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.

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.

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.

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.

Haemostatic alterations induced by treatment with asparaginases and clinical consequences.

The benefit of asparaginase for treating acute lymphoid leukaemia (ALL) has been well established. Native asparaginase derives from Escherichia coli (colaspase) or Erwinia chrysanthemi (crisantaspase); in a third preparation, colaspase is pegylated. Depletion of asparagine leads to decreased synthesis of procoagulant, anticoagulant, and fibrinolytic proteins, with resultant hypercoagulability and greater risk of venous thromboembolism (VTE). Colaspase and crisantaspase are not dose-equivalent, with crisantaspase displaying haemostatic toxicity only at dosages much higher and administered more frequently than those of colaspase. Cerebral venous thrombosis and pulmonary embolism are two life-endangering manifestations that occur during treatment with asparaginase particularly in children and in adults with ALL, respectively. Approximately one-third of VTEs are located in the upper extremities and are central venous line-related. Other risk factors are longer duration of asparaginase treatment and concomitant use of prednisone, anthracyclines, and oral contraceptives. The risk associated with inherited thrombophilia is uncertain but is clearly enhanced by other risk factors or by the use of prednisone. VTE prevention with fresh frozen plasma is not recommended; the efficacy of antithrombin (AT) concentrates has occasionally been reported, but these reports should be confirmed by proper studies, and AT should not be routinely employed. Therapeutic or prophylactic heparin doses are only partially effective, and direct thrombin or factor Xa inhibitors could play significant roles in the near future.

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.

Chlorambucil plus Rituximab as Front-Line Therapy in Elderly/Unfit Patients Affected by B-Cell Chronic Lymphocytic Leukemia: Results of a Single-Centre Experience.

The current standard first line therapy for fit patients with B-CLL/SLL is based on combination of fludarabine-cyclophosphamide and rituximab. However, elderly patients or patients with comorbidities poorly tolerate purine analogue-based chemotherapy and they are often treated with Chlorambucil (Chl) only. However, complete response (CR) and overall response (OR) rates with Chl are relatively low. We now investigated whether the addition of Rituximab to Chl will improve the efficacy without impairing the tolerability in elderly and unfit patients. We included in our study 27 elderly or unfit patients that had not received prior therapy. All patients were treated with Chl (1mg/Kg per 28-day cycle for 8 cycles) plus Rituximab (375 mg/m(2) for the first course and 500 mg/m(2) for subsequent cycles until the 6(th) cycle). We obtained an OR rate of 74%. The most frequent adverse effect was grade 3-4 neutropenia, which occurred in 18.5% of the patients. Infections or grade 3-4 extra-hematological side effects were not recorded. None of the patients required reduction of dose, delay of therapy or hospitalization. Overall, these data suggest that Chl-R is an effective and well tolerated regimen in elderly/unfit patients with CLL.

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.

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.

IgD multiple myeloma a descriptive report of 17 cases: survival and response to therapy.

BACKGROUND: Immunoglobulin D multiple myeloma (MM) is rare and has a poorer prognosis than other MM isotypes. DESIGN AND METHODS: Seventeen patients (pts) diagnosed from 1993 to 2009 with IgD MM were selected from six institutions of Multiple Myeloma Latium-Region GIMEMA Working Group. RESULTS: Median age was 55 years, 14 patients had bone lesions, eight had renal impairment with estimated glomerular filtration rate (eGFR) < 50 ml/min, one serum calcium ≥ 12 mg/dl, 11 had lambda light chains, five stage III of ISS, six with chromosomal abnormalities. Six pts received conventional chemotherapy (CT): five melphalan + steroids based regimens. Eleven underwent high-doses of chemotherapy with autologous stem cell transplantation (HDT/ASCT), five single and six tandem ASCT: six received bortezomib and/or thalidomide as induction therapy and five VAD. Thalidomide maintenance was used in two pts: one in HDT/ASCT and one in CT group; bortezomib was used in one patient after HDT/ASCT. At a median follow up of 38 (range 19-60) and 50 months (range 17-148) for pts treated with CT and HDT/ASCT, respectively, the overall response rate (ORR) was 83% and 90%. In the group of patients treated with CT, median overall survival (OS) was 34 months (95% CI 15- 54 months), median progression free survival (PFS) was 18 months (95% CI 3-33 months) and median duration of response (DOR) was 7 months (95% CI 5-9 months). Median OS, PFS and DOR were not reached at the time of this analysis in the HDT/ASCT group of patients. Death was observed in 27.3% of pts treated with HDT/ASCT and in 66.7% undergone CT. CONCLUSIONS: Despite the retrospective analysis and the small number of pts our study showed that the use of HDT/ASCT seems to improve also the prognosis of IgD MM patients. Treatment options including new drugs, before and after stem cell transplantation, may further improve the outcomes of these patients.

In families with inherited thrombophilia the risk of venous thromboembolism is dependent on the clinical phenotype of the proband.

The utility of laboratory investigation of relatives of individuals with inherited thrombophilia is uncertain. To assess the risk of venous thromboembolism (VTE) among the carriers, we investigated a family cohort of 1,720 relatives of probands with thrombophilia who were evaluated because of VTE (n=1,088), premature arterial thrombosis (n=113), obstetric complication (n=257), or universal screening before pregnancy or hormonal contraception or therapy (n=262); 968 relatives were carriers of thrombophilia. A first deep venous thrombosis (DVT) occurred in 44 carriers and 10 non-carriers during 37,688 and 29,548 observation-years from birth, respectively. The risk of DVT among the carriers compared with non-carriers was estimated as a hazard ratio (HR). If the proband had VTE and factor V Leiden (FVL) and/or prothrombin (PT)20210A, the HR for DVT was 2.77 (95%CI 1.21-4.82) in the carriers overall, and 5.54 (95%CI 3.20-187.00) in those homozygous or double heterozygous for FVL and PT20210A. If the proband had VTE and a deficiency of antithrombin (AT), protein C or S, the HR for DVT was 5.14 (95%CI 0.88-10.03) in the carriers overall, and 12.86 (95%CI 2.46-59.90) in those with AT deficiency. No increase in risk was found among the carriers who were relatives of the probands who were evaluated for reasons other than VTE. In conclusion, familial investigation for inherited thrombophilia seems justified for probands with previous VTE, but appears of doubtful utility for the relatives of probands without VTE. This should be taken with caution regarding families with deficiency of natural anticoagulants, given the low number of cases analysed.