Elotuzumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: Extended 3-year follow-up of a multicenter, retrospective clinical experience with 319 cases outside of controlled clinical trials.

The combination of elotuzumab, lenalidomide, and dexamethasone (EloRd) enhanced the clinical benefit over Rd with a manageable toxicity profile in the ELOQUENT-2 trial, leading to its approval in relapsed/refractory multiple myeloma (RRMM). The present study is a 3-year follow-up update of a previously published Italian real-life RRMM cohort of patients treated with EloRd. This revised analysis entered 319 RRMM patients accrued in 41 Italian centers. After a median follow-up of 36 months (range 6-55), 236 patients experienced disease progression or died. Median progression-free survival (PFS) and overall survival (OS) were 18.4 and 34 months, respectively. The updated multivariate analyses showed a significant reduction of PFS and OS benefit magnitude only in cases with International Staging System stage III. Major adverse events included grade 3/4 neutropenia (18.5%), anemia (15.4%), lymphocytopenia (12.5%), and thrombocytopenia (10.7%), while infection rates and pneumonia were 33.9% and 18.9%, respectively. No new safety signals with longer follow-up have been observed. Of 319 patients, 245 (76.7%) reached at least a partial remission. A significantly lower response rate was found in patients previously exposed to lenalidomide. In conclusion, our study confirms that EloRd is a safe and effective regimen for RRMM patients, maintaining benefits across multiple unfavorable subgroups.

Experts' consensus on the definition and management of high risk multiple myeloma.

High risk multiple myeloma (HRMM) at diagnosis is currently recognized according to the Revised International Staging System (R-ISS) which was set up in 2015. Since then, new clinical and biological prognostic factors have been developed, which could implement the definition of High Risk (HR) category. We conducted a survey in order to identify which additional parameters, both clinical and biological, are considered more useful for the clinical practice and to evaluate if the management of Multiple Myeloma (MM) should change on the basis of the risk category. A questionnaire, consisting of 8 statements, was submitted to 6 Italian experts, from the European Myeloma Network (EMN) Research Italy, using the Delphi method. The colleagues were asked to answer each question using a scale between 0 and 100. If a statement did not reach at least 75 out of 100 points from all the participants, it was rephrased on the basis of the proposal of the experts and resubmitted in a second or further round, until a consensus was reached among all. From the first round of the survey a strong consensus was reached regarding the opportunity to revise the R-ISS including chromosome 1 abnormality, TP53 mutation or deletion, circulating plasma cells by next generation flow and extramedullary plasmacytomas. No consensus was reached for the definition of "double hit" MM and for the application in clinical practice of treatment strategies based on the risk category. In the second round of the Delphi questionnaire, "double-hit" MM was recognized by the association of at least two high-risk cytogenetic or molecular abnormalities. Moreover, the experts agreed to reserve an intensified treatment only to specific conditions, such as plasma cell leukaemia or patients with multiple extramedullary plasmacytomas, while they admitted that there are not sufficient real word data in order to modify treatment on the basis of MRD assessment in clinical practice. This survey suggests that the definition of HRMM should be implemented by additional clinical and biological risk factors, that will be useful to guide treatment in the future.

The role of positron emission tomography with 18F-fluorodeoxyglucose integrated with computed tomography in the evaluation of patients with multiple myeloma undergoing allogeneic stem cell transplantation.

Positron emission tomography (PET) integrated with computed tomography (PET/CT) has been reported to be useful for screening myelomatous lesions at diagnosis in patients with multiple myeloma (MM) and for monitoring response to autologous stem cell transplantation (auto-SCT). The aim of the study was to evaluate the prognostic significance of PET/CT in MM patients who received allogeneic stem cell transplantation (allo-SCT). Patients who underwent upfront auto-SCT followed by allo-SCT, either as consolidation or salvage treatment, were studied with PET/CT before and/or within 6 months after allo-SCT. The number, the maximum standard uptake value (SUV), and the location (medullary or extramedullary) of focal lesions (FLs) were recorded and investigated as predictors of progression-free survival (PFS) and overall survival (OS) by univariate and multivariate analyses. Fifty-four patients had a PET/CT scan before allo-SCT. Of these, 22 patients (41%) had a negative PET/CT scan, 11 patients (20%) showed 1 to 3 FLs, and 21 patients (39%) had either a diffuse bone marrow involvement or more than 3 FLs. SUV was >4.2 in 21 patients (39%) and extramedullary disease (EMD) was present in 6 patients (11%). Multivariate analysis of prognostic factors before allo-SCT showed that persistence of EMD at transplantation was an independent predictor of poor PFS, whereas OS was negatively influenced by unrelated donor and SUV > 4.2. Fifty-nine patients had a PET/CT scan within 6 months after allo-SCT. Multivariate analysis of post-treatment variables showed that persistence of EMD and failure to obtain complete response or very good partial response after allo-SCT were strongly associated with shorter PFS and OS. Of the 46 patients with evaluable PET/CT scans both before and 6 months after allo-SCT, the 23 patients who maintained or reached a PET complete remission showed a significantly prolonged PFS and OS compared with the 23 patients with persistence of any PET positivity (2-year PFS: 51% versus 25%, P = .03; 2-year OS: 81% versus 47%, P = .001). This study indicates that PET/CT imaging before and after allo-SCT is significantly associated with the outcome, suggesting the utility of this technique for MM staging before allo-SCT and for response monitoring after the transplantation.

Sclerodermatous chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: incidence, predictors and outcome.

Scleroderma may be one of the most severe forms of chronic graft-versus-host disease (GVHD). We retrospectively evaluated its incidence, predictor variables and outcome in 133 patients who survived at least 4 months after allogeneic hematopoietic stem cell transplantation. The 5-year cumulative incidence was 15.5% in patients with chronic GVHD. The generalized form had a progressive course despite immunosuppressive therapy. Eosinophilia, autoimmune markers, and previous skin involvement by chronic GVHD with disorders of pigmentation were significantly associated with an increased probability of developing scleroderma.

Effect of amifostine on the cytotoxicity of daunorubicin and daunoxome in tumor and normal cells.

Anthracyclines are powerful cytotoxic agents, used as first-line treatment of leukemias and many other tumors, but host-tissue toxicity is their main dose-limiting factor. However, their therapeutic effects depend not only on the toxicity, hence on the dose, but also on drug resistance. Among the mechanisms that can account for cell sensitivity to anthracyclines, there is an overexpression of drug transport proteins, like the transmembrane P-glycoprotein (PGP), the multidrug- resistance-related protein (MRP) and the lung-resistance-related protein (LRP). Attempts to reduce the toxicity of chemotherapeutic agents without affecting their efficacy have been made using liposomal anthracyclines or cytoprotective agents, as Amifostine. The aim of this study was to evaluate and compare the toxic effects of Daunorubicin, in normal or liposomal formulation, used in combination with WR1065, the active metabolite of Amifostine, against normal and tumor cells. In conclusion these data show that the preincubation with WR-1065 does not inhibit the drug toxic effect on blast cells and on tumor cell lines, independently by their multidrug resistance phenotype, but has a cytoprotective effect on stem cells causing a drug cytotoxicity reduction of 10-20%. This advantage is even higher using the liposomal formulation of DNR. Therefore, Amifostine can offer a chance of protecting normal cells from the toxicity of anthracyclines, in normal or liposomal formulation. The combination of liposomal anthracyclines with Amifostine can confer further advantages in management of leukemic patients, especially the elderly where treatment toxicity is a main problem. These patients may be candidates for alternative therapeutic strategies and the combination of DNX and Amifostine is an attractive treatment for these cases where a low nonhematological toxicity is required.

Antibody binding capacity for evaluation of MDR-related proteins in acute promyelocytic leukemia: Onset versus relapse expression.

BACKGROUND: Multidrug resistance (MDR) remains a major obstacle for successful treatment in cancer, in particular in acute leukemia. In acute promyelocytic leukemia (APL), the high sensitivity to anthracyclines appears to be attributable to the low frequency of MDR proteins overexpression at onset even if 30% of patients still relapse and become resistant to therapy. In attempt to explain different blast cell sensitivity, we studied the expression of PGP, MRP1, MRP2, and LRP in 45 cases of APL, comparing onset of disease with relapse. METHODS: PGP, LRP, and MRP on bone marrow or peripheral blood blast cells were evaluated by flow cytometry using the MRK-16, LRP-56, MRP-m6, and MRP2 antibodies and results expressed by the mean fluorescence index (MFI). The antibody binding capacity (ABC) for each MDR protein was also calculated. RESULTS: At diagnosis, only 2 of 45 patients overexpressed PGP and 1 overexpressed LRP. PGP and LRP overexpressing cases significantly grew up during disease progression and at second relapse mean PGP MFI and mean LRP MFI were significantly higher than at onset (P = 0.001 and P = 0.008, respectively). By analyzing ABC, the same trend was more evident because a significant increment of PGP and LRP was observed at second (P = 0.002 and P = 0.002, respectively), but even at first relapse (P = 0.018 and P = 0.002, respectively). No changes were demonstrated in MRP1 and MRP2 expression in any phase of disease considered. CONCLUSIONS: Our data confirm the low expression at diagnosis of proteins related to development of drug resistance in APL. The evidence of a relative easy induction of PGP and LRP, but not of MRP, can be useful in choosing drugs to employ for consolidation or rescue therapy.

CD56 and PGP expression in acute myeloid leukemia: impact on clinical outcome.

BACKGROUND AND OBJECTIVES: Overexpression of P-glycoprotein (PGP), a multidrug-related (MDR) protein, is one of the most important factors responsible for reduced drug sensitivity in acute myeloid leukemia (AML). Recently, we demonstrated that the presence of CD56 antigen, an isoform of the neural adhesion molecule, in AML cells is a negative independent prognostic factor for the achievement of complete remission (CR) and correlates with shorter survival. Since in our previous report we observed a more frequent PGP expression in CD56+ patients, we hypothesized that the reduced response to chemotherapy in this group of patients was due to increased PGP-mediated drug efflux. To confirm this hypothesis in this study PGP and CD56 expression on AML cells was correlated with other clinical and biological features and treatment response. DESIGN AND METHODS: Immunophenotypic analysis, including evaluation of CD56 and PGP expression, was performed using multiparameter flow cytometry on fresh and/or cryopreserved blast cells, obtained after informed consent, from bone marrow and/or peripheral blood of 143 consecutive newly diagnosed AML cases at the time of diagnosis. Samples expressing CD56 in at least 15% or more cells were considered as positive (CD56+). PGP expression was expressed as a mean fluorescence index (MFI) i.e. as the ratio of sample mean fluorescence channel and the isotypic control mean fluorescence channel. RESULTS: Overall results showed that 67/143 cases were PGP-/CD56-, 23/143 were PGP+ /CD56+, 40/143 were PGP+/CD56- and the remaining 13/143 were PGP-/CD56+. CD56+ and PGP+ on AML cells significantly reduced the CR rate (83% in the PGP-/CD56- group vs 60% in the PGP-/CD56+ group, 46% in the PGP+/CD56- group and 58% in the PGP+/CD56+ group, p = 0.002). In addition we observed a significantly higher proportion of total failures in patients expressing PGP or CD56 compared to in the group not expressing either (73% vs 27%, respectively; p = 0.0001). CD56 and PGP overexpression influenced the overall survival: in fact, the median survival of CD56+ and PGP+ patients ranged from 10 to 23 months, while the actuarial survival of CD56-/PGP- patients at 5 years is 52% (p = 0.023). INTERPRETATION AND CONCLUSIONS: Our data underline the independent negative prognostic role of PGP and CD56 expression in acute myeloid leukemia. Since the mechanism by which CD56 reduces drug sensitivity is still unknown, further investigations are required.

P-glycoprotein, lung resistance-related protein and multidrug resistance-associated protein in de novo adult acute lymphoblastic leukaemia.

P-glycoprotein (P-gp), lung resistance-related protein (LRP) and multidrug resistance-associated protein (MRP) expression, and blast cell intracellular daunorubicin accumulation (IDA) were evaluated in 95 previously untreated cases of adult acute lymphoblastic leukaemia (ALL) using flow cytometry. Forty-five out of 95 (47%) patients were P-gp positive (+), 12/66 (18%) were LRP+ and 11/66 (17%) were MRP+. Eighteen out of 66 (28%) patients showed a simultaneous multidrug resistance (MDR)-related protein expression higher than controls for more than one protein, while 24/66 (36%) cases did not overexpress any protein. Twenty-one out of 24 (87%) cases overexpressing at least one MDR-related protein had a defect in accumulating daunorubicin into their blast cells, while only 4/24 (16%) cases who did not overexpress any protein had similar features. The complete remission rates were similar in MDR-positive and -negative (-) patients but relapses within 6 months were more frequent in P-gp+ cases, and therefore the disease-free survival duration was shorter in P-gp+ than in P-gp- patients (P = 0.01). The number of MRP+ and/or LRP+ cases was too small to be able to draw any conclusion on their role in affecting or predicting therapy outcome. In conclusion, P-gp overexpression associated with a defect in daunorubicin accumulation is a frequent feature in adult ALL at onset and seems to be related to poorer therapy outcome and, consequently, a shorter disease-free survival. LRP and MRP overexpression seems to be a rare event and no conclusion can be drawn on its prognostic role.

Autologous stem cell transplantation for Hodgkin's lymphoma: results and prognostic factors in 51 high-risk patients.

Autologous stem cell transplantation (ASCT) is largely employed in primary resistant or recurrent Hodgkin's Lymphoma (HL), while its role early in the course of the disease is still controversial. Our purpose was to analyse the results of 51 high-risk HL patients autografted at our Institution and the role of possible prognostic risk factors for the outcome. Twelve (23.5%) patients were in complete remission at transplant and were transplanted as having an high risk disease; 20 (39.5%) patients were in partial response and 19 (37.0%) were transplanted as primary induction failure. At a median time of 38 (6-111) months from ASCT, 36 (70.5%) patients are alive in complete remission, 8 (15.5%) patients are alive with disease and 7 (14.0%) died for progression. Thirty out of 32 (94.0%) patients transplanted with responsive disease (either complete or partial response) are alive without disease. Six out of 19 (32.0%) patients transplanted with resistant disease are alive in complete remission. The overall survival of the entire population is 77.0% at 60 (14-151) months from diagnosis. Disease free survival of the 22 patients that achieved a complete remission after ASCT (16 in partial response and 6 with resistant disease) is 100%. In our experience, more than 90% of patients transplanted with responsive but high risk disease, seem achieving and maintaining a durable complete remission, and more than 30.0% of patients submitted to ASCT with refractory disease can be potentially rescued by transplant.