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Systemic amyloidosis arises from monoclonal CD38+ plasma cells that produce misfolded immunoglobulin light chains, which form amyloid fibrils that are deposited into different tissues, leading to organ damage. Daratumumab is a human IgG/k monoclonal antibody that targets CD38, a glycoprotein uniformly expressed on human plasma cells. Daratumumab has been utilized in recent years with unprecedented responses in multiple myeloma. In patients with relapsed or refractory AL amyloidosis, daratumumab has shown promising efficacy in terms of hematologic responses and improvement in organ function. Here, we report real-life treatment with Daratumumab in 33 AL amyloidosis patients treated within the Regional Tuscan Myeloma network at 5 centers with associated MGUS or SMM (n = 15) or symptomatic MM (n = 18). Patients were treated at relapsed/refractory disease stages (n = 29) with a median of one previous line of therapy or at diagnosis (n = 4). Daratumumab showed good efficacy, representing 60% of good hematological responses and 50% of organ responses in a real-life population of patients with an acceptable toxicity profile. [ABSTRACT FROM AUTHOR]

In recent years, the clinical outcome of multiple myeloma (MM) patients has improved due to the introduction of several new agents and of immunotherapy. The lenalidomide starting dose was reduced in seven patients (16%) according to the renal function, mainly due to amyloidosis; only one patient received a 5 mg dose while on dialysis treatment following renal failure due to MM relapse. At the time of analysis, 32 (73%) patients were currently on treatment whereas twelve patients (27%) discontinued Dara-Rd combination mainly because of disease progression (81%). [Extracted from the article]

Objectives: ASCT is currently the "gold standard" first‐line treatment for multiple myeloma patients younger than 65 years old, and limited data on efficacy and safety in older patients are available. Methods: We retrospectively analyzed a cohort of 83 newly diagnosed multiple myeloma patients aged 65 or older. All patients were evaluated for fitness at diagnosis and after bortezomib‐based induction treatment. Results and conclusions: All patients collected an adequate PBSC graft, mainly after G‐CSF plus cyclophosphamide; a median of 6.47 × 106/kg CD34 + cells was collected. The conditioning regimen consisted of melphalan 100, 140 and 200 mg/m2 in 40, 15 and 28 patients, respectively. Median time to neutrophils' and platelets' recovery was 11 and 12 days, respectively. Adverse events of any grade were referred by 40% of patients. The overall response rate was 93%, CR/sCR were 39%. Median PFS was 35 months; median OS was not reached. In our study cohort, the achievement of at least VGPR after induction therapy and the obtainment of CR/sCR after ASCT are the only parameters that were associated with an improved PFS. ASCT is an effective and safe first‐line treatment approach, a careful patients selection reduce the toxicity of the procedure. [ABSTRACT FROM AUTHOR]

Objective: We investigate safety and efficacy in common clinical practice of the combination of carfilzomib and dexamethasone (Kd56) approved for the ENDEAVOR trial for the treatment of relapsed or refractory multiple myeloma. Methods: We retro‐prospective analyzed 75 patients in three centers in Tuscany, 48 of whom had a clinically relevant comorbidity and 50 of whom were older than 65 years, treated with a median use in the fourth line of therapy. We assessed the efficacy based on the International Myeloma Working Group criteria. Results: The overall response rate was 60%. Median PFS was 10 months in the general cohort; in patients treated for more than 1 cycle of therapy PFS was 12 months. Quality of response to Kd56 treatment was found to positively impact PFS. Refractory status to previous line of therapy or to lenalidomide or an history of exposure to pomalidomide, seemed to have no impact on survival. We also showed a low adverse events rate, with no neuropathy events, and a relatively small number of cardiovascular events above grade 3 (10%). Conclusion: Kd56 is an effective and well tolerated regimen in highly pretreated and elderly patients with a good safety profile. [ABSTRACT FROM AUTHOR]

ALK-negative anaplastic large cell lymphoma is a rare T-cell neoplasm with an aggressive course requiring prompt diagnostic work-up and treatment. Few cases of concomitant multiple myeloma and T-cell neoplasm are described in the literature, mainly regarding primary cutaneous anaplastic large cell lymphoma. We present the case of a 65-year-old man, simultaneously diagnosed with ALK-negative anaplastic large cell lymphoma with extranodal localization in the gastrocnemius muscle (stage 1AE) and IgG lambda multiple myeloma (ISS 2, Durie-Salmon stage 3A). Both diseases required therapeutic intervention due to the high proliferative index of lymphoma and the presence of bone lesions attributable to myeloma. The therapeutic program initially included chemotherapy (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone; CHOEP), radiotherapy on the leg, bortezomib, and then consolidation with autologous hematopoietic stem cell transplantation. Despite being on bortezomib treatment and waiting for transplantation, the patient experienced an early myeloma progression that turned out to be refractory to second-line lenalidomide-based treatment. To our knowledge, this is the first case of concurrent diagnosis of extranodal ALK-negative anaplastic large cell lymphoma of the muscle and multiple myeloma. Simultaneous onset can be challenging for clinicians as both diseases may have an aggressive course requiring multiple treatments with increased risk of toxicity and complicated management. [ABSTRACT FROM AUTHOR]

The article offers information on Philadelphia chromosome (Ph)-negative classic myeloproliferative neoplasms (MPNs), the clonal disorders characterized by exaggerated proliferation of terminally differentiated myeloid cells. Drugs used as first-line therapy are hydroxyurea and interferon-α (IFN-α). Criteria for assessing response to treatment in PV and ET are presented.

Objective: A direct comparison of the incidence and risk factors of major thrombosis in essential thrombocythemia (ET) and polycythemia vera (PV) according to their respective JAK2V617F allele burden is the object of this study. Materials and Methods: We compared the rate (%/patients/year) of major thrombosis in 867 ET patients (57% JAK2V617F) with that of 415 PV patients (all JAK2V617F) and examined risk factors. Results: Patients with ET wild-type, ET V617F, and PV showed a rate of thrombosis of 1.4%, 2.1%, and 2.7%/patients/year, respectively. The latter was found to progressively increase according to time of diagnosis. Actuarial probability of arterial and venous thrombosis in the first 5 years of diagnosis was roughly similar in the three groups. While in the subsequent periods, the curves of mutated ET patients diverged from wild-type, and after 10 to 15 years the ET-mutated arm approached PV. Conclusion: These findings support the concept of a continuum between ET JAK2 mutated and PV, not only in reference to the hematological phenotype, but also in terms of vascular events. [Copyright &y& Elsevier]

Subcutaneous (SC) bortezomib-based regimens represent the standard induction therapy prior to autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma patients. Published data are based principally on intravenous (IV) administration: this retrospective observational study aimed to define patients' outcomes upon SC bortezomib administration, before and after ASCT. Of 131 enrolled patients, 86% received bortezomib-dexamethasone plus thalidomide (VTD), 5% plus cyclophosphamide (VCD), and 9% alone (VD), for a median of 4 cycles induction therapy, followed by single (52%) or double (48%) ASCT. 48 patients received consolidation with the same induction regimen. 35% had at least one adverse event, mainly gastrointestinal disorders and peripheral neuropathy (PN). ORR was 93.1%, 97.7% and 100%, after induction, ASCT(s) and consolidation, respectively. Median PFS and PFS2 were 55.8 months and 72 months, respectively, (median follow-up 45.3 months), while median OS was unreached. Concluding, SC bortezomib has similar efficacy with reduced PN than IV administration. [ABSTRACT FROM AUTHOR]

In three of the eight patients with SCD, the presenting rhythm was unknown (Patients 1, 2, 3), pulseless electrical activity (PEA) was the presenting rhythm in Patient 4 and documented ventricular tachyarrhythmia was the presenting rhythm in Patients 5, 6, 7, 8. All eight patients with SCD had known AL cardiac involvement, whereas cardiac involvement was present in 48 (82%) of patients not experiencing SCD. Keywords: chemotherapy; light-chain amyloidosis; AL; ventricular arrhythmias; sudden cardiac death; SCD EN chemotherapy light-chain amyloidosis AL ventricular arrhythmias sudden cardiac death SCD e27 e31 5 05/17/21 20210515 NES 210515 Sudden cardiac death (SCD) is not uncommon in immunoglobulin light-chain amyloidosis (AL) and has been usually attributed to pulseless electrical activity (PEA) or agonal bradycardia occurring in the late stages of the cardiomyopathy.1,2 In addition, the historically reported survival of <12 months in patients with cardiac AL has represented a contraindication to an implantable cardioverter defibrillator (ICD).3 Reports based on small series have further discouraged use of an ICD in this disease.4,5 However, recently, the evolution of treatment options has improved overall survival,6 opening new perspectives in terms of cardiac protection, and calling for further understanding of the arrhythmic profile and SCD prevention in patients with AL. The LVEF in patients experiencing SCD ranged from 45% (mild reduction) to 65% (normal) and in patients without SCD ranged from 30% (severely impaired) to 69%; therefore EF may prove falsely reassuring in discriminating patients at risk of SCD. [Extracted from the article]

A letter to the editor is presented in response to the article "Inconsistencies in the Association Between the JAK2V617F Mutation and PRV-1 Over-Expression Among the Chronic Myeloproliferative Diseases," published in the 2005 issue.

A letter to the editor is presented in response to the article "Chronic myeloproliferative neoplasms and subsequent cancer risk: a Danish population-based cohort study" by Henrick Frederiksen, D.K. Farkas, C.F. Christiansen, H.C. Hasselbalch and H.T. Sorensen in the April 19, 2012 issue.

Light-chain amyloidosis (AL) is considered a rare disease, although few studies have assessed its epidemiology. Therefore, we felt it appropriate to examine the regional incidence of new AL diagnosis at Careggi University Hospital, the only multidisciplinary regional referral centre for amyloidosis serving the Florence metropolitan area, in Italy. At our institution, AL diagnosis was performed by biopsy of abdominal fat pad or of another involved organ, showing amyloid deposits characterised as AL type by immunohistochemistry, optic/immunoelectron microscopy or proteomics [[1]]. [Extracted from the article]

In addition to dysregulated JAK/STAT signaling, activation of the AKT/mTOR pathway occurs in myelofibrosis, a myeloproliferative neoplasm with no approved therapies. We conducted a phase 1/2 study with everolimus, an mTOR inhibitor, in 39 high- or intermediate-risk primary or postpolycythemia vera/postessential thrombocythemia myelofibrosis subjects. Responses were evaluated in 30 patients of phase 2. No dose-limiting toxicity was observed in phase 1 up to 10 mg/d. When this dose was used in phase 2, grade ⩾ 3 toxicities were infrequent; the commonest toxicity was grade 1-2 stomatitis. Rapid and sustained splenomegaly reduction of > 50% and > 30% occurred in 20% and 44% of subjects, respectively. A total of 69% and 80% experienced complete resolution of systemic symptoms and pruritus. Response in leukocytosis, anemia, and thrombocytosis occurred in 15%-25%. Clinical responses were not associated with reduced JAK2V617F burden, circulating CD34+ cells, or cytokine levels, whereas CCDN1 mRNA and phospho-p70S6K level, known targets of mTOR, and WT1 mRNA were identified as possible biomarkers associated with response. Response rate was 60% when European Network for Myelofibrosis criteria were used (8 major, 7 moderate, 3 minor responses) or 23% when IWG-MRT criteria (1 partial response, 6 clinical improvements) were used. These results provide proof-of-concept that targeting mTOR pathway in myelofibrosis may be clinically relevant. [ABSTRACT FROM AUTHOR]

The article discusses osteonecrosis of the jaw associated with zoledronate therapy in a patient with multiple myeloma. A 76-year-old man presented with severe mouth pain, trismus and swallowing difficulties, which had developed following a dental extraction, and steadily progressed until he was able to take liquid food only; speech was impaired and painful. A skeletal survey showed no osteolytic lesions. Therapy with pulsed melphalan/prednisone was started in 2001, together with monthly doses of zoledronate; the disease had remained stable until the current presentation

The clinical and haematological phenotype of patients with myelofibrosis harbouring MPL W515 L/ K mutation has not been thoroughly investigated. Of 217 myelofibrosis subjects, 18 (8·2%) had an MPL mutation, four of which (22%) co-existed with JAK2 V617 F mutation. When compared with MPL wild-type patients, irrespective of JAK2 V617 F status, those with MPL W515 L/ K, were more frequently female, were older (61 years vs. 57 years; P = 0·02), presented with more severe anaemia (haemoglobin, 101 g/l vs. 121 g/l; P = 0·002) and were more likely to require regular transfusional support ( P = 0·012). These data indicate that MPL mutation in myelofibrosis characterises patients with more severe anaemic phenotype. [ABSTRACT FROM AUTHOR]

Although several parameters are useful for risk stratification of patients with acute myeloid leukaemia (AML), there are no firm criteria for predicting response to induction treatment of individual patients. Daily flow cytometry (FC) analysis, carried out during induction treatment in 30 AML patients, showed that the clearance of blasts from peripheral blood (PBC) correlated closely with response, as assessed by bone marrow FC on day 14, and by morphologic analysis at haematopoietic recovery. Therefore, a major treatment outcome can be predicted very early in AML patients, thus providing an opportunity for tailoring treatment modalities from the outset. [ABSTRACT FROM AUTHOR]

Females with the monoclonal type of essential thrombocythaemia (ET), based on the X-chromosome inactivation pattern (XCIP), have previously been shown to present a higher incidence of thrombosis than polyclonal ones. We aimed to assess correlations between XCIP, thrombosis, and three epigenetic markers of ET, namelyPRV-1overexpression, endogenous erythroid colony (EEC) formation, and reduced platelet Mpl content. Fifty-three (60%) of 88 subjects studied had monoclonal myelopoiesis and presented a 32% incidence of major thrombosis compared with 6% of polyclonal subjects (P = 0·009). The frequency of abnormalities ofPRV-1, EEC, or Mpl was similar in monoclonal and polyclonal subjects (respectively, 28%, 48%, 75%, and 37%, 27%, 63%), and none of them correlated with thrombosis. We conclude that the exploited epigenetic markers constitute independent phenotypic variations and are not clustered according to monoclonality of myelopoiesis in ET; none of them could serve as a surrogate marker of thrombotic risk in male subjects with ET. [ABSTRACT FROM AUTHOR]

A letter to the editor discussing the performance of percutaneous vertebroplasty and kyphoplasty in patients with multiple myeloma is presented.

Objective: Expression profiling of microRNA (miRNA) was performed in granulocytes isolated from patients with primary myelofibrosis (PMF), with the aim of identifying abnormally expressed miRNAs in comparison with normal subjects or patients with polycythemia vera (PV) or essential thrombocythemia (ET). Patients and Methods: Using stem loop–primed reverse transcription and TaqMan quantitative real-time polymerase chain reaction, the expression of 156 mature miRNAs was evaluated using pooled granulocytes from PMF patients, either wild-type or JAK2617V>F mutant with >51% allele burden, and control subjects. Differentially expressed miRNAs were then validated on additional control and PMF samples, and also on PV or ET granulocytes. Results: There was a global downregulation of miRNA expression in PMF granulocytes; 60 miRNAs, of 128 called present, displayed differential expression compared to normal samples. Twelve miRNAs, which had been selected based on statistically different expression level, were finally validated. In PMF granulocytes, levels of miR-31, -150, and -95 were significantly lower, while those of miR-190 significantly greater, than control and PV or ET samples; on the other hand, miR-34a, -342, -326, -105, -149, and -147 were similarly reduced in patients with PMF, PV, or ET compared to controls. Increased expression of miR-182 and -183 correlated with JAK2617V>F allele burden. Three in silico–predicted putative target genes (DTR, HMGA2, and MYB), showed deregulated expression in PMF granulocytes that correlated with expression level of regulatory miRNA. Conclusions: A defined miRNA profile distinguishes PMF granulocytes from those of normal subjects and, partially, also from PV or ET patients. [Copyright &y& Elsevier]