Frontline treatment in elderly patients with multiple myeloma.

Melphalan-prednisone-thalidomide (MPT) and melphalan-prednisone-bortezomib (MPV) currently appear to be the treatments of choice for a large proportion of elderly multiple myeloma (MM) patients ineligible for autologous stem cell transplantation (ASCT). It seems certain that in the near future cyclophosphamide-thalidomide-dexamethasone, with an attenuated dose of dexamethasone (CTDa), and melphalan-prednisone-lenalidomide (MPR) will also be proved superior to MP, thus providing four therapeutic options in this patient group. These options could lead to more personalized treatment approaches, based on patient comorbidities, as the three novel agents have somewhat different toxicity profiles.

Lenalidomide in combination with dexamethasone at first relapse in comparison with its use as later salvage therapy in relapsed or refractory multiple myeloma.

This subset analysis of data from two phase III studies in patients with relapsed or refractory multiple myeloma (MM) evaluated the benefit of initiating lenalidomide plus dexamethasone at first relapse. Multivariate analysis showed that fewer prior therapies, along with beta(2)-microglobulin (< or = 2.5 mg/L), predicted a better time to progression (TTP; study end-point) with lenalidomide plus dexamethasone treatment.

Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: impact of a dose-modification guideline.

The frequency, characteristics and reversibility of bortezomib-associated peripheral neuropathy were evaluated in the phase III APEX (Assessment of Proteasome Inhibition for Extending Remissions) trial in patients with relapsed myeloma, and the impact of a dose-modification guideline on peripheral neuropathy severity and reversibility was assessed. Patients received bortezomib 1.3 mg/m(2) (days 1, 4, 8, 11, eight 21-d cycles, then days 1, 8, 15, 22, three 35-d cycles); bortezomib was held, dose-reduced or discontinued depending on peripheral neuropathy severity, according to a protocol-specified dose-modification guideline.

Analysis of herpes zoster events among bortezomib-treated patients in the phase III APEX study.

Purpose: The aim of this subset analysis was to determine if bortezomib treatment is associated with increased incidence of varicella-zoster virus (VZV) reactivation in patients with relapsed multiple myeloma (MM).

Patients And Methods: Incidence of herpes zoster was evaluated in 663 patients with relapsed MM from the phase III APEX trial comparing single-agent bortezomib with high-dose dexamethasone.

Results: Bortezomib was associated with a significantly higher incidence of herpes zoster compared with dexamethasone treatment (13%, 42 of 331 v 5%, 15 of 332; P = .

The relationship between quality of response and clinical benefit for patients treated on the bortezomib arm of the international, randomized, phase 3 APEX trial in relapsed multiple myeloma.

Quality of response is associated with prolonged overall survival (OS) in newly diagnosed multiple myeloma patients. This cohort study within the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial of bortezomib versus dexamethasone in relapsed myeloma assessed the relationship between quality of response to bortezomib (n = 315) and clinical benefit. Treatment-free interval (TFI), time to alternative therapy (TTAT), time to progression (TTP) and OS were assessed in response-evaluable patients in the bortezomib arm in cohorts defined by achievement of complete response (CR; n = 27), very good partial response (VGPR; n = 31), partial response (PR; n = 77), minimal response (MR; n = 21) or non-response (NR, including stable and progressive disease; n = 159).

Frontline treatment of multiple myeloma in elderly patients.

Until 2007, frontline chemotherapy with melphalan and prednisone (MP) was considered as the standard of care in the treatment of elderly patients with multiple myeloma (MM). Recently, several prospective randomized studies comparing MP with the same combination plus new agents such as thalidomide (MPT) or bortezomib (MPV) clearly showed that MPT and MPV were superior to MP in terms of progression-free and overall survival. Melphalan-prednisone-lenalidomide (MPR) is currently compared to MP in one prospective trial and will also probably be superior to MP.

[Osteonecrosis of the jaw and bisphophonates in oncology].

Bisphosphonates are potent osteoclastic inhibitors that are indicated in the prevention of bone complications. They could also be of interest in the prevention of bone metastases. Several recent international publications have highlighted the onset of osteonecrosis of the jaw (ONJ) in patients treated with bisphosphonates.

Lenalidomide in the treatment of multiple myeloma: a review.

Lenalidomide is an immunomodulatory drug derived from thalidomide. It was developed to maximize the anti-inflammatory and anti-neoplasic properties of thalidomide and to reduce its toxicity. The molecular mechanism of action of lenalidomide is unclear, but its therapeutic activity is mainly due to its well defined anti-inflammatory, immunomodulatory, anti-proliferative and anti-angiogenic properties.

Serum immunoglobulin free light chain correlates with tumor burden markers in Waldenstrom macroglobulinemia.

The serum IgM level has been utilised as a marker of tumor progression and to assess response to therapy in patients with Waldenstrom macroglobulinemia (WM). However, there are many limitations to the IgM protein level. The objective of this study was to evaluate the association of known tumor burden markers and prognostic factors with serum free light chain (sFLC) in 98 patients with WM.

Clinical relevance of soluble HLA class I molecules in Waldenstrom Macroglobulinemia.

Objectives: Waldenstrom Macroglobulinemia (WM) is a B-cell neoplasm characterised by secretion of IgM by lymphoplasmacytic bone marrow cells and by cytopenias and hypogammaglobulinemia in a subset of patients. Beta-2 microglobulin (b2m) is a major prognostic factor in WM and the heavy chain of HLA class I molecules, which are known to have immunosuppressive properties and have been implicated in the pathogeny of several malignancies.

Methods: We assessed the serum levels of the total soluble HLA-I molecules and the HLA-Gs molecules in 105 patients with IgM-related disorders [WM (n = 42) and IgM MGUS (n = 63)], and compared the results to 41 healthy subjects.

Thalidomide for treatment of multiple myeloma: 10 years later.

Thalidomide, bortezomib, and lenalidomide have recently changed the treatment paradigm of myeloma. In young, newly diagnosed patients, the combination of thalidomide and dexamethasone has been widely used as induction treatment before autologous stem cell transplantation (ASCT). In 2 randomized studies, consolidation or maintenance with low-dose thalidomide has extended both progression-free and overall survival in patients who underwent ASCT at diagnosis.

Efficacy and safety of bortezomib in patients with renal impairment: results from the APEX phase 3 study.

Renal impairment is associated with poor prognosis in multiple myeloma (MM). This subgroup analysis of the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study of bortezomib vs high-dose dexamethasone assessed efficacy and safety in patients with relapsed MM with varying degrees of renal impairment (creatinine clearance (CrCl) <30, 30-50, 51-80 and >80 ml min(-1)). Time to progression (TTP), overall survival (OS) and safety were compared between subgroups with CrCl < or =50 ml min(-1) (severe-to-moderate) and >50 ml min(-1) (no/mild impairment).

Frontline treatment in multiple myeloma patients not eligible for stem-cell transplantation.

Melphalan-prednisone-thalidomide (MPT) currently appears to be the treatment of choice for a large proportion of elderly patients ineligible for autologous stem-cell transplantation (ASCT). It seems certain that in the near future melphalan-prednisone-Velcade (MPV) and melphalan-prednisone-lenalidomide (MPR) will also be proved superior to melphalan-prednisone (MP), thus providing three therapeutic options (MPT, MPV and MPR) in this patient group with multiple myeloma (MM). These therapeutic options could lead to more personalized treatment approaches, based on patient comorbidities, as the three novel therapies have somewhat different toxicity profiles.

Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma.

Background: Lenalidomide is a structural analogue of thalidomide with similar but more potent biologic activity. This phase 3, placebo-controlled trial investigated the efficacy of lenalidomide plus dexamethasone in the treatment of relapsed or refractory multiple myeloma.

Methods: Of 351 patients who had received at least one previous antimyeloma therapy, 176 were randomly assigned to receive 25 mg of oral lenalidomide and 175 to receive placebo on days 1 to 21 of a 28-day cycle.

Thirteen cases of jaw osteonecrosis in patients on bisphosphonate therapy.

Introduction: We report on our experience with 13 cases of jaw osteonecrosis in patients treated with amino-bisphosphonates.

Method: Data were collected by a regional observatory for jaw osteonecrosis in northern France via letters sent to all physicians likely to manage patients with this condition. All study patients were evaluated at a multidisciplinary jaw osteonecrosis clinic between June and December 2005.

Hyperdiploidy is a common finding in monoclonal gammopathy of undetermined significance and monosomy 13 is restricted to these hyperdiploid patients.

Purpose: Two pathways, hyperdiploid and nonhyperdiploid, are proposed for progression to plasma cell neoplasia. Implication of monosomy 13 (Delta13) is unclear in monoclonal gammopathy of undetermined significance (MGUS), and data on DNA content of plasma cells [DNA index (DI)] are rare.

Experimental Design: We ascertained DI in 169 multiple myeloma (MM) and 96 MGUS patients.

Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial.

Background: In multiple myeloma, combination chemotherapy with melphalan plus prednisone is still regarded as the standard of care in elderly patients. We assessed whether the addition of thalidomide to this combination, or reduced-intensity stem cell transplantation, would improve survival.

Methods: Between May 22, 2000, and Aug 8, 2005, 447 previously untreated patients with multiple myeloma, who were aged between 65 and 75 years, were randomly assigned to receive either melphalan and prednisone (MP; n=196), melphalan and prednisone plus thalidomide (MPT; n=125), or reduced-intensity stem cell transplantation using melphalan 100 mg/m2 (MEL100; n=126).

Plasma cell growth fraction using Ki-67 antigen expression identifies a subgroup of multiple myeloma patients displaying short survival within the ISS stage I.

The current most powerful prognostic model in Multiple Myeloma (MM) combines beta-2 microglobulin (b2m) with albumin, corresponding to the International Staging System (ISS). However, the prognosis of patients within the ISS stage I (high albumin and low b2m) may vary. Ki-67 is a nuclear protein associated with cell proliferation.

Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial.

Initial analysis of the Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial of relapsed multiple myeloma patients showed significantly longer time to progression, higher response rate, and improved survival with single-agent bortezomib versus high-dose dexamethasone. In this updated analysis (median follow-up: 22 months), survival was assessed in both arms, and efficacy updated for the bortezomib arm. Median survival was 29.

Heterogeneity of t(4;14) in multiple myeloma. Long-term follow-up of 100 cases treated with tandem transplantation in IFM99 trials.

One hundred de novo multiple myeloma patients with t(4;14) treated with double intensive therapy according to IFM99 protocols were retrospectively analyzed. The median overall survival (OS) and event-free survival (EFS) were 41.4 and 21 months, respectively, as compared to 65 and 37 for patients included in the IFM99 trials without t(4;14) (P<10(-7)).

Long-term outcomes after reduced-intensity conditioning allogeneic stem cell transplantation for low-grade lymphoma: a survey by the French Society of Bone Marrow Graft Transplantation and Cellular Therapy (SFGM-TC).

Background And Objectives: High-dose chemotherapy with allogeneic stem cell transplantation (SCT) has proven to be a successful treatment for low-grade lymphoma (LGL), but is associated with considerable transplant-related mortality (TRM). In an effort to reduce toxic mortality while maintaining the graft-versus-leukemia effect, allogeneic SCT has been combined with a reduced-intensity conditioning (RIC) regimen. The aim of this study was to determine the outcome of patients with LGL treated with RIC allogeneic SCT.

Safety and efficacy of bortezomib in high-risk and elderly patients with relapsed multiple myeloma.

Adverse prognostic factors in multiple myeloma include advanced age, number of prior therapies, and higher International Staging System (ISS) disease stage. In the international, randomised, phase-3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study, bortezomib demonstrated significantly longer time to progression (TTP), higher response rates and improved survival compared with high-dose dexamethasone in patients with relapsed multiple myeloma following one to three prior therapies. In this APEX subgroup analysis, efficacy of bortezomib and dexamethasone was compared in elderly (age > or =65 years) and high-risk (>1 prior line of therapy; ISS stage II/III; refractory to prior therapy) patients.

A phase II multicenter study of troxacitabine in relapsed or refractory lymphoproliferative neoplasms or multiple myeloma.

Options for patients with relapsed/refractory lymphoproliferative disorders and multiple myeloma are currently limited. Troxacitabine has shown promise in preclinical studies in a variety of malignancies; hence, the current study was conducted to evaluate the activity of troxacitabine in relapsed or refractory lymphoid malignancies. This was a phase II, open-label, multinational, multicenter study of patients with relapsed or refractory lymphoproliferative disorders or multiple myeloma.