Catarina Geraldes

Lenalidomide and Dexamethasone in Transplant-Ineligible Patients with Myeloma

BACKGROUND The combination melphalan-prednisone-thalidomide (MPT) is considered a standard therapy for patients with myeloma who are ineligible for stem-cell transplantation. However, emerging data on the use of lenalidomide and low-dose dexamethasone warrant a prospective comparison of the two approaches. METHODS We randomly assigned 1623 patients to lenalidomide and dexamethasone in 28-day cycles until disease progression (535 patients), to the same combination for 72 weeks (18 cycles; 541 patients), or to MPT for 72 weeks (547 patients). The primary end point was progression-free survival with continuous lenalidomide-dexamethasone versus MPT. RESULTS The median progression-free survival was 25.5 months with continuous lenalidomide-dexamethasone, 20.7 months with 18 cycles of lenalidomide-dexamethasone, and 21.2 months with MPT (hazard ratio for the risk of progression or death, 0.72 for continuous lenalidomide-dexamethasone vs. MPT and 0.70 for continuous lenalidomide-dexamethasone vs. 18 cycles of lenalidomide-dexamethasone; P<0.001 for both comparisons). Continuous lenalidomide-dexamethasone was superior to MPT for all secondary efficacy end points, including overall survival (at the interim analysis). Overall survival at 4 years was 59% with continuous lenalidomide-dexamethasone, 56% with 18 cycles of lenalidomide-dexamethasone, and 51% with MPT. Grade 3 or 4 adverse events were somewhat less frequent with continuous lenalidomide-dexamethasone than with MPT (70% vs. 78%). As compared with MPT, continuous lenalidomide-dexamethasone was associated with fewer hematologic and neurologic toxic events, a moderate increase in infections, and fewer second primary hematologic cancers. CONCLUSIONS As compared with MPT, continuous lenalidomide-dexamethasone given until disease progression was associated with a significant improvement in progression-free survival, with an overall survival benefit at the interim analysis, among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. (Funded by Intergroupe, Francophone du Myélome and Celgene; FIRST ClinicalTrials.gov number, NCT00689936; European Union Drug Regulating Authorities Clinical Trials number, 2007-004823-39.).

European data on stem cell mobilization with plerixafor in non-Hodgkin's lymphoma, Hodgkin's lymphoma and multiple myeloma patients. A subgroup analysis of the European Consortium of stem cell mobilization

The effectiveness of the novel hematopoietic stem cell mobilizing agent plerixafor was evaluated in nationwide compassionate use programs in 13 European countries. A total of 580 poor mobilizers with non-Hodgkins lymphoma (NHL), Hodgkins lymphoma (HL) and multiple myeloma (MM) were enrolled. All patients received plerixafor plus granulocyte CSF with or without chemotherapy. Overall, the collection yield was significantly higher in MM patients (>2.0 × 106 CD34+ cells/kg: 81.6%; >5.0 × 106 CD34+ cells/kg: 32.0%) than in NHL patients (>2.0 × 106 CD34+ cells/kg: 64.8%; >5.0 × 106 CD34+ cells/kg: 12.6%; P<0.0001) and also significantly higher in HL patients (>2.0 × 106 CD34+ cells/kg: 81.5%; >5.0 × 106 CD34+ cells/kg: 22.2%) than in NHL patients (P=0.013). In a subgroup analysis, there were no significant differences in mobilization success comparing patients with diffuse large B-cell lymphoma, follicular lymphoma and mantle cell lymphoma. Our data emphasize the role of plerixafor in poor mobilizers, but further strategies to improve the apheresis yield especially in patients with NHL are required.

Plerixafor for Autologous Peripheral Blood Stem Cell Mobilization in Patients Previously Treated with Fludarabine or Lenalidomide

Fludarabine and lenalidomide are essential drugs in the front-line treatment of non-Hodgkin lymphoma (NHL) and multiple myeloma (MM), respectively. Data suggests that fludarabine and lenalidomide therapy may have a deleterious effect on stem cell mobilization. In the European compassionate use program, 48 patients (median age 57 years) previously treated with fludarabine (median 5 cycles; range: 1-7 cycles) were given plerixafor plus granulocyte colony-stimulating factor (G-CSF) for remobilization following a primary mobilization attempt. The overall median number of CD34+ cells collected was 2.3 × 10(6)/kg (range: 0.3-13.4). The minimum required number of CD34+ cells (≥2.0 × 10(6)/kg) was collected from 58% of patients in a median of 2 days. Thirty-five patients (median age = 57 years) previously treated with lenalidomide (median 5 cycles; range: 1-10 cycles) were given plerixafor plus G-CSF for remobilization. The overall median number of CD34+ cells collected was 3.4 × 10(6)/kg (range: 1.1-14.8). The minimum required number of CD34+ cells (≥2.0 × 10(6) per kg) was collected from 69% of patients in a median of 2 days. In conclusion, salvage mobilization with plerixafor plus G-CSF is successful in the majority of patients with MM previously treated with lenalidomide. In fludarabine-exposed patients, only 58% of patients will achieve successful salvage mobilization with plerixafor plus G-CSF, suggesting the need for novel mobilization regimens algorithms in this subgroup of patients.

European data on stem cell mobilization with plerixafor in patients with nonhematologic diseases: an analysis of the European consortium of stem cell mobilization.

BACKGROUND: Plerixafor with granulocyte–colony‐stimulating factor (G‐CSF) has been shown to enhance stem cell mobilization in patients with multiple myeloma and lymphoma with previous mobilization failure. In this European named patient program we report the experience in insufficiently mobilizing patients diagnosed with nonhematologic diseases.

Higher BMI is not a barrier to stem cell mobilization with standard doses of plerixafor and G-CSF

Higher BMI is not a barrier to stem cell mobilization with standard doses of plerixafor and G-CSF

Monoclonal Gammopathies of Indetermined Significance: Diagnosis and Clinical Follow-up Guidelines

The Portuguese group of multiple myeloma of the Portuguese Society of Hematology proposes a national protocol for diagnosis and clinical follow-up of monoclonal gammopathies. The proposed protocol aims to standardize clinical management of monoclonal gammopathies. Furthermore, it would also define the major risk factors for progression to Multiple Myeloma that require a precocious close articulation between general practitioners and a Hematology Clinic.

Metalloproteinase inhibitors as a potential therapeutic approach in multiple myeloma: a preliminary study

Multiple Myeloma (MM) is one of the B-cell malignancies with a poor prognosis, characterized by the clonal expansion of neoplastic plasma cells within the bone marrow, elevated serum immunoglobulin, and osteolytic bone disease. The first pathogenic step is a premalignant monoclonal gamopathy of undetermined significance (MGUS). With progression of MGUS to myeloma, complex genetic/epigenetic events occur in the neoplastic plasma cell, and in the bone marrow microenvironment. The resultant interactions of myeloma cells, bone marrow stromal cells, and microvessels contribute to persistence of the tumour and resistance to drugs. Matrix metalloproteinases (MMPs) play a critical rule in bone remodeling (osteolitic lesions) and tumor invasion, and could be a new therapeutic target in MM. The aim of this study is to evaluate the therapeutic potential of a metalloproteinase inhibitor, batimastat (BB-94), in a multiple myeloma cell line in culture. For this purpose a MM cell line, the NCI-H929 [H929] cells were cultured in absence and presence of different concentrations of the MMP inhibitor, BB-94, during different periods of time. Cell viability and death was determined by the alamar blue assay and by flow cytometry using the annexin V/propidium iodide incorporation. Our preliminary results show that BB-94 has, along a broad concentration range, an antiproliferative effect in MM cells that is accompanied by a cytotoxic effect as results of increased apoptosis levels as the concerntratio increases from 1 to 5µM . This study suggests that batimastat could be a new therapeutic approach in multiple myeloma in monotherapy.