducted by clinical psychologists. Data from individual interviews were audiotaped and transcribed and then analysed with the “Text Emotional Analysis”, a methodology based on clinical-psychological models and on statistical multivariate analysis techniques.The analysis, conducted with the statistical software Alceste (Analyse des Léxèmes Cooccurrents dans les Enoncés Simples d'un Texte), highlighted 4 word clusters (Table 1: the words that characterize the clusters are reported in the table with a decreasing χ2 value that indicates the importance of the single words in the belonging clusters): Cluster 1 “The relationship with family and friends”; Cluster 2 “The relationship with pain and drugs”; Cluster 3 “The elaboration of the experience”; Cluster 4 “The relationship with physicians and the hospital”.The position of the different clusters in the factorial space can also originate a second kind of analysis that is based on the relation between clusters (Table 2: values of the relationships between Clusters and Factors). On the first factor, cluster 4 and cluster 1 oppose themselves. This is the factor of relationships: the new relationships (the physician and the hospital) oppose to the old relationships (the family); the socialization with the new environment (positively connoted: attention, professionalism, commitment, ability) that is in opposition with the isolation and the shelter of the family (children, family, wife, mother, home). On the second factor, Cluster 2 and Cluster 1 oppose themselves. This is the factor that highlights the complexity of the experience towards the body due to the disease and the drugs (pain, effects, improvements, results, care, discomfort). The third factor is characterized by cluster 3 and expresses coping strategies towards ones condition (shame, companion, emotions, to get accustomed to).This study shows that one of the most important aspects for patients affected by MM is the creation/reorganization of all relationships. The patient's psychological dimension that defines the relationship with the haematologist is driven by an “all-absorbing” taking in charge of the physician fantasy, that often clashes with the hospital practicality. The relationship with other patients, with others that live the same experience, so called “companion” (from latin cum panis, who eats the same bread). Moving on from the results of this research, in the period of May 2010-July 2010, a first intervention was performed. In 5 pilot centres seminars were conducted by clinical psychologists in order to let patients interact with their physicians in a dedicated “space” different from a waiting room or an informative seminar. More than 100 people participated between patients, family members, physicians and nurses. With the findings of this research a questionnaire will be designed and administered to a wider multiple myeloma patient sample.Pelagalli: Celgene: Research Funding. Boccadoro:Celgene, Janssen-Cilag: Consultancy, scientific advisory board, research support. Petrucci:Janssen-Cilag, Celgene: Honoraria.

No relevant conflicts of interest to declare.

This study aimed at evaluating the impact of three different pre-transplant therapies on the outcome of patients (pts) eligible for high-dose therapy.two-hundred sixty eight newly diagnosed MM pts aged £65 years, Durie-Salmon stage III, II, or I in progression, were consecutively enrolled from 2000 to 2007 in three different protocols, with three different pre-transplant therapy: Group 1: (145 pts) 3 pulse-VAD cycles; Group 2: (67 pts) 3 pulse-VAD cycles plus 3 Thal-Dex cycles (thalidomide at the dose of 100 mg/day orally at bedtime, continuously for 3 months, oral dexamethasone at the dose of 20 mg on days 1-4 and 14-17 every 28 days); Group 3: (57pts) 4 Vel-Dex courses (Bortezomib 1.3 mg/m2 i.v. on days 1, 4, 8, 11; oral Dexamethasone 40 mg on days 1-4 and 8-11 every 3 weeks). After induction all pts received two DCEP-short cycles as mobilization (oral Dexamethasone 40 mg/day on days 1-4 + Cyclophosphamide 700 mg/m2/day i.v., Etoposide 100 mg/ m2/day i.v., cisPlatin 25 mg/m2/day for 2 days) with peripheral blood stem-cell (PBSC) collection prompted by G-CSF followed by one or two transplants (Tx) with melphalan 200 mg/m2 as conditioning regimen. Response was defined according to IMWG uniform criteria. Pts were considered responsive when obtaining at least a PR.pts in the three group were similar for age, gender, Ig type, ISS stage. A significant higher percentage of Durie and Salmon stages III was found in group 3 (83% vs 68% in group 1 and 67% in group 2, p=0.0002). The median follow-up was 46 (1-150) months for group 1, 43 (1-68) months for group 2, and 29.7 (1-79) months for group 3. At the time of this analysis in the three groups 51%, 65%, 90% of transplanted pts respectively were still alive, and progression after transplant was registered in 84%, 80%, 50% respectively. Patient flow before Tx was similar (p=0.45): 19% in group 1, 27% in group 2, 23% in group 3. In group 1, 2% of pts went off-study after VAD, and 17% after mobilization phase. In group 2, patient flow was equally distributed: 7% after pulse VAD, 10% after thal-dex, 9% after DCEP. In group 3, 12% of the pts went off-study after Vel-Dex, 11% after DCEP. Table 1 summarized responses. In group 3 (Vel-Dex) response was better along all protocol phases with respect to group 1 or 2 (p<0.00001). The number of responsive pts progressively increased from 87% after Vel-Dex (CR 31%), to 96% after transplant (CR 38%). Response rates of group 1 and 2 patients were not significantly different either after induction (p=0.6), after DCEP (p=0.5), and after Tx (p=0.65). On intention to treat basis, vel-dex induction produced a better, although not significant, PFS (34.6 months vs 29 in group 1 and 26.8 in group 2, p=0.56). OS were not statistically different among the three groups, event though the different follow-up could affect the analysis (median OS 110 in group 1, 66 months in group 2, and not reached in group 3, p=0.37). In multivariate analysis PFS was improved only by the achievement of CR (p=0.001). No significant difference was observed between VGPR or PR (p=0.43).In this study, only CR not VGPR impacts on the outcome. Vel-Dex producing a significant high CR rate after TX (38%), seems to improve survival of MM patients candidate to high-dose therapy with respect to conventional pre-transplant strategies.Morra: Roche:.

An increased incidence of second cancers has been reported in some lymphoproliferative disorders. Whether the predisposition to other malignancies is due to disease-related immune-suppression rather than to the carcinogenic role of therapy given to treat the hematologic disease is still poorly understood.The aims of this study were to assess the frequency, characteristics and factors predicting second cancers in patients with WM and to evaluate whether WM patients are at increased risk of developing other malignancies as compared to an age- and sex-matched control population.The clinical records of 220 consecutive WM patients seen in two Hematologic centres of Northern Italy from 1980 to 2008 were reviewed. All cancers, with exception of non-melanoma skin cancers, were considered for this analysis. Standardized incidence ratios (SIRs), defined as the ratio between observed and expected cases, were used to compare the incidence of second cancers in WM with that of the general population. The number of expected cancers was obtained from age, sex and calendar-specific incidence rates reported by AIRTUM (Associazione Italiana Registri Tumori) for Northern Italy. A multivariate Cox proportional hazards regression model was used to examine risk factors for the development of second cancers. Therapy was analyzed as a time-dependent covariate.The median age of patients was 61 years (range: 26-86), 131 (60%) were males and 89 females (40%). The median follow-up was 4.8 years (range: 0.5-25). Overall, 136 patients (62%) with symptomatic WM received therapy, whereas a watch-and-wait policy was adopted in 84 patients (38%) with asymptomatic WM. Among treated patients, first-line therapy consisted of chlorambucil in 93 cases (68%), cyclophosphamide-based regimens in 15 (11%) and nucleoside analogs-containing regimens in 17 (13%). Rituximab was associated to chemotherapy in 19 patients (14%). Details on therapy were not available in 11 cases (8%). Overall, 52 second cancers were observed in 49 patients (22%). Forty-six patients (94%) had one malignancy and 3 (6%) developed two cancers. The types of cancer were: gastrointestinal (n=9, 17%), lung (n=8, 15%), breast (n=7, 13%), urinary tract (n=6, 11%), prostate (n=5, 10%), diffuse large B cell lymphoma (n=5, 10%), myelodysplastic syndrome/acute leukemia (n=3, 6%), brain (n=3, 6%), thyroid (n=2, 4%), mouth (n=2, 4%), other cancers (n=2, 4%). The diagnosis of cancer preceded that of WM in 13 cases (27%), was concomitant (within 3 months) in 6 (12%) and subsequent in 30 (61%). The median time from diagnosis of WM to the occurrence of a subsequent cancer was 4.3 years (range: 0.2-12.9). The cumulative probability of developing a second cancer after WM was respectively 11% at 5 years, 21% at 10 years and 33% at 15 years. As compared to the control population, the risk of second cancer in WM was 1.66 times higher than expected (95% CI: 1.16-2.37, p=0.005), without significant difference between males and females (p=0.7). In multivariate analysis, the risk of second cancer was not influenced by age (p=0.91), sex (p=0.45), reduction of IgG (p=0.91) or IgA (p=0.58) levels. In a time-dependent analysis, therapy given for WM did not increase the risk of developing a second malignancy (hazard ratio: 1.12, p=0.76).This study shows that WM are at higher risk of developing second cancers as compared to the general population. We did not find an association between the occurrence of second cancers and treatment of WM. Disease-related immune-suppression may predispose WM patients to develop other malignancies.No relevant conflicts of interest to declare.

Background.Monoclonal gammopathy of undetermined significance (MGUS) is defined by the presence of a serum M-protein <3 g/dL, bone marrow plasma cells (BMPC) <10% and absence of end-organ damage. The risk of malignant transformation is 1% per year. Size and type of M-protein and an abnormal serum free-light chains (FLC) ratio at diagnosis are reported as the main risk factors for transformation.

Introduction: Lenalidomide is effective in the treatment of multiple myeloma (MM). The MM-009 and MM-010 randomized, double-blind, placebo-controlled phase III trials showed that lenalidomide in combination with dexamethasone induced significantly higher overall response (OR), and longer median time-to-progression (TTP) than dexamethasone alone in patients with relapsed or refractory MM (Weber et al, NEJM 2007; Dimopoulos et al, NEJM 2007). Previously identified predictors of high-risk disease and poor prognosis in MM include age (≥ 65 vs. < 65 years), Eastern Cooperative Oncology Group (ECOG) performance status (ECOG score ≥ 1 vs. 0), IgA status (IgA MM vs. non-IgA MM), disease stage (Durie-Salmon stage III vs. I–II), and β2-microglobulin level (> 2.5 mg/L vs. ≤ 2.5 mg/L). Here, we compared safety and efficacy outcomes of lenalidomide plus dexamethasone in patients with or without these high-risk factors. Methods: Patients with or without high-risk factors, pooled from MM-009 and MM-010, were randomized to receive lenalidomide (25 mg/day on days 1–21 of each 28-day cycle) plus dexamethasone (40 mg/day on days 1–4, 9–12, and 17–20 of each 28-day cycle for 4 cycles, with 40 mg/day on days 1–4 only from cycle 5 onwards). OR and TTP were based on data obtained before unblinding (June 2005 [MM-009] and August 2005 [MM-010]). Results: OR rate and median TTP were comparable between low- and high-risk patients based on age, ECOG score, IgA status, and Durie-Salmon disease stage. Patients with β2-microglobulin ≤ 2.5 mg/L had significantly better OR and TTP than those with β2-microglobulin >2.5 mg/L (Table). Grade 3 or 4 adverse events for the different subgroups were similar to those observed for the overall study population. Most grade 3 or 4 adverse events were similar between high-risk and low-risk groups. Significant differences in grade 3 or 4 adverse events were neutropenia for patients with Durie-Salmon stage III vs. I–II (40% vs. 28%, p=0.03), thrombocytopenia for ≥ 65 years vs. < 65 years (17% vs. 9%, p=0.03) and those with β2-microglobulin ≤ 2.5 mg/L vs. >2.5 mg/L (16% vs. 7%, p=0.03), and anemia for those with β2-microglobulin ≤ 2.5 mg/L vs. >2.5 mg/L (15% vs. 1%, p=0.0001). Grade 3 or 4 peripheral neuropathy was uncommon (≤2%) for all subgroups and not significantly different between those with high- and those with low-risk features. Conclusion: High OR rates, long TTP and manageable adverse events were observed with lenalidomide plus dexamethasone for patients with high-risk features. Advanced age, high ECOG score, presence of IgA, and advanced Durie-Salmon stage did not affect efficacy outcomes. Patients with high β2-microglobulin levels did have lower efficacy and more adverse events. Risk group OR rate, % P Median, TTP months P < 65 years (n=192) 61 0.73 11.1 0.91 ≥ 65 years (n=161) 60 13.2 ECOG 0 (n=152) 59 0.52 10.2 0.30 ECOG ≥ 1 (n=192) 62 13.1 Non-IgA (n=72) 57 0.10 11.2 0.65 IgA (n=267) 68 10.2 Durie-Salmon I–II (n=123) 61 0.89 13.6 0.21 Durie-Salmon III (n=229) 60 10.6 β2-microglobulin ≤ 2.5 mg/L (n=103) 73 0.002 15.2 0.004 β2-microglobulin > 2.5 mg/L (n=250) 56 9.5

Extramedullary myeloma (EMM) at diagnosis or during the course of the disease is rare and often anecdotal. We reviewed the records of 965 consecutive MM pts diagnosed and followed from 1969 to July 2007 in order to evaluate: the overall incidence of EMMs and the changes over time clinical presentation, response to treatment and outcome of EMM pts divided into two subgroups according to the time of appearance, at diagnosis or during the course of the disease. We considered three periods: 1969–1989 (conventional chemotherapy, CCT); 1990–1999 (introduction of high-dose therapy, HDT); 2000–2007, (era of novel agents). The overall incidence of EMM was of 13% (129/965 pts), 87/42 M/F, median age 58 (31–80) years. A prior MGUS was present in 24 pts and a solitary plasmacytoma in 10 (8%). Characteristics at the time of EMM were: 77 pts IgG (60%), 23 IgA (18%), 2 IgM (2%), 16 light chain (12%), 11 not secretory (8%); 29 pts were in stage I, 14 in stage II, 86 in stage III; 30/129 pts (23%) were asymptomatic. More frequently involved sites were: paravertebral (40%), rib cage (32%), pelvis (10%). Multiple localizations were present in 27 pts (21%). A plasmacytic leukemia was observed during the follow-up in 9 pts (7%). The overall median follow-up was 24.4 (2.5–148) months. Seventy-three pts presented EMM at the time of diagnosis with different incidences in the 3 periods: 1969–1989 4.5%, 1990–99 4.3%, 2000–07 12.7%. These pts were treated with HDT in 43 cases (59%) and CCT in 30 (41%). Radiotherapy (RT) was associated in 38 pts (52%). A partial response (PR) was achieved in 49 pts (67%). Progression or relapse were observed in 46 pts (63%) and the median time to progression (TTP) and overall survival (OS) in this subgroup of pts were 17.3 and 21.5 months respectively. The other 56 pts showed an EMM during the course of the disease after a median time of 20 (2–144) months from diagnosis. EMM incidence varied as follows: 1969–1989 2.7%, 1990–99 7.2%, 2000–07 7.4%. Median number of previous lines of therapy was 1 (range: 1–7), including HDT in 22 pts (39%), thalidomide or lenalidomide in 18 (32%), bortezomib in 5 (9%). The median time from HDT to EMM was 17 (2–125) months. Treatment of these pts consisted of CCT in 36 cases (64%), thalidomide in 3 (5%) and bortezomib in 8 (14%). RT was given in 29 cases (52%). Response rate in this subgroup was low, only 30% of pts obtained a PR. The median TTP and OS from the time of appearance of EMM were 4.7 and 6.5 months respectively and the overall survival from the diagnosis was 29.9 months. The two groups of EMM pts were also compared for all the clinical characteristics, response to therapy and outcome. EMM pts at diagnosis showed higher levels of monoclonal component and haemoglobin, and lower bone marrow plasmacytosis with respect to the others. OS from diagnosis was similar in the two groups. In conclusion, our study shows an increased incidence of EMM over time. The more recent increase of EMM at diagnosis might be due to the wider use of more sensitive imaging techniques as CT scan and magnetic resonance, while during the course of the disease after 1990 could be related to the longer survival of pts thanks to the new therapeutic approaches. Anyway, the presence of EMM whether at diagnosis or at progression seems to negatively affect the outcome of pts since the OS is shorter than MM pts without EMM.

Introduction: A phase II multi-center study was performed to investigate the efficacy of Bortezomib with high-dose dexamethasone (Vel-Dex) as induction therapy in multiple myeloma (MM) patients (pts) candidates to high-dose therapy. Methods: Patients were planned to receive 4 courses of Vel-Dex (Bortezomib 1.3 mg/m2 i.v. on days 1, 4, 8, 11; oral Dexamethasone 40 mg on days 1–4 and 8–11 every 3 weeks), followed by 2 courses of DCEP 4 weeks apart with stem cell collection, and a single autologous transplant with melphalan 200 mg/m2. Patients were untreated, aged ≤65 years, with Durie-Salmon stage III, II, or I in progression. Criteria of response were: CR: negative serum/urine immunofixation with <5% bone marrow plasmacytosis (BMPC); nCR: positive serum/urine immunofixation with <5% BMPC; VGPR/PR: reduction of at least 90%/50% of serum/urine monoclonal component (MC), and of BMPC. Adverse events (AE) were graded by the NCI-CTC version 3.0. Mann-Whitney U test was used to correlate response and main prognostic parameters. Results: From March 2006 to June 2007, 52 out of the 54 planned pts entered the protocol. Patient characteristics at enrolment were: male/female 33/19; median age 57 years (37–65); IgG/IgA/light-chain 33/9/10 pts; stage III/II/I in progression 44/5/3 pts; ISS I/II/III 21/14/17 pts; cytogenetic analysis showed del 13 in 54%, t (4;14) in 15%. Thirty-nine of 52 enrolled pts are evaluable for efficacy and toxicity after 4 Vel-Dex courses. Six pts were withdrawn (3 for progression, 2 for toxicity, 1 patient withdrew informed consent). Overall response rate (ORR) was 85%, with 67% major responses (CR 33%, nCR 26%, VGPR 8%), PR 18%, stable disease 7%, progression 8%. No statistically significant correlation was found between response and either age, stage, ISS, or unfavorable cytogenetics. Friedman ANOVA (p=0.00001) and Wilcoxon Matched Pairs (p<.05) tests showed a statistically significant progressive decrease of serum MC after each Vel-Dex cycle. Urine MC and serum free light chain ratio showed a strikingly rapid reduction after the first course with no further statistically significant decrease during the following courses. Regarding toxicity, NCI grade 1 or 2 AE were: infection (19), constipation (16), peripheral neuropathy (13), diarrhea (9), gastritis (6), nausea (5). NCI grade 3 AE were: infection (9) with 5 varicella-zoster, peripheral neuropathy (4), cardiac arrhythmia (2). A single grade 4 AE (fatal sepsis) occurred. At the time of this analysis, 25 pts completed the stem cell mobilization phase. All pts collected adequate number of stem cells (median CD34+ cells 6.2x106/kg, range 3.5–18.0x106/kg, median number of collection procedures 1). Discussion: This study shows that Vel-Dex as first line therapy produces high response rates in MM pts (ORR 85%, major response 67%). Toxicity was generally predictable and manageable. Stem cells were successful harvested in all patients. Vel-Dex appears an effective and safe pre-transplant treatment for younger MM patients.

Background: Bortezomib (VELCADE®) is a first-in-class, reversible proteasome inhibitor with activity in multiple myeloma (MM) and other malignancies. Bortezomib showed significant activity in previous phase 2 and 3 studies in patients (pts) with previously treated MM. This international multicenter open-label phase 3b study allowed expanded access to bortezomib therapy in pts with relapsed/refractory MM treated with ≥ 2 previous lines of therapy. Methods: Pts with MM were eligible if they had received ≥ 2 prior lines of therapy and required treatment due to relapsed or progressive disease. Pts with grade ≥ 2 peripheral neuropathy (PN) were excluded. Pts received 1.3 mg/m2 IV bolus bortezomib on days 1, 4, 8, and 11 of each 3-week cycle for up to 8 cycles; dexamethasone (20 mg/d PO on the day of and day after bortezomib dose) could be added after cycle 2 for progressive disease or after cycle 4 for stable disease. Adverse events (AEs) were assessed beginning at the start of treatment and continuing until 30–42 days after treatment and were graded based on NCI-CTC version 2.0. Efficacy assessment was performed based on changes in disease burden as measured by monoclonal (M)-protein concentration in serum and urine every 2 cycles (6 weeks). Response was assessed using modified SWOG criteria: complete response (CR) was a 100% reduction in M-protein; very good partial response (VGPR), 75–99% reduction; partial response (PR), 50–74% reduction; minimal response (MR), 25–49% reduction; and stable disease, < 25% reduction. Increasing M-protein levels indicated progressive disease. Results: 624 pts in 93 centers from 21 countries received at least 1 dose of treatment and were evaluable for safety (55.3% male; median age 62.7 years). 68% of pts received 3–11 lines of previous therapy. Karnofsky performance status was ≤70 in 25.6% of pts; 141 pts (22.6%) were ≥ 70 years of age. Pts completed a median of 5 cycles of therapy (range 0–13); 39.3% of pts completed all 8 planned cycles. Grade 3/4 treatment-emergent (related and unrelated) AEs were reported in 430 pts (68.9%), with thrombocytopenia (29.2%), neutropenia (13.3%), and anemia (11.7%) the most common hematologic AEs. Grade 3/4 PN was reported in 8.2% of pts. Overall, 165 pts (26.4%) discontinued therapy due to treatment-related AEs. Best responses among evaluable pts (n = 593) included 12.0% CR, 23.1% VGPR, 19.1% PR, and 16.5% MR, for an overall response rate of 70.7%. Median time to first response was 42 days (range 7–125), and median time to best response was 63 days (range 7–235). Conclusions: Bortezomib 1.3 mg/m2 administered biweekly q3 weeks was well tolerated with manageable toxicities in pts with relapsed and/or refractory MM. Response rates with bortezomib were high, even in heavily pretreated pts, inducing > 25% CR/VGPR. This study confirms results from initial clinical trials in a broader population.

Background: In multiple myeloma (MM) patients (pts) undergone high dose therapy, the outcome of the transplant is better if a good response is achieved before the procedure. Therefore, different attempts have been made in intensifying pre-transplant chemotherapy to improve the response. Aim of the study was to evaluate the safety and efficacy of Thal-Dex in improving the response rate after initial VAD therapy. Methods: 61 untreated MM pts aged ≤65 years were addressed to high dose program with a debulking therapy with 3 pulse-VAD cycles followed by Thal-Dex for 3 months at the following schedule: Thal 100 mg/d orally at bed time, continuously for 3 months, Dex 20 mg/d orally on days 1–4 and 14–17 every 28 days. Response at the end of each phase was defined as follows: complete remission (CR), disappearance of serum and urine monoclonal component (MC) by immunofixation and bone marrow plasmocytosis (BMPC) <5%; very good partial remission (VGPR)/partial remission (PR)/minimal response (MR)/stable disease (SD), reduction of at least 90%/50%/25%/<25% of serum and urine MC, and of BMPC; progression, increase of serum and urine MC or BMPC. Toxicity was registered according to WHO classification. Results: Responses after VAD were evaluable in 60 pts: RC 7%, VGPR 38%, PR 27%, MR 10%, SD 10%, progression 8%. Four pts dropped out after pulse-VAD for progression and in 1 for toxicity. Responses after Thal-Dex in 52 evaluable pts were: RC 12%, VGPR 40%, PR 17%, MR 4%, SD 4%, Progression 23%. Three pts dropped-out during Thal-Dex, 1 for progression and 2 for toxicity. Of note, pts who obtained a scarce response to VAD, namely a MR or SD, showed a higher probability (85% of cases) to have a progression during or after the administration of Thal-Dex. Statistical analysis (Kendall Concordance Coefficient (p<0.0001); and non parametric Wilcoxon matched pairs test (p=0.12)) did not show any improvement of the response rate after Thal-Dex with respect to the evaluation after pulse-VAD cycles.The pulse-VAD related toxicity was as follows: 1 died for sepsis after the first pulse-VAD, 5 developed grade 2 WHO infections, 4 developed mild constipation. Side effects during Thal-Dex therapy were: grade 1–2 peripheral neuropathy in 7 pts, grade 1 constipation in 6 pts; 4 pts developed thrombotic events (TVP in 3, and a bowel infarction with subsequent colectomy in one). Conclusions: The combination thalidomide-dexamethasone after pulse-VAD is not effective in improving response rate, and shows an additional toxicity. Thus it does not seem useful for the intensification before transplant.