Real-world effectiveness of ixazomib combined with lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: the REMIX study.

Ixazomib (IXA) is an oral proteasome inhibitor (PI) used in combination with lenalidomide and dexamethasone (IXA-Rd) for patients with relapsed and/or refractory multiple myeloma (RRMM). The REMIX study is one of the largest prospective, real-world analysis of the effectiveness of IXA-Rd in the setting of RRMM. Conducted in France between August 2017 and October 2019, the REMIX study, a non-interventional prospective study, included 376 patients receiving IXA-Rd in second line or later and followed for at least 24 months. Primary endpoint was the median progression-free survival (mPFS). Median age was 71 years (Q1-Q3 65.0 - 77.5) with 18.4% of participants older than 80 years. IXA-Rd was initiated in L2, L3 and L4 + for 60.4%, 18.1% and 21.5%, respectively. mPFS was 19.1 months (95% CI [15.9, 21.5]) and overall response rate (ORR) was 73.1%. mPFS was 21.5, 21.9 and 5.8 months in patients receiving IXA-Rd as L2, L3, L4 + respectively. Among patients receiving IXA-Rd in L2 and L3, mPFS was similar for patients previously exposed to lenalidomide (19.5 months) than for those lenalidomide naive (not exposed, 22.6 months, p = 0.29). mPFS was 19.1 months in patients younger than 80 years and 17.4 months in those 80 years or older (p = 0.06) with similar ORR (72.4% and 76.8%) in both subgroups. Adverse events (AEs) were reported in 78.2% of patients including 40.7% of treatment-related AE. IXA discontinuation was due to toxicity in 21% of patients. To conclude, the results of the REMIX study are consistent with the results of Tourmaline-MM1 and confirm the benefit of IXA-Rd combination in real life. It shows the interest of IXA-Rd in an older and frailer population, with an acceptable effectiveness and tolerance.

Safe and prolonged survival with long-term exposure to pomalidomide in relapsed/refractory myeloma.

BACKGROUND: The IFM2009-02 trial studied pomalidomide (4 mg daily, 21/28 versus 28/28) and dexamethasone in very advanced relapsed or refractory multiple myeloma (RRMM). We observed that 40% of patients had a prolonged progression-free survival (PFS) and subsequently overall survival (OS). We sought to analyze the characteristics of these patients and study the effect of long exposure to pomalidomide. DESIGN: We separated the studied population into two groups: 3 months to 1 year (<1 year) and more than 1 year (≥1 year) of treatment with pomalidomide and dexamethasone based on clinical judgment and historical control studies. We then analyzed the characteristics of patients according to duration of treatment. RESULTS: The overall response rate (ORR) for the <1-year group was 43%, the median PFS 4.6 months [95% confidence interval (95% CI) 3.8-6.4] with only 6% at 12 months, and the median OS was 15 months (11.7-20.3) and 40% at 18 months. For the ≥1-year group, the response rate and survival were strikingly different, ORR at 83%, median PFS 20.7 months (14.7-35.4), median OS not reached, and 91% at 18 months. CONCLUSION: Pomalidomide and dexamethasone favored prolonged and safe exposure to treatment in 40% of heavily treated and end-stage RRMM, a paradigm shift in the natural history of RRMM characterized with a succession of shorter disease-free intervals and ultimately shorter survival. Although an optimization of pomalidomide-dexamethasone regimen is warranted in advanced RRMM, we claim that pomalidomide has proven once more to change the natural history of myeloma in this series, which should be confirmed in a larger study.

Treatment of older patients with mantle-cell lymphoma.

BACKGROUND: The long-term prognosis for older patients with mantle-cell lymphoma is poor. Chemoimmunotherapy results in low rates of complete remission, and most patients have a relapse. We investigated whether a fludarabine-containing induction regimen improved the complete-remission rate and whether maintenance therapy with rituximab prolonged remission. METHODS: We randomly assigned patients 60 years of age or older with mantle-cell lymphoma, stage II to IV, who were not eligible for high-dose therapy to six cycles of rituximab, fludarabine, and cyclophosphamide (R-FC) every 28 days or to eight cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) every 21 days. Patients who had a response underwent a second randomization to maintenance therapy with rituximab or interferon alfa, each given until progression. RESULTS: Of the 560 patients enrolled, 532 were included in the intention-to-treat analysis for response, and 485 in the primary analysis for response. The median age was 70 years. Although complete-remission rates were similar with R-FC and R-CHOP (40% and 34%, respectively; P=0.10), progressive disease was more frequent with R-FC (14%, vs. 5% with R-CHOP). Overall survival was significantly shorter with R-FC than with R-CHOP (4-year survival rate, 47% vs. 62%; P=0.005), and more patients in the R-FC group died during the first remission (10% vs. 4%). Hematologic toxic effects occurred more frequently in the R-FC group than in the R-CHOP group, but the frequency of grade 3 or 4 infections was balanced (17% and 14%, respectively). In 274 of the 316 patients who were randomly assigned to maintenance therapy, rituximab reduced the risk of progression or death by 45% (in remission after 4 years, 58%, vs. 29% with interferon alfa; hazard ratio for progression or death, 0.55; 95% confidence interval, 0.36 to 0.87; P=0.01). Among patients who had a response to R-CHOP, maintenance therapy with rituximab significantly improved overall survival (4-year survival rate, 87%, vs. 63% with interferon alfa; P=0.005). CONCLUSIONS: R-CHOP induction followed by maintenance therapy with rituximab is effective for older patients with mantle-cell lymphoma. (Funded by the European Commission and others; ClinicalTrials.gov number, NCT00209209.).

The use of bisphosphonates in multiple myeloma: recommendations of an expert panel on behalf of the European Myeloma Network.

BACKGROUND: Bisphosphonates (BPs) prevent, reduce, and delay multiple myeloma (MM)-related skeletal complications. Intravenous pamidronate and zoledronic acid, and oral clodronate are used for the management of MM bone disease. The purpose of this paper is to review the current evidence for the use of BPs in MM and provide European Union-specific recommendations to support the clinical practice of treating myeloma bone disease. DESIGN AND METHODS: An interdisciplinary, expert panel of specialists on MM and myeloma-related bone disease convened for a face-to-face meeting to review and assess the evidence and develop the recommendations. The panel reviewed and graded the evidence available from randomized clinical trials, clinical practice guidelines, and the body of published literature. Where published data were weak or unavailable, the panel used their own clinical experience to put forward recommendations based solely on their expert opinions. RESULTS: The panel recommends the use of BPs in MM patients suffering from lytic bone disease or severe osteoporosis. Intravenous administration may be preferable; however, oral administration can be considered for patients unable to make hospital visits. Dosing should follow approved indications with adjustments if necessary. In general, BPs are well tolerated, but preventive steps should be taken to avoid renal impairment and osteonecrosis of the jaw (ONJ). The panel agrees that BPs should be given for 2 years, but this may be extended if there is evidence of active myeloma bone disease. Initial therapy of ONJ should include discontinuation of BPs until healing occurs. BPs should be restarted if there is disease progression. CONCLUSIONS: BPs are an essential component of MM therapy for minimizing skeletal morbidity. Recent retrospective data indicate that a modified dosing regimen and preventive measures can greatly reduce the incidence of ONJ.

Rituximab salvage therapy in adults with immune thrombocytopenia: retrospective study on efficacy and safety profiles.

Splenectomy remains the preferred treatment for chronic immune thrombocytopenia (ITP) after corticosteroid failure, despite the risks of despite surgical complications and infection. The aim of this study was to assess the efficacy of and tolerance to rituximab through a retrospective analysis of 35 refractory/relapsing ITP patients treated from 2004 to 2013. The median age of subjects was 46 years (14-80). Rituximab was given at a weekly dose of 375 mg/m(2) for 4 weeks. Median time from diagnosis to first infusion was 17 months (1-362) and follow-up was 47 months (2-133). The overall response rates at 1 and 2 years after the first infusion were 47 and 38 %, with complete response rates of 24 and 25 %, respectively. Median duration of response was 38 months (1-123), with 37 % of patients maintaining a durable response (>1 year). Twenty-nine percent of patients had undergone splenectomy. A durable response after rituximab was more frequently observed in patients undergoing second-line therapy than those in third or later (83 versus 35 %, P = 0.01). Forty-four percent of patients experienced mild hypogammaglobulinaemia after rituximab, and no clinical infection occurred. To conclude, rituximab should be considered as an alternative treatment to splenectomy. Its efficacy and safety profile should lead us to choose this medical option therapy before surgery for ITP patients.

Prognostic factors in patients with aggressive non-Hodgkin's lymphoma treated by front-line autotransplantation after complete remission: a cohort study by the Groupe d'Etude des Lymphomes de l'Adulte.

PURPOSE: Improved survival has been observed in aggressive non-Hodgkin's lymphoma (NHL) patients with adverse prognostic factors when autotransplantation (ASCT) was performed after complete remission. However, there is no agreement on the prognostic factors for patients treated with ASCT. We aimed to estimate the prognostic effect of clinical and biologic variables on relapse and survival rates by pooling the data from two trials. PATIENTS AND METHODS: Of the patients treated in the LNH87 and LNH93 trials, 330 under age 60 years achieved complete remission after high-dose cyclophosphamide, doxorubicin, vincristine, and prednisone, and received consolidative ASCT; 16% of patients had T-cell NHL. The International Prognostic Index (IPI) score was 0 for 11%, 1 for 23%, 2 for 51%, and 3 for 15%. Univariate and Cox multivariate survival analyses were retrospectively performed on this population. RESULTS: Overall survival was 75 +/- 5% at 5 years and disease-free survival (DFS) 67 +/- 5%. For T-cell NHL, these scores were 54% and 44%, respectively. The IPI score had no prognostic value and only the following parameters adversely affected overall survival and DFS (P <.05): marrow involvement; more than one extranodal site; histology (nonanaplastic T-cell v others); and type of anthracycline (mitoxantrone v doxorubicin, for DFS only). CONCLUSION: These results suggest that ASCT can prevent relapse in patients with adverse IPI factors. However, patients presenting with a nonanaplastic T-cell phenotype, more than one extranodal site, or marrow involvement still have a higher risk of relapse. These factors should be taken into account when designing post-ASCT maintenance studies.

Unusual Extramedullary Plasmacytoma: A Rare but Possible Cause of Lymphadenopathy in Chronic Lymphocytic Leukemia.

Cervical bilateral lymphadenopathy is a frequent event during chronic lymphocytic leukemia (CLL) natural history. However, lymph node biopsy is generally not required as long as transformation into an aggressive lymphoma (Richter syndrome) is not suspected. We present here a rare case of CLL patient who developed progressive bilateral cervical lymph node and bilateral tonsillar hypertrophy. CLL front-line therapy was ineffective leading to adenectomy and diagnosis of concomitant extramedullary plasmacytoma. Radiotherapy did not result in the disappearance of lymphadenopathy. Adenectomy should be performed in CLL cases to avoid misdiagnosis.

[Pomalidomide for multiple myeloma]. / Le pomalidomide dans le myélome multiple.

Once characterized by a very poor outcome, multiple myeloma (MM) now has a significantly prolonged survival, with major improvements allowed by the use of "novel agents": proteasome inhibitors (first-in-class bortezomib) and immunomodulatory compounds (IMiDs; first-in-class thalidomide and lenalidomide). However, the vast majority - if not all - of patients with MM ultimately end up being refractory to all existing drugs, including these efficient novel agents. There is a clear unmet medical need in this situation, which warrants the development of the next generation of proteasome inhibitors and IMiDs, as well as new drug classes. This review focuses on pomalidomide, the next generation IMiD, recently approved by the US FDA and the EMA for patients with relapsed or refractory MM who have received at least two prior therapies, including lenalidomide and bortezomib, and have demonstrated disease progression on their last therapy.

Modulation of rabbit articular chondrocyte (RAC) proliferation by TGF-beta isoforms.

We have previously shown that TGF-beta 1 exerts a bifunctional effect on RAC proliferation. Added to quiescent cultures, it inhibits the entry of G0/G1 cells into S phase whereas in S phase synchronized populations, it stimulates the DNA replication rate with a delayed G2 + M phase and a subsequent transient increase of cell number. As TGF-beta 2 and beta 3 isoforms are also expressed in bone and cartilage tissues, it was of interest to study their effect on RAC proliferation, in comparison to that of TGF-beta 1. Using cell counting and tritiated thymidine incorporation, we found that all the TGF-beta s used here induced an increase of RAC proliferation rate occurring between 24 and 48 h of exposure. TGF-beta 2 appeared as the most efficient form as judged from the maximum of thymidine labelling. However, TGF-beta 3 induced an increase of cell number slightly higher than both TGF-beta 1 and TGF-beta 2 (+30% versus 20% for TGF-beta 1 and beta 2). TGF-beta 2 and beta 3 were able to stimulate the DNA replication rate as previously demonstrated for TGF-beta 1. However, the effect occurred later for TGF-beta 2 and beta 3 (12 h) than for TGF-beta 1 (6 h). This was confirmed by flow cytometric analysis of DNA content. In addition, immunodetection by flow cytometry demonstrated that all TGF-beta isoforms enhanced endogenous expression of TGF-beta-related peptides. The effect was shown to be associated with the cell cycle S phase and was greater for TGF-beta 3 than for TGF-beta 1 and beta 2. These findings suggest that TGF-beta s could act on RAC functions via autocrine and paracrine ways. Taken together, these data indicate that TGF-beta s may modulate proliferation of articular chondrocytes and therefore could play a role in the activation of these cells in the early stages of osteoarthritis.

Cyclin D1 expression in patients with multiple myeloma.

INTRODUCTION: Chromosomal abnormalities are detected in 50 to 70% of patients with multiple myeloma (MM). By conventional cytogenetic analysis, a t(11;14)(q13;q32) is observed at a frequency of 3 to 14%. MATERIALS AND METHODS: To demonstrate a cyclin D1 expression in MM patients or MM cell lines, 14 patients with multiple myeloma (MM) and nine human multiple myeloma cell lines (HMCL) were screened by a competitive RT-PCR and/or Northern blot analysis for cyclin D1 expression. Furthermore, we screened 10 MM patients with FISH to demonstrate a relationship between the cyclin D1 expression and the presence of the t(11;14). RESULTS: Five HMCL had a cyclin D1 overexpression: three of them had a t(11;14)(q13;q32) and two had extra copies of chromosome 11. A cyclin D1 expression was found at diagnosis in seven out of 14 untreated MM patients (50%). Out of 14 MM patients, FISH studies were performed in 10 patients. A t(11;14) was detected in three out of 10 patients and extra copies of chromosome 11 were found in two additional patients. CONCLUSION: Cyclin D1 expression is a common event in MM patients (50%) and is associated either with a t(11;14)(q13;q32) or extra copies of chromosome 11. The prognostic role of the cyclin D1 expression and the level of this expression, as compared to other B-cell chronic lymphoproliferative disorders such as mantle cell lymphoma or hairy cell leukemia, remains to be determined in the pathogenesis of multiple myeloma.

IgE multiple myeloma.

IgE multiple myeloma is a rare disease characterized by a high frequency of Bence-Jones proteinuria and plasma cell leukaemia when compared to other isotypes of monoclonal proteins. Only 35 cases have been reported. We describe a 70-year-old woman with a stage III IgE kappa multiple myeloma presenting with a sacral plasmacytoma. Immunological and biochemical studies showed IgE kappa producing tumoral plasma cells. Serum total IgE was high without clinical symptoms suggesting an hyperIgE syndrome or mast cell activation. The patient underwent surgical removal of the sacral tumor and monthly melphalan-prednisone treatment together with intravenous pamidronate infusions. Magnetic Resonance Imaging (MRI) of the dorsolumbar spine revealed an epidural process leading to T6-T9 radiotherapy. Bone densitometry showed a decreased bone mineral content supporting the management of myeloma-related osteoporosis with bisphosphonate infusions. A good partial response with plateau-phase and increase of bone mineral content was achieved after 1 year of treatment and still persists after a 28 months follow-up.

Severe lupus with infectious thyroiditis and lethal cardiomyopathy.

Clinical cardiomyopathy is an uncommon complication of systemic lupus erythematosus (SLE) and intracavitary thrombosis is rare. We describe a patient with active SLE who developed rapidly progressive cardiomyopathy, the fatal course of which was complicated by an intracavitary thrombus. Repeat cardiac echography studies and the endomyocardial biopsy proved to be helpful in diagnosing the lupus myocarditis and aided the regulation of therapy. Furthermore, the patient presented an acute suppurative thyroiditis never before described, to our knowledge, in SLE.

[Polycythemia vera and pregnancy]. / Maladie de Vaquez et grossesse.

Polycythemia vera is a rare chronic myeloproliferative disease. Its exceptional association with pregnancy can lead to severe complications. Antithrombotic treatment could prevent such adverse outcome. A patient with two previous pregnancies complicated by preeclampsia, was treated by hydroxyurea for polycythemia vera. She started a new unexpected gestation without this myelosuppressive treatment and the pregnancy was conducted uneventfully with low molecular weight heparin and low dose aspirin. Thrombotic complications required the reintroduction of hydroxyurea. Diagnosis of polycythemia vera during pregnancy is a very difficult task due to physiologic changes occurring during gestation. Adverse outcome including severe vascular complications can be a preclinical phase of the disease. An adequate therapy could prevent these complications.

Transforming growth factor-beta (TGF-beta) and articular chondrocytes.

Transforming growth factor-beta (TGF-beta) has a dual effect on the proliferation of joint chondrocytes. In medium with a low serum concentration, it inhibits cell growth, while in medium supplemented with 10% fetal calf serum it stimulates cell growth. This stimulation leads to a higher replication rate an a larger number of cells in the G2/M phase of the cell cycle. Since these cells have already replicated their DNA, they can begin mitosis when stimulated by a EGF type factor. This mechanism involves the systems of the TGF-beta receptors which appear to vary with the cell cycle. In addition, a glycane inositophosphate may play a role as a second messenger for TGG-beta in this action. Finally, TGF-beta cannot restore the chondrocyte phenotype in dedifferentiated cells nor limit the dedifferentiation process. It exerts a opposing effect to the deleterious effects of interleukin-1 by inhibiting the expression of the receptors of this cytokine at the level of transcription. These in vitro effects would suggest that TGF-beta plays an important role in the repair potentiality of joint cartilage especially in arthrosis. In vivo studies are however necessary to verify this hypothesis.

[Autoimmune thrombopenic purpura. Therapeutic modalities]. / Purpura thrombopénique auto-immun. Modalités thérapeutiques.

TOP PRIORITY: Preventing hemorrhage is the number one priority in the treatment of idiopathic thrombocytopenic purpura. There are three main treatments: corticosteroids, intravenous immunoglobulins and splenectomy. CORTICOSTEROIDS: The main effects of corticosteroids are to reduce platelet phagocytosis, counteract mechanisms leading to inhibited thrombopoiesis, limit vascular fenestration and endothelial fragility, and immuno-depression. Corticosteroids are usually started at 1 to 2 mg/kg/day for 2 or 3 weeks before rapidly tapering off to final withdrawal after 3 or 4 weeks. IV IMMUNOGLOBULINS: Administered by intravenous injections, immunoglobulins saturate the Fc fragment of the IgGs on the surface of the macrophages, neutralize antiplatelet antibodies, and inhibits synthesis of antiplatelet autoantibodies. Treatment cost is high as is the risk of adverse effects. SPLENECTOMY: The most effective long-term treatment, splenectomy is particularly useful when platelet sequestration, as identified by radiolabeling occurs mainly in the spleen. OTHER THERAPIES: Anti-D immunoglobulins (limited availability), danazol or immuno-suppressors have a beneficial effect which disappears after withdrawal. INDICATIONS: Essential elements are the risk of hemorrhage (low or nil above 30000 platelets/mm3), its severity, patients status (childhood cases usually resolve spontaneously) and prognosis factors (idiopathic thrombocytopenic purpura is a benign disorder).

[Psoriatic onycho-pachydermo-periostitis]. / Onycho-pachydermo-périostite psoriasique.

Psoriatic-onycho-pachydermo-periostitis is a particular form of psoriatic arthropathy recently described, which combine psoriatic onychosis, thickening of the distal soft tissues and osteo-periostitis of the distal phalanx without lesion of the interphalangeal joint. Biological examinations are normal. Radiological lesions show a phalanx condensation which gives a spicule aspect. Two cases of onycho-pachydermo-periostitis are described. We report the first one with all the fingers and toes concerned.

[Classical Kaposi sarcoma and volcanic soil in southern Italy: a case-control study]. / Sarcoma di Kaposi classico e suolo vulcanico nel Sud Italia: uno studio caso-controllo.

We tested the hypothesis of a relationship between Kaposi's sarcoma (KS) and volcanic soil by means of a case-control study based on 70 cases of classic KS and 280 hospital controls from the Campania region, an area of active volcanism in the South of Italy. Birth and residence in volcanic areas were associated with approximately two-fold elevated KS risks. If not due to chance, increased risk in the presence of volcanic soil can have different interpretations, including local immune impairment and correlation with unknown environmental or genetic KS predisposing factors.

[Concomitant pulmonary nocardiosis and Hodgkin's disease: importance of long-term treatment]. / Nocardiose pulmonaire lors du diagnostic de maladie de Hodgkin.

A 32-year-old patient taking corticosteroid therapy for 10 months for autoimmune hemolytic anemia developed Hodgkin's disease and concomitant acute pulmonary nocardiosis. After treatment with imipenen and amikacin for 15 days, which was adapted to susceptibility tests, multiple-drug chemotherapy using the ABVD protocol (doxorubicin, bléomycin, vinblastine, dacarbazine) was given without recurrence of the pulmonary infection. Antibiotic prophylaxis using a minocycine-erythromycin combination was continued for 8 months. We discuss the importance of long-term treatment based on data in the literature.

[Congestive outbreaks of osteo-arthrosis]. / Les poussées congestives de l'arthrose.

Osteo-arthritis is often interspersed with congestive episodes due to inflammation of the synovial membranes, the vascular component of which is more important than the cellular component. This explains why the clinical signs of inflammation are moderate and characterized mainly by a mechanical-type formula. The mechanism of these episodes involves several factors, and osteo-cartilaginous fragments, microcrystals and perhaps immune complexes have been blamed for their occurrence. The influence of inflammation on cartilage degradation has been proved experimentally, and this is supported by some clinical findings. Treatment consists of non-steroidal anti-inflammatory agents, intra-articular corticosteroid injections and relief of articular overload.

Predictive factors for a single successful cytapheresis session during the first mobilisation.

To avoid repeated apheresis, the objective of this study was to analyse the predictive factors for a single successful cytapheresis during the first mobilisation. The pre-collection characteristics of 170 lymphoma and 95 myeloma patients were analysed. Among 60 lymphoma patients who had less than 30 CD34 cells/mm(3) the day before the first apheresis, an increase in the CD34 cell count between Day -1 and Day 1 was predictive of first stem cell mobilisation success, with a sensitivity of 100% if the Day 1 was higher than 30/mm(3) (10/60 patients). Success rate of obtaining an appropriate number of stem cells in one apheresis was 120 among 170 patients.