Carfilzomib, cyclophosphamide and dexamethasone for newly diagnosed, high-risk myeloma patients not eligible for transplant: a pooled analysis of two studies

none20: Despite remarkable advances in the treatment of multiple myeloma in the last decades, the prognosis of patients harboring high-risk cytogenetic abnormalities remains dismal as compared to that of standard-risk patients. Proteasome inhibitors demonstrated to partially ameliorate the prognosis of high-risk patients. We pooled together data from two phase I/II trials on transplant-ineligible patients with multiple myeloma receiving upfront carfilzomib cyclophosphamide and dexamethasone followed by carfilzomib maintenance. The aim of this analysis was to compare treatment outcomes in patients with standard- versus high-risk cytogenetic abnormalities detected by fluorescence in situ hybridization (FISH) analysis. High risk was defined by the presence of at least one chromosomal abnormality, including t(4;14), del17p and t(14;16). Overall, 94 patients were included in the analysis: 57 (61%) in the standard-risk and 37 (39%) in the high-risk group. Median follow-up was 38 months. In standard- vs. high-risk patients, we observed similar progression-free survival (3-year PFS: 52% vs. 43%, respectively; p=0.50), overall survival (3-year OS: 78% vs. 73%; p=0.38), and overall response rate (88% vs 95%; p=0.47), with no statistical differences between the two groups. No difference in terms of progression-free survival was observed between patients with or without del17p. Carfilzomib, used both as induction and maintenance agent for transplant-ineligible newly diagnosed multiple myeloma patients, mitigated the poor prognosis carried by high-risk cytogenetics and resulted into similar progression-free survival and overall survival, as compared to standard-risk patients. ClinicalTrials.gov IDs: NCT01857115 (IST-CAR-561) and NCT01346787 (IST-CAR-506).noneMina, Roberto; Bonello, Francesca; Petrucci, Maria Teresa; Liberati, Anna Marina; Conticello, Concetta; Ballanti, Stelvio; Musto, Pellegrino; Olivieri, Attilio; Benevolo, Giulia; Capra, Andrea; Gilestro, Milena; Galieni, Piero; Cavo, Michele; Siniscalchi, Agostina; Palumbo, Antonio; Montefusco, Vittorio; Gaidano, Gianluca; Omedé, Paola; Boccadoro, Mario; Bringhen, SaraMina, Roberto; Bonello, Francesca; Petrucci, Maria Teresa; Liberati, Anna Marina; Conticello, Concetta; Ballanti, Stelvio; Musto, Pellegrino; Olivieri, Attilio; Benevolo, Giulia; Capra, Andrea; Gilestro, Milena; Galieni, Piero; Cavo, Michele; Siniscalchi, Agostina; Palumbo, Antonio; Montefusco, Vittorio; Gaidano, Gianluca; Omedé, Paola; Boccadoro, Mario; Bringhen, Sar

Lenalidomide-based induction and maintenance in elderly newly diagnosed multiple myeloma patients: updated results of the EMN01 randomized trial

In the EMN01 trial, the addition of an alkylator (melphalan or cyclophosphamide) to lenalidomide-steroid induction has been prospectively evaluated in transplant-ineligible multiple myeloma patients. After induction, patients were randomly assigned to maintenance treatment with lenalidomide alone or with prednisone continuously. This analysis (median follow-up of 71 months) focused on maintenance treatment and on subgroup analyses according to the International Myeloma Working Group Frailty Score. 217 patients in lenalidomide-dexamethasone, 217 in melphalan-prednisone-lenalidomide and 220 in cyclophosphamide-prednisone-lenalidomide arms were evaluable. 284 (43%) patients were fit, 205 (31%) intermediate-fit and 165 (25%) frail. After induction, 402 patients were eligible for maintenance, (lenalidomide arm: 204; lenalidomide-prednisone: 198). After a median duration of maintenance of 22.0 months, progression-free survival from start of maintenance was 22.2 months with lenalidomide-prednisone vs 18.6 months with lenalidomide (HR 0.85,p=0.14), with no differences across frailty subgroups. The most frequent grade ≥3 toxicity was neutropenia (10% of lenalidomide-prednisone and 21% of lenalidomide patients; p=0.001). Grade ≥3 non-hematologic adverse events were rare (<15%). In fit patients, melphalan-prednisone-lenalidomide significantly prolonged progression-free survival compared to cyclophosphamide-prednisone-lenalidomide (HR 0.72,p=0.05) and lenalidomide-dexamethasone (HR 0.72, p=0.04). Likewise, a trend towards a better overall survival was noted for melphalan-prednisone-lenalidomide and cyclophosphamide-prednisone-lenalidomide, as compared to lenalidomide-dexamethasone. No differences were observed in intermediate-fit and frail patients. This analysis showed positive outcomes of maintenance with lenalidomide-based regimens, with a good safety profile. For the first time, we showed that fit patients benefit from a triplet full-dose regimen, while intermediate-fit and frail patients from gentler regimens. ClinicalTrials.gov registration number: NCT01093196

Diagnostic considerations about visceral leishmaniasis. Two case report

Two cases of visceral leishmaniasis (VL) in immunocompetent patients have been described. Both patients lived in endemicic areas for leishmaniasis in the south of Italy, tested positive for anti-Leishmania antibodies. A definitive diagnosis of VL was delayed by false negative microscopic examinations. Both patients were treated successfully with liposomal amphotericin B

Outcome and toxicity in the modern era of new drugs for multiple myeloma: A reappraisal for comparison with future investigational trials

The introduction of new drugs such as thalidomide, lenalidomide, and bortezomib has led to novel treatment strategies and significantly improved the outcome of patients with multiple myeloma (MM). The enhanced knowledge of myeloma pathogenesis has allowed the identification of new therapeutic targets and many clinical trials are either planned or in progress to evaluate these more selective drugs in the near future. The results of these studies, however, will have to be compared with the results of existing novel therapies for the treatment of MM in order to define whether new protocols do not duplicate current new standards and constitute a real improvement. We reviewed the results of a series of phase I, II, III studies with thalidomide, lenalidomide, and bortezomib combinations for newly diagnosed MM in order to define a reasonable standard in terms of activity, efficacy, and toxicity and to have a potentially useful starting point for comparisons with future investigational trials. Three-drug regimens appear to double the complete remission (CR) rate (20%), though regimens containing 4 drugs triple the CR rate (30%), compared with those containing only 2 agents (10%). These improvements in the depth and quality of response translate into a progressive increase in the progression-free survival rate at 2 years (from approximately 54%-62% to 75%, respectively). Conversely, by using additional agents, a marked increase in hematologic toxicity has been described (8%, 28%, and 28% respectively), whereas nonhematologic toxicity appears to be similar (26%, 24%, and 27%, respectively). These results suggest that new trials in the future will constitute significant progress if they can improve on the current relatively favorable efficacy/toxicity ratio. Nonetheless, exciting new combinations in development do hold promise and results from these studies are eagerly awaited

High-dose thiotepa, etoposide and carboplatin as conditioning regimen for autologous stem cell transplantation in patients with high-risk non-Hodgkin lymphoma

High-dose chemotherapy conditioning regimens followed by autologous stem cell transplantation generally provide good results in non-Hodgkin lymphoma. We have evaluated the effects of a high-dose regimen comprising thiotepa, etoposide and carboplatin. After debulking and mobilization with high-dose cyclophosphamide or other schedules, forty-five patients at various disease stages were conditioned with thiotepa, etoposide and carboplatin prior to autologous stem cell transplantation. The overall response rate was 77.8% (30 CR, 66.7%; 5 PR, 11.1%). Ten patients (22.2%) did not respond. Two patients (4.4%) died from transplant-related complications. The mean 5-year overall survival was 71.1%: 12 patients relapsed within the first 5 years of follow-up. The overall response rate and 5-year overall survival were better for patients with an International Prognostic Index (IPI) 1 at diagnosis than for those with IPI 2 and IPI 3 (P < 0.005 for all). The thiotepa, etoposide and carboplatin conditioning regimen for autologous stem cell transplantation in non-Hodgkin lymphoma has a good anti-lymphoma effect and provides encouraging results in terms of response to treatment and 5-year overall survival. Its good tolerance and acceptable toxicity suggest that it may a very useful in the management of non-Hodgkin lymphoma. © 2011 Springer-Verlag

High-dose thiotepa, etoposide and carboplatin as conditioning regimen for autologous stem cell transplantation in patients with high-risk Hodgkin's lymphoma

Background: Autologous stem cell transplantation (ASCT) generally provides good results in Hodgkin's lymphoma (HL). We studied a high-dose chemotherapy regimen based on thiotepa, etoposide and carboplatin (TECA). Methods: Fifty-eight patients with advanced HL were treated with thiotepa, etoposide and carbo platin for transplant induction. Results: The overall response rate was 79.3% (39 CR: 67.2%; and 7 PR: 12.1%); 12 patients (20.1%) were non-responders. The 5-year overall survival rate was 77.6%; five initially responder patients relapsed within the first 5 years of follow-up and underwent salvage therapy. Conclusion: The TECA conditioning regimen for ASCT in HL results in a good anti-HL effect, positive response to treatment and high 5-year overall survival rate. It was also well tolerated and did not induce excessive toxicity, suggesting that TECA may be a very useful conditioning regimen for HL. © W. S. Maney & Son Ltd 2012

Candidaemia in haematological malignancy patients from a SEIFEM study: epidemiological patterns according to antifungal prophylaxis

Candidaemia is an important infectious complication for haematological malignancy patients. Antifungal prophylaxis reduces the incidence of candidaemia but may be associated with breakthrough candidaemia