Elotuzumab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma: Extended follow-up of a multicenter, retrospective real-world experience with 321 cases outside of controlled clinical trials.

The ELOQUENT-3 trial demonstrated the superiority of the combination of elotuzumab, pomalidomide, and dexamethasone (EloPd) in terms of efficacy and safety, compared to Pd in relapsed/refractory multiple myeloma (RRMM), who had received at least two prior therapies, including lenalidomide and a proteasome inhibitor. The present study is an 18-month follow-up update of a previously published Italian real-life RRMM cohort of patients treated with EloPd. This revised analysis entered 319 RRMM patients accrued in 41 Italian centers. After a median follow-up of 17.7 months, 213 patients (66.4%) experienced disease progression or died. Median progression-free survival (PFS) and overall survival (OS) were 7.5 and 19.2 months, respectively. The updated multivariate analysis showed a significant reduction of PFS benefit magnitude both in advanced International Staging System (ISS) (II and III) stages and previous exposure to daratumumab cases. Instead, advanced ISS (II and III) stages and more than 2 previous lines of therapy maintained an independent prognostic impact on OS. Major adverse events included grade three-fourths neutropenia (24.9%), anemia (13.4%), lymphocytopenia (15.5%), and thrombocytopenia (10.7%), while infection rates and pneumonia were 19.3% and 8.7%, respectively. A slight increase in the incidence of neutropenia and lymphocytopenia was registered with longer follow-up. In conclusion, our real-world study still confirms that EloPd is a safe and possible therapeutic choice for RRMM. Nevertheless, novel strategies are desirable for those patients exposed to daratumumab.

Prolonged treatment with arsenic trioxide (ATO) and all-trans-retinoic acid (ATRA) for relapsed acute promyelocytic leukemia previously treated with ATRA and chemotherapy.

Prolonged therapy with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is highly effective in newly diagnosed acute promyelocytic leukemia (APL) but there is limited data on the efficacy of this regimen in the relapse setting. We report here on 22 APL patients treated with prolonged ATRA-ATO therapy at the time of disease relapse. Twenty patients obtained molecular complete remission (CRm) after 2 cycles (90%). Of these, two patients underwent hematopoietic stem cell transplant (HSCT) while the remaining proceeded to receive additional cycles (up to a total of 5) of ATRA-ATO. With a median follow-up of 58 months from the time of relapse (range: 21-128 months), the 4-year OS probability was 0.85 (95% CI 0.61-0.94), DFS was 0.74 (95% CI 0.49-0.88), and EFS 0.68 (95% CI 0.45-0.83). Two patients were resistant to ATRA-ATO salvage and five relapsed at a median of 19 months. Of these, four died due to progressive disease while three relapsed achieved a new CRm after further salvage therapy. This experience confirms the potentially curative effect of prolonged ATRA-ATO therapy in relapsed APL, especially in patients with long first complete remission.

Pre-treatment staging of multiple myeloma patients: comparison of whole-body diffusion weighted imaging with whole-body T1-weighted contrast-enhanced imaging.

BACKGROUND: Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of plasma cells. Accurate staging is of pivotal importance in the management of MM. Advanced imaging techniques, such as magnetic resonance imaging (MRI), are increasingly used for the initial diagnosis and staging of MM. PURPOSE: To compare whole-body (WB) MR diffusion-weighted imaging with background body signal suppression (DWIBS) with (WB) MR fat-suppressed T1-weighted contrast-enhanced imaging (T1-CE) in the pre-treatment staging evaluation of multiple myeloma (MM) patients. MATERIAL AND METHODS: Thirty-six patients with MM were included in the study. T1-CE and DWIBS were performed using a 3 T scanner. The Durie-Salmon plus staging system was used. Kappa statistics was used to assess agreement. RESULTS: For all MM stages good to very good agreement was found for both T1-CE and DWIBS. The unweighted kappa statistic indicated a moderate, good and very good agreement between T1-CE and DWIBS for stages I, II, and III, respectively. In particular, in 67% of patients the MM staging according to T1-CE was not different from DWIBS. In the remaining 33% of patients, the MM stage obtained with T1-CE was lower than that provided by DWIBS. CONCLUSION: DWIBS and T1-CE were concordant in the majority of patients. In a minority of cases DWIBS evidenced areas of water restriction that did not correspond to contrast enhancement areas. Studies monitoring therapeutic response in relation to tumour burden and aggressiveness should be performed to assess the clinical relevance of DWIBS findings.

Age and organ damage correlate with poor survival in myeloma patients: meta-analysis of 1435 individual patient data from 4 randomized trials.

Thalidomide and bortezomib are extensively used to treat elderly myeloma patients. In these patients, treatment-related side effects are frequent and full drug doses difficult to tolerate. We retrospectively analyzed data from 1435 elderly patients enrolled in 4 European phase III trials including thalidomide and/or bortezomib. After a median follow up of 33 months (95%CI: 10-56 months), 513 of 1435 patients (36%) died; median overall survival was 50 months (95%CI: 46-60 months). The risk of death was increased in patients aged 75 years or over (HR 1.44, 95%CI: 1.20-1.72; P<0.001), in patients with renal failure (HR 2.02, 95%CI: 1.51-2.70; P<0.001), in those who experienced grade 3-4 infections, cardiac or gastrointestinal adverse events during treatment (HR 2.53, 95%CI: 1.75-3.64; P<0.001) and in those who required drug discontinuation due to adverse events (HR 1.67, 95%CI; 1.12-2.51; P=0.01). This increased risk was restricted to the first six months after occurrence of adverse events or drug discontinuation and declined over time. More intensive approaches, such as the combination of bortezomib-thalidomide, negatively affected outcome. Bortezomib-based combinations may overcome the negative impact of renal failure. Age 75 years or over or renal failure at presentation, occurrence of infections, cardiac or gastrointestinal adverse events negatively affected survival. A detailed geriatric assessment, organ evaluation and less intense individualized approaches are suggested in elderly unfit subjects.

A tryptophan metabolite prevents depletion of circulating endothelial progenitor cells in systemic low-grade inflammation.

Background: Chronic systemic inflammation reduces the bioavailability of circulating endothelial progenitor cells (EPCs). Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme of immune tolerance catalyzing the initial step of tryptophan degradation along the so-called l-kynurenine (l-kyn) pathway, that is induced by inflammatory stimuli and exerts anti-inflammatory effects. A specific relationship between IDO1 activity and circulating EPC numbers has not yet been investigated. Methods: In this study, circulating EPCs were examined in mice treated with low doses of lipopolysaccharide (LPS) to mimic low-grade inflammation. Moreover, the association between IDO1 activity and circulating EPCs was studied in a cohort of 277 patients with variable systemic low-grade inflammation. Results: Repeated low doses of LPS caused a decrease in circulating EPCs and l-kyn supplementation, mimicking IDO1 activation, significantly increased EPC numbers under homeostatic conditions preventing EPC decline in low-grade endotoxemia. Accordingly, in patients with variable systemic low-grade inflammation, there was a significant interaction between IDO1 activity and high-sensitivity C-reactive protein (hs-CRP) in predicting circulating EPCs, with high hs-CRP associated with significantly lower EPCs at low IDO1 activity but not at high IDO1 activity. Interpretation: Overall, these findings demonstrate that systemic low-grade inflammation reduces circulating EPCs. However, high IDO1 activity and l-kyn supplementation limit circulating EPC loss in low-grade inflammation.

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.

Daratumumab combined with dexamethasone and lenalidomide or bortezomib in relapsed/refractory multiple myeloma (RRMM) patients: Report from the multiple myeloma GIMEMA Lazio group.

The multiple myeloma (MM) treatment has changed over the last years due to the introduction of novel drugs. Despite improvements in the MM outcome, MM remains an incurable disease. Daratumumab is a human IgGK monoclonal antibody targeting CD38 with tumor activity associated with immunomodulatory mechanism. In combination with standard of care regimens, including bortezomib (Vd) or lenalidomide (Rd), daratumumab prolonged progression-free survival (PFS) in patients (pts) with relapsed/refractory multiple myeloma (RRMM) and in new diagnosis MM. We report the data of the MM GIMEMA Lazio group in 171 heavily treated pts who received daratumumab, lenalidomide and dexamethasone (DRd) or daratumumab, velcade and dexamethasone (DVd). The overall response rate was 80%, and the overall survival (OS) and PFS were 84% and 77%, respectively. In addition, pts treated with DRd showed a better median PFS compared to pts treated with DVd, at 12 and 24 months, respectively. The most common hematologic treatment-emergent adverse events (TAEs) were neutropenia, thrombocytopenia, and anemia. The most common nonhematologic TAEs were peripheral sensory neuropathy and infections. Our data confirmed that DRd or DVd therapy is effective and safe in RRMM pts, and our real-life analysis could support the physicians regarding the choice of optimal therapy in this setting of pts.

New insight into the catalytic -dependent and -independent roles of METTL3 in sustaining aberrant translation in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by the presence of tyrosine kinase BCR-ABL1 fusion protein, which deregulate transcription and mRNA translation. Tyrosine kinase inhibitors (TKIs) are the first-choice treatment. However, resistance to TKIs remains a challenge to cure CML patients. Here, we reveal that the m6A methyltransferase complex METTL3/METTL14 is upregulated in CML patients and that is required for proliferation of primary CML cells and CML cell lines sensitive and resistant to the TKI imatinib. We demonstrate that depletion of METTL3 strongly impairs global translation efficiency. In particular, our data show that METTL3 is crucial for the expression of genes involved in ribosome biogenesis and translation. Specifically, we found that METTL3 directly regulates the level of PES1 protein identified as an oncogene in several tumors. We propose a model in which nuclear METTL3/METTL14 methyltransferase complex modified nascent transcripts whose translation is enhanced by cytoplasmic localization of METTL3, independently from its catalytic activity. In conclusion, our results point to METTL3 as a novel relevant oncogene in CML and as a promising therapeutic target for TKI resistant CML.

Adherence, persistence and efficacy of dasatinib and nilotinib in the treatment of patients resistant or intolerant to imatinib with chronic myeloid leukemia in chronic phase: an Italian multicenter study over two years in real life.

BACKGROUND: The use of dasatinib and nilotinib in the treatment of patients with chronic myeloid leukemia represents a valid therapeutic option for patients resistant or intolerant to imatinib. In this multicentre study, adherence, persistence and efficacy in real life over two years of treatment were evaluated. MATERIALS AND METHODS: Adherence to treatment was calculated as the ratio between the dose received and the prescribed dose. The dose received was calculated using pharmacy refill data. The persistence with treatment was calculated as the difference between the end and the beginning of the treatment. Efficacy was assigned as Progression-Free Survival (PFS) and Events-Free Survival (EFS) and represented through the Kaplan-Meier curve. RESULTS: The number of patients analysed was 117, 70 treated with dasatinib and 47 with nilotinib. Adherence to treatment for dasatinib and nilotinib at two years was 0.91 and 0.82 respectively. Persistence at two years was 77% while the PFS was 92% for both drugs in the study. CONCLUSION: Adherence to the treatment calculated over two years showed a superiority of dasatinib over nilotinib. Nevertheless, the efficacy in terms of PFS and EFS is superimposable between the two drugs in the study.

Digital PCR improves the quantitation of DMR and the selection of CML candidates to TKIs discontinuation.

Treatment-free remission (TFR) by tyrosine kinase inhibitors (TKI) discontinuation in patients with deep molecular response (DMR) is a paramount goal in the current chronic myeloid leukemia (CML) therapeutic strategy. The best DMR level by real-time quantitative PCR (RT-qPCR) for TKI discontinuation is still a matter of debate. To compare the accuracy of digital PCR (dPCR) and RT-qPCR for BCR-ABL1 transcript levels detection, 142 CML patients were monitored for a median time of 24 months. Digital PCR detected BCR-ABL1 transcripts in the RT-qPCR undetectable cases. The dPCR analysis of the samples, grouped by the MR classes, revealed a significant difference between MR4.0 and MR4.5 (P = 0.0104) or MR5.0 (P = 0.0032). The clinical and hematological characteristics of the patients grouped according to DMR classes (MR4.0 vs MR4.5-5.0 ) were superimposable. Conversely, patients with dPCR values <0.468 BCR-ABL1 copies/µL (as we previously described) showed a longer DMR duration (P = 0.0220) and mainly belonged to MR4.5-5.0 (P = 0.0442) classes compared to patients with higher dPCR values. Among the 142 patients, 111 (78%) discontinued the TKI treatment; among the 111 patients, 24 (22%) lost the MR3.0 or MR4.0 . RT-qPCR was not able to discriminate patients with higher risk of MR loss after discontinuation (P = 0.8100). On the contrary, according to dPCR, 12/25 (48%) patients with BCR-ABL1 values ≥0.468 and 12/86 (14%) patients with BCR-ABL1 values <0.468 lost DMR in this cohort, respectively (P = 0.0003). Treatment-free remission of patients who discontinued TKI with a dPCR <0.468 was significantly higher compared to patients with dPCR ≥ 0.468 (TFR at 2 years 83% vs 52% P = 0.0017, respectively). In conclusion, dPCR resulted in an improved recognition of stable DMR and of candidates to TKI discontinuation.

Recurrent Sweet's syndrome in a patient with multiple myeloma.

We report on a case of Sweet's syndrome associated with multiple myeloma, as harbinger for disease relapse.

Identification of i(X)(p10) as the sole molecular abnormality in atypical chronic myeloid leukemia evolved into acute myeloid leukemia.

The World Health Organization classifies atypical chronic myeloid leukemia (aCML) as a myeloproliferative/myelodisplastic hematological disorder. The primary manifestations are leukocytosis with disgranulopoiesis, absence of basophilia and/or monocytosis, splenomegaly and absence of Philadelphia chromosome or BCR/ABL fusion. Overall 50-65% of patients demonstrate karyotypic abnormalities, although no specific cytogenetic alterations have been associated with this disease. X chromosome alterations have been rarely reported in myeloid malignancies. Although Isodicentric X, idic(X)(q13) is well known in females with myelodysplastic syndromes (MDS), little data are available on X isochromosome and its pathogenetic potential in these disorders. i(X)(p10) is observed in a variety of hematologic malignancies, both myeloid and lymphoid, as a unique abnormality, as well as part of a more complex karyotype, in females and less frequently in male patients. The present report describes the first patient with aCML, with documented isolated i(X)(p10), who developed a secondary acute myeloid leukemia (sAML).

Impact of IFN lambda 3/4 single nucleotide polymorphisms on the cytomegalovirus reactivation in autologous stem cell transplant patients.

Cytomegalovirus (CMV) infection represents one of the main cause mortality after Stem Cell Transplantation. Recently, a protective effect of the T allele of rs12979860 IL28B Single Nucleotide Polymorphisms (SNPs) against CMV infection in the allogenic stem cell transplantation was suggested. We investigate whether the rs12979860 IL28B SNP and the relative rs368234815 (IFNλ4) genotype may affect the incidence of active CMV infection in Autologous stem cell transplantation (Auto-SCT) setting. The study included 99 patients who underwent to Auto-SCT. IL28 and IFNΔ4 SNPs were correlated with CMV reactivation along with other clinical and treatment parameters. CMV reactivation by CMV DNAemia was evaluated once a week until day 100 from Auto-SCT. CMV reactivation was documented in 50% (TT-ΔG/ΔG), 35% (CC-TT/TT) and 29.2% (CT-TT/ΔG) of the patients respectively. No differences in CMV copies number were recorded at reactivation between different IL28/IFNλ4 genotypes. The analysis of patients older than 60 years showed a significantly higher incidence of active CMV infection in the TT-ΔG/ΔG (83%) population with respect to CC-TT/TT (21%) and CT-TT/ΔG (40%) patients. Our data suggest a negative role of TT-ΔG/ΔG genotype in the CMV reactivation in Auto-SCT. The exposure to rituximab and the pre-infusion presence of anti CMV IgG also significantly influenced CMV reactivation.

Dasatinib first-line: Multicentric Italian experience outside clinical trials.

Dasatinib was approved for the treatment of chronic phase (CP) chronic myeloid leukemia (CML) patients in first line therapy based on the demonstration of efficacy and safety reported in patients enrolled in clinical trials. We describe a multicentric Italian "real-life" experience of dasatinib used as frontline treatment outside clinical trials. One hundred and nine patients (median age 54 years) were treated from January 2012 to December 2013. Increased incidence of high risk patients were detected according to stratification (26% according to Sokal score, 19% according to Euro score and 16% according to EUTOS) when compared to company sponsored studies. Median time from diagnosis to start of dasatinib was 18 days. Ten patients received unscheduled starting dose (6 patients 50mg and 4 patients 80 mg QD), whereas 99 patients started with 100mg QD. At 3 months, 92% of patients achieved a BCR-ABL ratio less than 10%. At 6 months, the rate of CCyR was 91% and the rate of MR3 was 40%, with 8% of the patients reaching MR4.5. Ninety-three patients were evaluable at 12 months: the rate of MR3 was 62%, with MR4.5 being achieved by 19% of the patients. At a median follow-up of 12 months, 27 patients (24.7%) were receiving the drug at reduced dose. Two patients (1.8%) experienced a lymphoid blast crisis and the overall incidence of resistance was 8%. As regards safety, the major side effects recorded were thrombocytopenia, neutropenia and pleural effusions, which occurred in 22%, 10% and 8% of patients, respectively. Present results, achieved in a large cohort of patients treated outside clinical trials, further confirm the efficacy and safety of dasatinib as firstline treatment in CML.