Lenalidomide, Melphalan, and Prednisone Association Is an Effective Salvage Therapy in Relapsed Plasma Cell Leukaemia

Plasma cell leukemia (PCL) is a rare and aggressive plasma cell disorder, characterized by the presence of a peripheral blood absolute plasma cell count of at least 2 × 109/l and more than 20% circulating plasma cells. The prognosis of PCL patients remains poor. Even by using autologous or allogenic transplant procedures, median survival does not exceed 3 years (Saccaro et al., 2005). Thalidomide, bortezomib and lenalidomide (Revlimid) have emerged as high active agents in the treatment of PCL (Johnston and abdalla, 2002; Musto et al., 2007; Finnegan et al., 2006). In particular, Lenalidomide is a structural analogue of thalidomide with similar but more potent biological activity; it is used as first line therapy in MM (Palumbo et al., 2007; Niesvizky et al., 2007), although information regarding its associated use with dexamethasone use as salvage therapy in PCL derives from anecdotal single case reports (Musto et al., 2008). We would like to describe a case of primary PCL with adverse cytogenetic in which excellent response was achieved with the combination of lenalidomide, melphalan, and prednisone as salvage therapy

Efficacy and safety of once-weekly bortezomib in multiple myeloma patients

AbstractIn a recent phase 3 trial, bortezomib-melphalan-prednisone-thalidomide followed by maintenance treatment with bortezomib-thalidomide demonstrated superior efficacy compared with bortezomib-melphalan-prednisone. To decrease neurologic toxicities, the protocol was amended and patients in both arms received once-weekly instead of the initial twice-weekly bortezomib infusions: 372 patients received once-weekly and 139 twice-weekly bortezomib. In this post-hoc analysis we assessed the impact of the schedule change on clinical outcomes and safety. Long-term outcomes appeared similar: 3-year progression-free survival rate was 50% in the once-weekly and 47% in the twice-weekly group (P > .999), and 3-year overall survival rate was 88% and 89%, respectively (P = .54). The complete response rate was 30% in the once-weekly and 35% in the twice-weekly group (P = .27). Nonhematologic grade 3/4 adverse events were reported in 35% of once-weekly patients and 51% of twice-weekly patients (P = .003). The incidence of grade 3/4 peripheral neuropathy was 8% in the once-weekly and 28% in the twice-weekly group (P < .001); 5% of patients in the once-weekly and 15% in the twice-weekly group discontinued therapy because of peripheral neuropathy (P < .001). This improvement in safety did not appear to affect efficacy. This study is registered at http://www.clinicaltrials.gov as NCT01063179

Prognostic or predictive value of circulating cytokines and angiogenic factors for initial treatment of multiple myeloma in the GIMEMA MM0305 randomized controlled trial

Abstract Background Several new drugs are approved for treatment of patients with multiple myeloma (MM), but no validated biomarkers are available for the prediction of a clinical outcome. We aimed to establish whether pretreatment blood and bone marrow plasma concentrations of major cytokines and angiogenic factors (CAFs) of patients from a phase 3 trial of a MM treatment could have a prognostic and predictive value in terms of response to therapy and progression-free and overall survival and whether these patients could be stratified for their prognosis. Methods Blood and bone marrow plasma levels of Ang-2, FGF-2, HGF, VEGF, PDGF-β, IL-8, TNF-α, TIMP-1, and TIMP-2 were determined at diagnosis in MM patients enrolled in the GIMEMA MM0305 randomized controlled trial by an enzyme-linked immunosorbent assay (ELISA). These levels were correlated both reciprocally and with the type of therapy and patients’ characteristics and with a group of non-MM patients as controls. Results No significant differences were detected between the blood and bone marrow plasma levels of angiogenic cytokines. A cutoff for each CAF was established. The therapeutic response of patients with blood plasma levels of CAFs lower than the cutoff was better than the response of those with higher levels in terms of percentage of responding patients and quality of response. Conclusion FGF-2, HGF, VEGF, and PDGF-β plasma levels at diagnosis have predictive significance for response to treatment. The stratification of patients based on the levels of CAFs at diagnosis and their variations after therapy is useful to characterize different risk groups concerning outcome and response to therapy. Trial registration Clinical trial information can be found at the following link: NCT0106317

mTOR pathway activation in multiple myeloma cell lines and primary tumour cells: pomalidomide enhances cytoplasmic-nuclear shuttling of mTOR protein

mTOR is a protein kinase that plays a central role in regulating critical cellular processes. We evaluated the activation and cellular localization of the mTOR pathway in multiple myeloma (MM) and analyzed the role of pomalidomide in regulating mTOR. By immunohistochemistry cytoplasmic p-mTOR stained positive in 57 out 101 (57.6%) cases with a nuclear p-mTOR localization in 14 out 101 samples (13.8%). In the 70 MM samples analyzed for the entire pathway, p-mTOR expression significantly correlated with p-AKT, p-P70S6K, and p-4E-BP1 suggesting that the AKT/mTOR pathway is activated in a subset of MM patients. Immunofluorescence assays demonstrated that mTOR protein is distributed throughout the cytoplasm and the nucleus at baseline in MM cell lines and in plasma cells of 13 MM patients and that pomalidomide facilitated the shift of the mTOR protein in the nucleus. By western blotting, treatment with pomalidomide increased nuclear mTOR and p-mTOR expression levels in the nucleus with a concomitant decrease of the cytoplasmic fractions while does not seem to affect significantly AKT phosphorylation status. In MM cells the anti-myeloma activity of pomalidomide may be mediated by the regulation of the mTOR pathway

Bortezomib and plasma cell leukemia

Bortezomib (Velcade) is currently approved in USA and EU for the treatment of resistant/relapsed multiple mieloma (MM). Some reports have suggested that bortezomib is particularly effective for the treatment of extramedullary MM. However, there are very few data about the efficacy of this drug in plasma cell leukemia (PCL), a MM variant usually characterized by very poor prognosis. We retrospectively evaluated 9 patients with PCL diagnosed between October, 2002, and May, 2006, who had received bortezomib for the treatment of their disease (6 males, 3 females; median age 63 years, range 55\u201374). Six patients had primary and 3 secondary PCL. Eight patients had previously received 1 to 4 lines of chemotherapy, including autologous transplantation (5) and thalidomide (4). One patient was treated at diagnosis. Circulating plasma cells ranged from 2 to 71 x 10e9/L. Median WBC count was 23 x 10e9/L (range 8.1\u2013113). Two patients had a moderate degree of renal failure, 3 had extramedullary disease (jaw, liver, soft tissues). Del 13 was observed in 4 out of 5 patients with available karyotype. Bortezomib was given using the standard schedule of 1.3 mg/sqm days 1, 4, 8, 11, with an interval of 10 days between cycles. Two patients received dexamethasone and thalidomide, 1 thalidomide alone and 3 doxorubicin and dexamethasone in combination with bortezomib. A median of 4 cycles was administered (range 2\u20136). Grade 3\u20134 hematological toxicity occurred in 7 patients, while neurological grade 3 toxicity was observed in a single patient. Infections (grade 3) occurred in 4 patients. Other toxicities (diarrhoea, nausea, skin rash) never reached grade 3. Three patients required red cell and/or platelet support. In 3 subjects a reduction of bortezomib dose was required due to hematological or neurological toxicity. Four partial remissions (reduction of M-component &gt; 50%), 3 near-complete remissions (disappearance of M-component at electrophoresis, but positive immunofixation) and 2 complete remissions (negative immunofixation) were achieved (100% overall response), whose duration ranged from 2 to 14 months. In 4 patients autologous transplant procedures were started after response induced by bortezomib. Eight patients are currently alive 7\u201345 months after diagnosis of PCL. One patient, who had interrupted the treatment after 2 cycles due to herpes zoster, died of progressive disease 7 months later. Our data indicate that bortezomib is very effective in inducing significant responses in patients with primary or secondary PCL and that this drug should be considered for the initial treatment of this disease. Curiously, during the review work, we recorded 3 cases of PCL developed in MM patients under salvage therapies including bortezomib. This intriguing finding, which strongly contrasts with the very good results obtained in patients with previously established PCL, would warrant to be further investigated with "ad hoc" studies