Prognostic significance of normalized FDG-PET parameters in patients with multiple myeloma undergoing induction chemotherapy and autologous hematopoietic stem cell transplantation: a retrospective single-center evaluation.

PURPOSE: The purpose of this study was to determine retrospectively, through a single-center evaluation, whether FDG PET-CT normalized semi-quantitative parameters may predict response to induction chemotherapy (iChT) and hematopoietic stem cell transplantation (HSCT), as well as disease progression and progression-free survival in multiple myeloma (MM) patients, thus becoming a tool of personalized medicine. METHODS: Patients undergoing iChT and HSCT with baseline and post-treatment FDG PET-CTs from January 2008 to July 2015 were included. The following baseline and post-treatment parameters were obtained: SUVmax, SUVmean, SUVpeak, MTVsum, TLGsum, rPET (lesion SUVmax/liver SUVmax) and qPET (lesion SUVpeak/liver SUVmean). Baseline-to-post-treatment changes (Δ) were also calculated. Metabolic and clinical laboratory progression or response at follow-up were noted; time-to-metabolic-progression (TMP) was defined as the interval from post-treatment scan to eventual progression at follow-up FDG PET-CTs. Possible association between each functional parameter and metabolic/clinical-laboratory progression or response was determined. Kaplan-Meier curves allowed to depict the TMP trend according to FDG PET-CT parameters. RESULTS: Twenty-eight patients were included. Significantly higher ΔrPET and ΔqPET values were observed in ten patients with "metabolic response", with respect to 18 patients having "metabolic progression" (median 0.62 [IQR 0.32 - 1.34] vs median 0.00 [IQR -0.25 - 0.49] for ΔrPET; P = 0.045; median 0.51 [IQR 0.32 - 1.13] vs median 0.00 [IQR -0.31 - 0.67] for ΔqPET; P = 0.035). Neither normalized nor non normalized parameters differed significantly between the 20 patients with "clinical-laboratory response" and the eight patients with "clinical-laboratory progression". ΔrPET value lower than 0.38 and ΔqPET value lower than 0.27 predicted a significantly shorter TMP (P = 0.003 and P = 0.005, respectively). CONCLUSIONS: Normalized semi-quantitative parameters are effective in predicting persistent response to treatment and shorter TMP in patients with MM undergoing iChT and HSCT.

Cyclophosphamide's addition in relapsed/refractory multiple myeloma patients with biochemical progression during lenalidomide-dexamethasone treatment.

OBJECTIVE: The aim of this study was to evaluate the addition of cyclophosphamide in relapsed-refractory multiple myeloma patients (RRMM) who experienced biochemical relapse or progression without CRAB, during treatment with lenalidomide and dexamethasone (Rd), to slow down the progression in active relapse. METHODS: This analysis included 31 patients with RRMM treated with Rd who received cyclophosphamide (CRd) at biochemical relapse. The CRd regimen was continued until disease progression. RESULTS: The median number of CRd cycles administered was 8 (range: 1-35). A response was observed in 9 (29%) patients. After a median observation time of 11 months, the median overall survival (OS) from the beginning of CRd was 17.7 months. The median progression-free survival (PFS) from the beginning of CRd was 13.1 months. CONCLUSION: The addition of cyclophosphamide delays the progression in patients who present a biochemical relapse during Rd treatment. The response rate and the duration of PFS obtained with minimal toxicities and low costs induced us to setting up a randomized clinical trial.

Venous thromboembolism in multiple myeloma.

As for other malignancies, multiple myeloma is associated with an increased risk of venous thromboembolism (VTE). The incidence of VTE is estimated as 8 to 22 per 1,000 person-years; risk factors can be patient related (advanced age, other risk factors shared with the general population), disease related, and treatment related. Disease-related risk factors can derive from the monoclonal component (rarely hyperviscosity or inhibition of natural anticoagulants) or hypercoagulability sustained by inflammatory cytokines (increased von Willebrand factor, factor VIII, fibrinogen levels, decreased protein S levels, acquired activated protein C resistance). The 1 to 2% baseline of incident VTE associated with conventional therapies as melphalan and prednisone is at least doubled by the use of doxorubicin or other chemotherapeutic agents. The VTE rate associated with thalidomide or lenalidomide as monotherapy is similar, whereas combination with high-dose dexamethasone or multiple chemotherapeutic agents induces a multiplicative effect on the VTE rate up to 25%. Low-molecular-weight heparin (LMWH), fixed low-dose warfarin, and aspirin are acceptable strategies for antithrombotic prophylaxis, reducing VTE to 5 to 8% in thalidomide-treated patients and 1 to 3% in lenalidomide-treated patients. LMWH shows an advantage in efficacy not statistically significant. Prophylaxis should be tailored considering individual risk factors for VTE, the stage of disease, the possible occurrence of thrombocytopenia, or renal insufficiency.

Arterial and venous thrombosis in patients with monoclonal gammopathy of undetermined significance: incidence and risk factors in a cohort of 1491 patients.

Monoclonal gammopathy of undetermined significance (MGUS) has been associated with an increased risk of thrombosis. We carried out a retrospective multicentre cohort study on 1491 patients with MGUS. In 49 patients (3.3%) MGUS was diagnosed after a thrombotic event. Follow-up details for a period of at least 12 months after diagnosis of MGUS were obtained in 1238 patients who had no recent history of thrombosis (<2 years) prior to diagnosis, for a total of 7334 years. During the follow-up, 33 of 1238 patients (2.7%) experienced thrombosis, with an incidence of 2.5 arterial events and 1.9 venous events per 1000 patient-years. Multivariate analysis showed increased risks of arterial thrombosis in patients with cardiovascular risk factors [hazard ratio (HR) 4.92, 95%confidence interval (CI) 1.42-17.04], and of venous thrombosis in patients with a serum monoclonal (M)-protein level >16 g/l at diagnosis (HR 3.08, 95%CI 1.01-9.36). No thrombosis was recorded in patients who developed multiple myeloma (n = 50) or other neoplastic diseases (n = 21). The incidence of arterial or venous thrombosis in patients with MGUS did not increase relative to that reported in the general population for similarly aged members. Finally, the risk of venous thrombosis did increase when the M-protein concentration exceeded >16 g/l.

Carfilzomib, lenalidomide and dexamethasone followed by a second ASCT is an effective strategy in first relapse multiple myeloma: a study on behalf of the Chronic malignancies working party of the EBMT.

In the setting of a first relapse of multiple myeloma (MM), a second autologous stem cell transplant (ASCT) following carfilzomib-lenalidomide-dexamethasone (KRd) is an option, although there is scarce data concerning this approach. We performed a retrospective study involving 22 EBMT-affiliated centers. Eligible MM patients had received a second-line treatment with KRd induction followed by a second ASCT between 2016 and 2018. Primary objective was to estimate progression-free survival (PFS) and overall survival (OS). Secondary objectives were to assess the response rate and identify significant variables affecting PFS and OS. Fifty-one patients were identified, with a median age of 62 years. Median PFS after ASCT was 29.5 months while 24- and 36-months OS rates were 92.1% and 84.5%, respectively. Variables affecting PFS were an interval over four years between transplants and the achievement of a very good partial response (VGPR) or better before the relapse ASCT. Our study suggests that a relapse treatment with ASCT after KRd induction is an effective strategy for patients with a lenalidomide-sensitive first relapse. Patients with at least four years of remission after a frontline ASCT and who achieved at least a VGPR after KRd induction appear to benefit the most from this approach.

Consensus for Flow Cytometry Clinical Report on Multiple Myeloma: A Multicenter Harmonization Process Merging Laboratory Experience and Clinical Needs.

Flow cytometry is a highly sensitive and specific approach for discriminating between normal and clonal plasma cells in multiple myeloma. Uniform response criteria after treatment have been established by the International Myeloma Working Group and the EuroFlow Group; however, the way in which flow cytometry data are reported has suffered from no collaborative or multicentre efforts. This study, involving 8 expert laboratories and 12 clinical hematology units of the Lazio region in Italy, aims to produce a uniform and shared report among the various Centres. From the pre-analytical phase to sample processing, data acquisition, analysis, and evaluation of the potential limitations and pitfalls of the entire process, the study reaches a final conclusion shared by laboratories and clinicians according to the most updated principles and recommendations. The aim was to identify the necessary data to be included in the clinical report by using multiple-choice questionnaires at every single stage of the process. An agreement of more than 75% of the laboratories was considered mandatory for the data to be included in the report. By ensuring the operational autonomy of each laboratory, this study provides a clear report that limits subjective interpretations and highlights possible bias in the process, better supporting clinical decision-making.

Prognostic factors associated with progression of smoldering multiple myeloma to symptomatic form.

BACKGROUND: Smoldering multiple myeloma (SMM) presents a high risk of progression to symptomatic MM (sy-MM). Herein, we analyzed some predictors of development of sy-MM. In 144 patients with SMM, we also compared the risk of progression predicted by bone marrow plasma cell (BMPC) involvement on the bone marrow biopsy (BMB) versus bone marrow aspirates (BMA). METHODS: From January 1980 to July 2010, 397 patients with SMM observed in 12 centers of the Multiple Myeloma GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) Latium Working Group have been analyzed. At progression to sy-MM, the severity of clinical presentation was graded according to the need of intensive supportive care. RESULTS: After a median follow-up of 135 months, the cumulative incidence of progression rates to sy-MM were 45%, 55%, and 75% at 10, 15, and 20 years, respectively. Hemoglobin ≤12.5 g/dL, monoclonal component ≥2.5 g/dL, and BMPC ≥60% were the only parameters negatively affecting the cumulative incidence of progression. In particular, 10 of 397 (2.5%) patients with BMPC ≥60% had a 5.6-fold increased risk of fast progression (within 2 years), which occurred with severe clinical manifestations in 62% of cases. BMB was more sensitive for the detection of BMPC involvement, even though BMA was a more reliable indicator of a rapid progression to sy-MM. CONCLUSIONS: The highest risk of rapid evolution to sy-MM and the severity of clinical manifestation at the progression suggest that SMM patients with a BMPC ≥60% should be treated soon after diagnosis. Moreover, BMPC is a more reliable index for progression to sy-MM if assessed by BMA.

Hydroxyurea-related toxicity in 3,411 patients with Ph'-negative MPN.

Hydroxyurea (Hydroxycarbamide; HU) is commonly used for the long-term treatment of patients with Philadelphia-chromosome negative chronic myeloproliferative neoplasms (MPNs). It is considered a first-choice agent for the treatment of these disorders as underlined by the European Leukemia Net Consensus Conference [1], although it is formally approved for this indication in some countries only. The drug is reportedly well tolerated in the large majority of subjects, although systemic and/or localized toxicities have been reported. Consensus criteria for definition of "intolerance" to HU have been described;patients who develop intolerance are candidate for second-line therapy and, more recently, for investigational drugs. However, no epidemiologic information about the occurrence of the most clinically significant HU-associated adverse events is yet available. In this study, the authors report on a multicenter series of 3,411 patients who were treated with HU among which 184, accounting for 5% of total, developed significant drug-related toxicities. These data provide an estimate of the frequency and a detailed characterization of clinically significant HU-related toxicities; these information have relevance for the management of MPN patients who require second-line therapy after developing HU-related intolerance.

Impact of radiotherapy on pain relief and recalcification in plasma cell neoplasms: long-term experience.

PURPOSE: To evaluate the impact of radiotherapy on pain relief and on recalcification in patients with osteolytic lesions due to plasma cell neoplasm. PATIENTS AND METHODS: Pain relief was evaluated according to a 0-10 verbal numerical rating scale (NRS) and recalcification was measured using radiological imaging. RESULTS: From 1996-2007, 52 patients were treated (Table 1). Median total dose was 38 Gy (range, 16-50 Gy). Pain be-fore radiotherapy was reported by 45 of 52 (86.5%) patients (Table 2) as being severe (8 ≤ NRS ≤ 10) in 5 (11%), moderate (5 ≤ NRS ≤ 7) in 27 (60%), and mild in 13 (29%). Pain relief was achieved in 41 of 45 patients (91%): complete relief was obtained in 21 (51.2%) and partial relief in 20 patients (48.8%); patients with severe pain experienced resolution and none present-ed an increase of pain. Drugs reduction/suspension was achieved in 7 of the 21 patients with complete response. Of 42 patients evaluable for recalcification (Table 3), 21 (50%) presented a radiological response, which was identified as complete in 16 (38%). CONCLUSION: Our data confirm the effectiveness of radiotherapy for pain relief, including a reduction in drug intake, and on recalcification, thus, supporting its use in a multidisciplinary approach.

Progression to Symptomatic Multiple Myeloma Predicted by Texture Analysis-Derived Parameters in Patients Without Focal Disease at 18F-FDG PET/CT.

This retrospective study is focused on the possible clinical implications of texture analysis-derived PET parameters in patients with smoldering multiple myeloma. Several texture features are significantly associated with progression to symptomatic multiple myeloma and with a shorter time to progression. The results of this study may lead to early identification of patients who could benefit from specific therapies. BACKGROUND: The aim of the study was to determine whether positron emission tomography parameters derived from texture analysis of axial and peripheral skeleton predict progression to symptomatic multiple myeloma (MM) in patients undergoing 18F-​fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) without evidence of focal sites of 18F-FDG uptake. PATIENTS AND METHODS: Patients with smoldering MM who underwent 18F-FDG PET/CT from May 2014 to June 2018 were retrospectively reviewed. Volumes of interest (VOIs) were placed on T5-T7 and L2-L4, iliac crests, and femoral diaphyses. Dedicated software (LIFEx) allowed us to obtain PET-derived first-, second-, and higher order texture features. Possible associations between PET parameters and progression to symptomatic MM were determined. Kaplan-Meier curves allowed to assess time to progression (TTP) based on the PET parameters. RESULTS: Forty-five patients were included: 26 patients (58%) did not meet the criteria for symptomatic MM, but 19 patients (42%) progressed to symptomatic MM. Several texture features extracted from VOIs placed on iliac crests and femoral diaphyses were significantly associated with progression to symptomatic MM and with a shorter TTP (P < .05); conversely, the above-mentioned parameters extracted from VOIs placed on T5-T7 and L2-L4 did not significantly differ among the patients with regard to their progression to symptomatic MM and length of TTP, except for the gray-level zone length matrix-short-zone low-gray-level emphasis and gray-level zone length matrix-low gray-level zone emphasis. Particularly, second- and higher order texture features showed a significant association with the above-mentioned outcomes. CONCLUSION: Texture features derived from PET may be an expression of subtle disease distribution in the axial and peripheral bone marrow.

Increased risk of recurrent thrombosis in patients with essential thrombocythemia carrying the homozygous JAK2 V617F mutation.

Evidence suggests that the JAK2 V617F mutation is associated with an increased risk of first thrombosis in patients with essential thrombocythemia (ET). Whether this mutation is also a risk factor for recurrent thrombosis is currently unknown. To investigate the impact of the JAK2 V617F mutation on the risk of recurrent thrombosis in patients with ET, we carried out a multicentre retrospective cohort study. We recruited 143 patients with previous arterial (64.4%) or venous major thrombosis (34.8%) or both (0.8%); 98 of them (68.5%) carried the mutation. Thrombosis recurred in 43 of the patients (30%); overall, after adjustment for sex, age, presence of vascular risk factors, and treatment after the first thrombosis, the presence of the JAK2 mutation did not predict recurrence (multivariable hazard ratio, HR, 0.88, 95% CI 0.46-1.68). Indeed, the individuals homozygous for the JAK2 V617F (allele burden >50%) mutation had an increased risk of recurrence in comparison with wild-type patients (HR 6.15, 95% CI 1.51-24.92). In conclusion, a homozygous JAK2 V617F mutation is an independent risk factor for recurrent thrombosis in patients with ET.

Leukocytosis is a risk factor for recurrent arterial thrombosis in young patients with polycythemia vera and essential thrombocythemia.

There is evidence that leukocytosis is associated with an increased risk of first thrombosis in patients with polycythemia vera (PV) and essential thrombocythemia (ET). Whether it is a risk factor for recurrent thrombosis too is currently unknown. In the frame of a multicenter retrospective cohort study, we recruited 253 patients with PV (n = 133) or ET (n = 120), who were selected on the basis of a first arterial (70%) or venous major thrombosis (27.6%) or both (2.4%), and who were not receiving cytoreduction at the time of thrombosis. The probability of recurrent thrombosis associated with the leukocyte count recorded at the time of the first thrombosis was estimated by a receiver operating characteristic analysis and a multivariable Cox proportional hazards regression model. Thrombosis recurred in 78 patients (30.7%); multivariable analysis showed an independent risk of arterial recurrence (hazard ratio [HR] 2.16, 95% CI 1.12-4.18) in patients with a leukocyte count that was >12.4 x 10(9)/L at the time of the first thrombotic episode. The prognostic role for leukocytosis was age-related, as it was only significant in patients that were aged <60 years (HR for arterial recurrence 3.35, 95% CI 1.22-9.19).

Influence of the JAK2 V617F mutation and inherited thrombophilia on the thrombotic risk among patients with essential thrombocythemia.

It is uncertain whether the JAK2 V617F mutation increases the thrombotic risk in patients with essential thrombocythemia, and it is unknown whether inherited thrombophilia is an additive risk factor in mutated subjects. We studied 132 patients with essential thrombocythemia, 38 of them (29%) with a history of thrombosis. The JAK2 mutation was present in 83 (63%), and inherited thrombophilia in 7. The mutated patients <60 years had a relative risk (RR) for thrombosis at any time of 3.83 (95%CI 1.27-11.49) in comparison with wild-type patients; in those with both the mutation and thrombophilia the RR was 2.23 (95%CI 1.57-3.18) and 7.66 (95%CI 2.66-22.03) in comparison with mutated or wild-type patients without thrombophilia, respectively. During the follow-up, only the homozygotes for JAK2 V617F were more prone to thrombosis (RR 17.25, 95%CI 2.33-127.4). Among the patients >60 years, no increase in RR was associated with the JAK2 mutation. In conclusion, in the younger patients with ET the thrombotic risk is higher in the JAK2 V617F-mutated and is further increased by the presence of inherited thrombophilia.

The risk of symptomatic pulmonary embolism due to proximal deep venous thrombosis differs in patients with different types of inherited thrombophilia.

It is uncertain whether the presence of inherited thrombophilia influences the risk of developing symptomatic pulmonary embolism (PE) and whether different thrombophilic alterations are associated with different risks of symptomatic PE. To investigate such issue, we retrospectively studied 920 patients with proximal deep vein thrombosis (DVT) of the legs with or without symptomatic PE referred for thrombophilia screening; patients with overt cancer or antiphospholipid antibodies had been excluded. Three hundred fifty-four patients (38.5%) had deficiency of antithrombin (AT, n = 16), protein C (PC, n = 26), protein S (PS, n = 22), factor V Leiden (FVL, n = 168), prothrombin G20210A (PT-GA, n = 87), or multiple abnormalities (n = 35), and 566 had none of the studied thrombophilic abnormalities. Symptomatic PE complicated the first DVT in 242 patients (26%); the risk of PE was increased in patients with AT deficiency (relative risk [RR] 2.4, 95% confidence interval [CI] 1.6-3.6) or with PT-GA (RR 1.5, 95%CI 1.1-2.0) and decreased in those with FVL (RR 0.7, 95%CI 0.5-1.0) in comparison with those with unknown inherited defect. These data suggest that patients with proximal DVT have different risks of symptomatic PE according to the type of inherited thrombophilia.

Early diagnosis followed by front-line autologous peripheral blood stem cell transplantation for patients affected by POEMS syndrome.

The acronym POEMS refers to polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes. This disease is progressive and weakening for patients and lead to death generally for neurological problem without therapy. We treated four patients affected by POEMS syndrome with front-line chemotherapy and autologous peripheral blood stem cell transplantation (aPBSCT). After a median follow-up of 40.5 months (range 12-52), all patients are alive with slow but progressive improvement in neurological disease, skin changes, performance status and without evidence of clonal plasmacytosis and organomegaly. In conclusion early diagnosis is crucial to obtain best response and improve clinical outcome.

Recurrent thrombosis in patients with polycythemia vera and essential thrombocythemia: incidence, risk factors, and effect of treatments.

BACKGROUND: Prior thrombosis is a well-established risk factor for re-thrombosis in polycythemia vera and essential thrombocythemia but scarce data are available on the rate of re-thrombosis and the optimal strategy for prevention of recurrence. DESIGN AND METHODS: We retrospectively estimated the rate of recurrence in a multicenter cohort of 494 patients (poly-cythemia vera/essential thrombocythemia 235/259) with previous arterial (67.6%) or venous thrombosis (31%) or both (1.4%). First thrombosis was cerebrovascular disease in 191 cases, acute coronary syndrome in 106, peripheral arterial thrombosis in 44, and venous thromboembolism in 160. Microcirculatory events were not computed. RESULTS: Thrombosis recurred in 166 patients (33.6%), with an incidence of 7.6% patient-years. Sex, diagnosis (polycythemia vera or essential thrombocythemia), and presence of vascular risk factors did not predict recurrence, whereas age >60 years did (multivariable hazard ratio [HR], 1.67; 95% confidence interval [CI] 1.19-2.32). Increased leukocyte count at the time of the first thrombosis was a risk factor for recurrence in patients <60 years old (HR 3.55; 95% CI 1.02-12.25). Cytoreduction halved the risk in the overall cohort (HR 0.53; 95% CI 0.38-0.73) and the combination with antiplatelet agents or oral anticoagulants was more effective than administration of single drugs. Significant prevention of rethrombosis was independently achieved in patients with venous thromboembolism by both oral anticoagulants (HR 0.32; 95% CI 0.15-0.64) and antiplatelet agents (HR 0.42; 95% CI 0.22-0.77), in those with acute coronary syndrome by cytoreduction (HR 0.30; 95% CI 0.13-0.68), and in those with cerebrovascular disease by antiplatelet agents (HR 0.33; 95% CI 0.16-0.66). The overall incidence of major bleeding was 0.9% patient-years and rose to 2.8% in patients receiving both antiplatelet and anti-vitamin K agents. CONCLUSIONS: In patients with polycythemia vera and essential thrombocythemia, cytoreduction protects against recurrent thrombosis, particularly after acute coronary syndrome. The contemporary use of oral anticoagulants (after venous thromboembolism) or antiplatelet agents (after cerebrovascular disease or venous thromboembolism) further improves the protective effect. Such findings call for prospective studies aimed at investigating whether strategies tailored according to the type of first thrombosis could improve prevention of recurrences.

Role of flow-cytometric immunophenotyping in prediction of BCR/ABL1 gene rearrangement in adult B-cell acute lymphoblastic leukemia.

We performed a retrospective analysis of 88 adult patients with B-ALL diagnosed in our center by a flow-cytometric assessment. Immunophenotypic expression of leukemic cells was explored by simultaneous evaluation of positivity, percentage of expressing cells and median fluorescence intensity (MFI). BCR/ABL1 fusion transcripts were assessed by RT-PCR analysis and were identified in 36 patients (40.9%). CD10 and CD34 were positive in the totality of BCR/ABL1-positive cases. Patients with gene rearrangement had a greater frequency of CD66c, CD13 and CD33 positivity compared with BCR/ABL1-negative cases. Moreover, BCR/ABL1-positive cases exhibited a greater median percentage and MFI values of CD13, CD33, CD66c, CD10, CD34 and CD25 expressions, but a lower median percentage and MFI values of CD38 and CD22 expressions than patients without gene rearrangement. Multivariate logistic regression analysis showed that CD10, CD38 and CD13 expressions were independent predictors for the presence of BCR/ABL1 rearrangement. Predictive probabilities of molecular occurrence based on these markers are proposed. © 2017 International Clinical Cytometry Society.