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Meletios A. Dimopoulos - One of the best experts on this subject based on the ideXlab platform.
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pomalidomide bortezomib and dexamethasone for multiple myeloma previously treated with Lenalidomide optimismm outcomes by prior treatment at first relapse
Leukemia, 2020Co-Authors: Meletios A. Dimopoulos, Jesus F Sanmiguel, Darrell White, Katja Weisel, Philippe Moreau, Larry D Anderson, Pieter Sonneveld, Monika Engelhardt, Matthew W Jenner, Alessandro CorsoAbstract:In the phase 3 OPTIMISMM trial, pomalidomide, bortezomib, and dexamethasone (PVd) demonstrated superior efficacy vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma previously treated with Lenalidomide, including those refractory to Lenalidomide. This analysis evaluated outcomes in patients at first relapse (N = 226) by Lenalidomide-refractory status, prior bortezomib exposure, and prior stem cell transplant (SCT). Second-line PVd significantly improved PFS vs Vd in Lenalidomide-refractory (17.8 vs 9.5 months; P = 0.0276) and Lenalidomide-nonrefractory patients (22.0 vs 12.0 months; P = 0.0491), patients with prior bortezomib (17.8 vs 12.0 months; P = 0.0068), and patients with (22.0 vs 13.8 months; P = 0.0241) or without (16.5 vs 9.5 months; P = 0.0454) prior SCT. In patients without prior bortezomib, median PFS was 20.7 vs 9.5 months (P = 0.1055). Significant improvement in overall response rate was also observed with PVd vs Vd in Lenalidomide-refractory (85.9% vs 50.8%; P < 0.001) and Lenalidomide-nonrefractory (95.7% vs 60.0%; P < 0.001) patients, with similar results regardless of prior bortezomib or SCT. No new safety signals were observed. These data demonstrate the benefit of PVd at first relapse, including immediately after upfront Lenalidomide treatment failure and other common first-line treatments.
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daratumumab plus Lenalidomide and dexamethasone versus Lenalidomide and dexamethasone in relapsed or refractory multiple myeloma updated analysis of pollux
Haematologica, 2018Co-Authors: Meletios A. Dimopoulos, Jesus F Sanmiguel, Andrew Belch, Darrell White, Lotfi Benboubker, Gordon Cook, Merav Leiba, James Morton, Kihyun Kim, Naoki TakezakoAbstract:In the POLLUX study, daratumumab plus Lenalidomide/dexamethasone significantly reduced risk of progression/death versus Lenalidomide/dexamethasone alone in relapsed/refractory multiple myeloma. We provide one additional year of follow up and include the effect on minimal residual disease and in clinically relevant subgroups. After 25.4 months of follow up, daratumumab plus Lenalidomide/dexamethasone prolonged progression-free survival versus Lenalidomide/dexamethasone alone (median not reached vs. 17.5 months; hazard ratio, 0.41; 95% confidence interval, 0.31-0.53; P 12 and ≤12 months and >6 and ≤6 months. No new safety signals were observed. In relapsed/refractory multiple myeloma patients, daratumumab plus Lenalidomide/dexamethasone continued to improve progression-free survival and deepen responses versus Lenalidomide/dexamethasone. Trial Registration: clinicaltrials.gov identifier: 02076009.
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Lenalidomide and dexamethasone in transplant ineligible patients with myeloma
The New England Journal of Medicine, 2014Co-Authors: Lotfi Benboubker, Meletios A. Dimopoulos, Andrew Belch, Angela Dispenzieri, John Catalano, Michele Cavo, Antonello Pinto, Katja Weisel, Heinz Ludwig, Nizar J BahlisAbstract: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 len...
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Lenalidomide melphalan and prednisone followed by Lenalidomide maintenance improves health related quality of life in newly diagnosed multiple myeloma patients aged 65 years or older results of a randomized phase iii trial
Haematologica, 2013Co-Authors: Meletios A. Dimopoulos, Martin Kropff, Maria Teresa Petrucci, Michel Delforge, Roman Hajek, Philip Lewis, Annabel Nixon, Jingshan Zhang, Jay Mei, Antonio PalumboAbstract:The MM-015 trial assessed the effect of Lenalidomide-based therapy on health-related quality of life. Patients (n=459) with newly diagnosed multiple myeloma aged 65 years or over were randomized 1:1:1 to nine 4-week cycles of Lenalidomide, melphalan, and prednisone, followed by Lenalidomide maintenance; or Lenalidomide, melphalan, and prednisone, or melphalan and prednisone, with no maintenance therapy. Patients completed health-related quality of life questionnaires at baseline, after every third treatment cycle, and at treatment end. Health-related quality of life improved in all treatment groups during induction therapy. Patients receiving Lenalidomide maintenance had the most pronounced improvements, Global Health Status/Quality of Life (P<0.05), Physical Functioning (P<0.01), and Side Effects of Treatment (P<0.05) out of 6 pre-selected health-related quality of life domains. More patients receiving Lenalidomide maintenance achieved minimal important differences (P<0.05 for Physical Functioning). Therefore, Lenalidomide, melphalan, and prednisone, followed by Lenalidomide maintenance, improves health-related quality of life in patients with newly diagnosed multiple myeloma. (Clinicaltrials.gov identifier NCT00405756).
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Lenalidomide melphalan and prednisone followed by Lenalidomide maintenance improves health related quality of life in newly diagnosed multiple myeloma patients aged 65 years or older results of a randomized phase iii trial
Haematologica, 2013Co-Authors: Meletios A. Dimopoulos, Martin Kropff, Maria Teresa Petrucci, Michel Delforge, Roman Hajek, Philip Lewis, Annabel Nixon, Jingshan Zhang, Antonio PalumboAbstract:The MM-015 trial assessed the effect of Lenalidomide-based therapy on health-related quality of life. Patients (n=459) with newly diagnosed multiple myeloma aged 65 years or over were randomized 1:1:1 to nine 4-week cycles of Lenalidomide, melphalan, and prednisone, followed by Lenalidomide maintenance; or Lenalidomide, melphalan, and prednisone, or melphalan and prednisone, with no maintenance therapy. Patients completed health-related quality of life questionnaires at baseline, after every third treatment cycle, and at treatment end. Health-related quality of life improved in all treatment groups during induction therapy. Patients receiving Lenalidomide maintenance had the most pronounced improvements, Global Health Status/Quality of Life ( P <0.05), Physical Functioning ( P <0.01), and Side Effects of Treatment ( P <0.05) out of 6 pre-selected health-related quality of life domains. More patients receiving Lenalidomide maintenance achieved minimal important differences ( P <0.05 for Physical Functioning). Therefore, Lenalidomide, melphalan, and prednisone, followed by Lenalidomide maintenance, improves health-related quality of life in patients with newly diagnosed multiple myeloma. ( [Clinicaltrials.gov][1] identifier [NCT00405756][2]). [1]: http://Clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00405756&atom=%2Fhaematol%2F98%2F5%2F784.atom
Blake J Bartlett - One of the best experts on this subject based on the ideXlab platform.
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Lenalidomide enhances natural killer cell and monocyte mediated antibody dependent cellular cytotoxicity of rituximab treated cd20 tumor cells
Clinical Cancer Research, 2008Co-Authors: Mary Adams, Peter H Schafer, Troy Carter, Roger Shenchu Chen, George W Muller, David I Stirling, Blake J BartlettAbstract:Purpose: Lenalidomide has significant activity in myelodysplastic syndromes, multiple myeloma, and non-Hodgkin9s lymphoma (NHL). In previous studies, natural killer (NK) cell expansion by Lenalidomide was shown to enhance the cytotoxic effect of rituximab. This study assessed the ability of Lenalidomide to enhance antibody-dependent cellular cytotoxicity (ADCC) in rituximab-treated NHL cell lines and primary tumor cells from patients with B-cell chronic lymphocytic leukemia (B-CLL) in vitro . Experimental Design: An in vitro ADCC system was used to assess the ability of Lenalidomide to enhance human NK cell and monocyte function in response to rituximab. Results: Lenalidomide directly enhanced IFN-γ production via Fc-γ receptor-mediated signaling in response to IgG. It was also a potent enhancer of NK cell-mediated and monocyte-mediated tumor cell ADCC for a variety of rituximab-treated NHL cell lines in vitro , an effect that was dependent on the presence of antibody and either interleukin-2 or interleukin-12. Lenalidomide also enhanced the ability of NK cells to kill primary tumor cells derived from three patients with B-CLL who have been treated previously with fludarabine plus cyclophosphamide. Enhanced NK cell ADCC was associated with enhanced granzyme B and Fas ligand expression and could be inhibited by a granzyme B inhibitor and partially inhibited by antibody to FasL. Enhanced NK cell Fc-γ receptor signaling is associated with enhanced phosphorylated extracellular signal-related kinase levels leading to enhanced effector function. Conclusions: These findings suggest that Lenalidomide has the potential to enhance the rituximab-induced killing of NHL cell lines and primary B-cell chronic lymphocytic leukemia cells via a NK cell-mediated and monocyte-mediated ADCC mechanism in vitro , providing a strong rationale for the combination of Lenalidomide with IgG1 antibodies to target tumor-specific antigens in patients with cancer.
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Lenalidomide enhances natural killer cell and monocyte mediated antibody dependent cellular cytotoxicity of rituximab treated cd20 tumor cells
Clinical Cancer Research, 2008Co-Authors: Lei Wu, Peter H Schafer, Mary Adams, Troy Carter, Roger Shenchu Chen, George W Muller, David I Stirling, Blake J BartlettAbstract:Purpose: Lenalidomide has significant activity in myelodysplastic syndromes, multiple myeloma, and non-Hodgkin9s lymphoma (NHL). In previous studies, natural killer (NK) cell expansion by Lenalidomide was shown to enhance the cytotoxic effect of rituximab. This study assessed the ability of Lenalidomide to enhance antibody-dependent cellular cytotoxicity (ADCC) in rituximab-treated NHL cell lines and primary tumor cells from patients with B-cell chronic lymphocytic leukemia (B-CLL) in vitro . Experimental Design: An in vitro ADCC system was used to assess the ability of Lenalidomide to enhance human NK cell and monocyte function in response to rituximab. Results: Lenalidomide directly enhanced IFN-γ production via Fc-γ receptor-mediated signaling in response to IgG. It was also a potent enhancer of NK cell-mediated and monocyte-mediated tumor cell ADCC for a variety of rituximab-treated NHL cell lines in vitro , an effect that was dependent on the presence of antibody and either interleukin-2 or interleukin-12. Lenalidomide also enhanced the ability of NK cells to kill primary tumor cells derived from three patients with B-CLL who have been treated previously with fludarabine plus cyclophosphamide. Enhanced NK cell ADCC was associated with enhanced granzyme B and Fas ligand expression and could be inhibited by a granzyme B inhibitor and partially inhibited by antibody to FasL. Enhanced NK cell Fc-γ receptor signaling is associated with enhanced phosphorylated extracellular signal-related kinase levels leading to enhanced effector function. Conclusions: These findings suggest that Lenalidomide has the potential to enhance the rituximab-induced killing of NHL cell lines and primary B-cell chronic lymphocytic leukemia cells via a NK cell-mediated and monocyte-mediated ADCC mechanism in vitro , providing a strong rationale for the combination of Lenalidomide with IgG1 antibodies to target tumor-specific antigens in patients with cancer.
Peter H Schafer - One of the best experts on this subject based on the ideXlab platform.
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Lenalidomide efficacy in activated b cell like subtype diffuse large b cell lymphoma is dependent upon irf4 and cereblon expression
British Journal of Haematology, 2013Co-Authors: Linghua Zhang, Jolanta Kosek, Maria Wang, Carla Heise, Peter H Schafer, Rajesh ChopraAbstract:Durable responses with Lenalidomide monotherapy have been reported in patients with non-Hodgkin lymphoma. In relapsed/refractory diffuse large B-cell lymphoma (DLBCL), higher responses were observed in the activated B-cell-like (ABC) subtype than in the germinal centre B-cell-like subtype. Herein, the molecular mechanisms involved in the differential efficacy of Lenalidomide in DLBCL subtypes were investigated. Using DLBCL cell lines, Lenalidomide treatment was found to preferentially suppress proliferation of ABC-DLBCL cells in vitro and delay tumour growth in a human tumour xenograft model, with minimal effect on non-ABC-DLBCL cells. This tumouricidal effect was associated with downregulation of interferon regulatory factor 4 (IRF4), a hallmark of ABC-DLBCL cells. IRF4 inhibition by Lenalidomide induced downregulation of B-cell receptor (BCR)-dependent NF-κB. Whereas IRF4-specific small, interfering RNA mimicked the effects of Lenalidomide reducing NF-κB activation, IRF4 overexpression enhanced NF-κB activation and conferred resistance to Lenalidomide. These findings indicate the crucial role of IRF4 inhibition in Lenalidomide efficacy in ABC cells. Furthermore, Lenalidomide-induced IRF4 downregulation required the expression of cereblon, a molecular target of Lenalidomide. Taken together, these findings suggest that Lenalidomide has direct antitumour activity against DLBCL cells, preferentially ABC-DLBCL cells, by blocking IRF4 expression and the BCR-NF-κB signalling pathway in a cereblon-dependent manner.
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Lenalidomide efficacy in activated b cell like subtype diffuse large b cell lymphoma is dependent upon irf4 and cereblon expression
Blood, 2012Co-Authors: Linghua Zhang, Jolanta Kosek, Maria Wang, Carla Heise, Peter H Schafer, Rajesh ChopraAbstract:Abstract 3287 Background: Durable responses with Lenalidomide monotherapy have been reported in patients with non-Hodgkin lymphoma. In relapsed/refractory diffuse large B-cell lymphoma (DLBCL), higher responses were observed in the activated B-cell-like (ABC) subtype than in the germinal centre B-cell (GCB)-like subtype (Czuczman, et al. British Journal of Haematology, 2011, 154, 477–481). Herein, the molecular mechanisms involved in the differential efficacy of Lenalidomide in DLBCL subtypes were investigated. Methods: A panel of DLBCL cell lines, with 5 of ABC-subtype and 11 of non-ABC subtype, was collected and cell of origin subtype was confirmed based on literature, molecular and genetic analysis. The direct antiproliferative effect of Lenalidomide on DLBCL cells was assessed using the 3H-thymidine incorporation assay and apoptosis analysis. The molecular mechanisms involved in the antiproliferative efficacy of Lenalidomide in DLBCL subtypes were investigated by western blot, immunohistochemistry (IHC) and qRT-PCR analysis of key signaling events during B-cell receptor (BCR)-dependent NF-κB activation. The critical roles of interferon regulatory factor 4 (IRF4), and cereblon (CRBN) in Lenalidomide efficacy were established by knock-in or knock-down of these proteins in sensitive ABC cells. Finally, a mouse xenograft model was used to confirm the antitumor effect of Lenalidomide and the relevance of the molecular mechanism involved. Results: Using DLBCL cell lines, Lenalidomide treatment was found to preferentially suppress proliferation of ABC-DLBCL cells in vitro at a concentration range of 0.01–100 μM (the median plasma concentration at Cmax for patients receiving 25 mg Lenalidomide is 2.2 μM) and delay tumor growth in a human tumor xenograft model of OCI-Ly10 cells (Lenalidomide 3–30 mg/kg, p.o. qdX28), with minimal effect on non-ABC-DLBCL cells. This tumoricidal effect of Lenalidomide was associated with downregulation of IRF4, a survival factor in ABC-DLBCL cells. Treatment with Lenalidomide for 1–3 days, similar to the inhibitors of PKCb and MALT1 (LY-333,531 and z-VRPR-fmk, respectively), was found to significantly (p Furthermore, knockdown of CRBN in OCI-Ly10 (p Conclusions: These data may provide a mechanism for the preferential efficacy of Lenalidomide in ABC-DLBCL observed in clinical studies. These findings suggest that Lenalidomide has direct antitumor activity against DLBCL cells, preferentially ABC-DLBCL cells, by blocking IRF4 expression and the BCR-NF-κB signaling pathway in a cereblon-dependent manner (also see Figure below). Disclosures: Zhang:Celgene Corp: Employment, Equity Ownership. Kosek:Celgene Corp: Employment, Equity Ownership. Wang:Celgene Corporation: Employment, Equity Ownership. Heise:Celgene Corporation: Employment, Equity Ownership. Schafer:Celgene: Employment, Equity Ownership. Chopra:Celgene Corporation: Employment, Equity Ownership.
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Lenalidomide downregulates the cell survival factor interferon regulatory factor 4 providing a potential mechanistic link for predicting response
British Journal of Haematology, 2011Co-Authors: Antonia Lopezgirona, Linghua Zhang, Derek Mendy, Peter H Schafer, Daniel Heintel, Svetlana Gaidarova, Helen Brady, Justin B Bartlett, Martin Schreder, Arnold BolomskyAbstract:Summary Overexpression of the transcription factor interferon regulatory factor-4 (IRF4), which is common in multiple myeloma (MM), is associated with poor prognosis. Patients with higher IRF4 expression have significantly poorer overall survival than those with low IRF4 expression. Lenalidomide is an IMiD® immunomodulatory compound that has both tumouricidal and immunomodulatory activity in MM. This study showed that Lenalidomide downregulated IRF4 levels in MM cell lines and bone marrow samples within 8 h of drug exposure. This was associated with a decrease in MYC levels, as well as an initial G1 cell cycle arrest, decreased cell proliferation, and cell death by day 5 of treatment. In eight MM cell lines, high IRF4 levels correlated with increased Lenalidomide sensitivity. The clinical significance of this observation was investigated in 154 patients with MM. Among MM patients with high levels of IRF4 expression, treatment with Lenalidomide led to a significantly longer overall survival than other therapies in a retrospective analysis. These data confirm the central role of IRF4 in MM pathogenesis; indicate that this is an important mechanism by which Lenalidomide exerts its antitumour effects; and may provide a mechanistic biomarker to predict response to Lenalidomide.
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stimulation of t cells by Lenalidomide involves putative Lenalidomide binding proteins cd3 epsilon associated protein and gdp mannose pyrophosphorylase a
Blood, 2008Co-Authors: Anita K Gandhi, Derek Mendy, Antonia Lopezgirona, Audrey Rogovitz, Lisa Morrison, Weilin Xie, Peter H SchaferAbstract:Introduction: Lenalidomide is approved in the US for the treatment of transfusion-dependent patients with anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes associated with a del (5q) cytogenetic abnormality, with or without additional cytogenetic abnormalities. Lenalidomide is also approved for use in the US and Europe in combination with dexamethasone in previously treated multiple myeloma patients. In vitro and ex vivo studies have shown that Lenalidomide has a direct antiproliferative effect against tumor cells and induces antiangiogenesis. It has also been shown to have immunomodulatory activity, including co-stimulatory effects on T and NK cells. Using the yeast 3-hybrid system, based on a leukemia cDNA library and biotinylated Lenalidomide analog, we identified 16 putative Lenalidomide-binding proteins from 700,000 clones screened. These included CD3-epsilon-associated protein (CAST) and GDP-mannose pyrophosphorylase A (GMPPA). CAST binds to the T cell receptor and is also part of the RNA polymerase 1 complex. GMPPA is a nucleotidyl transferase that converts mannose-1-phosphate and GTP to GDP-mannose, which is involved in the production of N-linked oligosaccharides. To determine whether these proteins are required for Lenalidomide-induced immunomodulatory activity, we evaluated the Lenalidomide-induced upregulation of interleukin-2 (IL-2) production in primary T cells transfected with siRNA against CAST and GMPPA. Methods: Primary human peripheral blood T cells were transfected with CAST or GMPPA siRNA, or mock siRNA as a control. Reduction of CAST and GMPPA expression was confirmed by qRT-PCR. After 24 hours, transfected cells were stimulated with anti-CD3 mAb in the presence or absence of 0.1 and 1 μM Lenalidomide 48 hours. Cells were lysed after 48 hours, and IL-2 mRNA and mature protein levels were quantified using qPCR and ELISA, respectively. Results: CAST gene expression in T cells was reduced by 60% (p<0.05) in CAST siRNA-transfected cells. GMPPA gene expression was reduced by 66% (p<0.05) in GMPPA siRNA-transfected T cells. Lenalidomide-induced IL-2 mRNA production was reduced from 9-fold in controls to 6-fold in CAST siRNA transfectants (p<0.05) and from 15-fold in controls to 6-fold in GMPPA siRNA transfectants (p<0.05). Lenalidomide-induced IL-2 protein production was reduced from 22-fold in controls down to 8-fold in CAST siRNA transfectants (p<0.05) and from 5.6-fold in the controls down to 1.6-fold in GMPPA siRNA transfectants (p<0.05). Conclusion: These findings support the hypothesis that CAST and GMPPA play an important role in the Lenalidomide IL-2 induction mechanism in primary T cells.
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Lenalidomide enhances natural killer cell and monocyte mediated antibody dependent cellular cytotoxicity of rituximab treated cd20 tumor cells
Clinical Cancer Research, 2008Co-Authors: Mary Adams, Peter H Schafer, Troy Carter, Roger Shenchu Chen, George W Muller, David I Stirling, Blake J BartlettAbstract:Purpose: Lenalidomide has significant activity in myelodysplastic syndromes, multiple myeloma, and non-Hodgkin9s lymphoma (NHL). In previous studies, natural killer (NK) cell expansion by Lenalidomide was shown to enhance the cytotoxic effect of rituximab. This study assessed the ability of Lenalidomide to enhance antibody-dependent cellular cytotoxicity (ADCC) in rituximab-treated NHL cell lines and primary tumor cells from patients with B-cell chronic lymphocytic leukemia (B-CLL) in vitro . Experimental Design: An in vitro ADCC system was used to assess the ability of Lenalidomide to enhance human NK cell and monocyte function in response to rituximab. Results: Lenalidomide directly enhanced IFN-γ production via Fc-γ receptor-mediated signaling in response to IgG. It was also a potent enhancer of NK cell-mediated and monocyte-mediated tumor cell ADCC for a variety of rituximab-treated NHL cell lines in vitro , an effect that was dependent on the presence of antibody and either interleukin-2 or interleukin-12. Lenalidomide also enhanced the ability of NK cells to kill primary tumor cells derived from three patients with B-CLL who have been treated previously with fludarabine plus cyclophosphamide. Enhanced NK cell ADCC was associated with enhanced granzyme B and Fas ligand expression and could be inhibited by a granzyme B inhibitor and partially inhibited by antibody to FasL. Enhanced NK cell Fc-γ receptor signaling is associated with enhanced phosphorylated extracellular signal-related kinase levels leading to enhanced effector function. Conclusions: These findings suggest that Lenalidomide has the potential to enhance the rituximab-induced killing of NHL cell lines and primary B-cell chronic lymphocytic leukemia cells via a NK cell-mediated and monocyte-mediated ADCC mechanism in vitro , providing a strong rationale for the combination of Lenalidomide with IgG1 antibodies to target tumor-specific antigens in patients with cancer.
Paul G. Richardson - One of the best experts on this subject based on the ideXlab platform.
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Lenalidomide in combination or alone as maintenance therapy following autologous stem cell transplant in patients with multiple myeloma a review of options for and against
Expert Opinion on Pharmacotherapy, 2017Co-Authors: Paul G. Richardson, Robert L Schlossman, Michel Attal, Sarah A. Holstein, Kenneth C Anderson, Philip L MccarthyAbstract:ABSTRACTIntroduction: Lenalidomide has multifaceted antimyeloma properties, including direct tumoricidal and immunomodulatory effects. Several randomized controlled trials have demonstrated improved patient outcomes with Lenalidomide maintenance after autologous stem cell transplant (ASCT) in patients with newly diagnosed multiple myeloma (NDMM). Currently, single-agent Lenalidomide is the only approved post-ASCT maintenance therapy in the United States and European Union for patients with NDMM.Areas covered: This review article summarizes the efficacy and safety data of Lenalidomide maintenance, as monotherapy and in combination with other agents, following ASCT in patients with NDMM. In addition, emerging therapies with newer agents in this setting are discussed.Expert opinion: Following ASCT, maintenance therapy with Lenalidomide until progressive disease is an effective and well-tolerated regimen and represents the standard of care for patients with NDMM. Studies evaluating maintenance with lenalidomi...
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Lenalidomide in combination or alone as maintenance therapy following autologous stem cell transplant in patients with multiple myeloma a review of options for and against
Expert Opinion on Pharmacotherapy, 2017Co-Authors: Paul G. Richardson, Robert L Schlossman, Michel Attal, Sarah A. Holstein, Kenneth C Anderson, Philip L MccarthyAbstract:Lenalidomide has multifaceted antimyeloma properties, including direct tumoricidal and immunomodulatory effects. Several randomized controlled trials have demonstrated improved patient outcomes with Lenalidomide maintenance after autologous stem cell transplant (ASCT) in patients with newly diagnosed multiple myeloma (NDMM). Currently, single-agent Lenalidomide is the only approved post-ASCT maintenance therapy in the United States and European Union for patients with NDMM. Areas covered: This review article summarizes the efficacy and safety data of Lenalidomide maintenance, as monotherapy and in combination with other agents, following ASCT in patients with NDMM. In addition, emerging therapies with newer agents in this setting are discussed. Expert opinion: Following ASCT, maintenance therapy with Lenalidomide until progressive disease is an effective and well-tolerated regimen and represents the standard of care for patients with NDMM. Studies evaluating maintenance with Lenalidomide in combination with next-generation proteasome inhibitors, monoclonal antibodies, and histone deacetylase inhibitors may further improve patient outcomes.
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abstract 638 Lenalidomide treatment enhances the anti tumor activities of xbp1 specific cytotoxic t lymphocytes by increasing the frequency and tumor specific response of central memory cd3 cd8 t cells
Cancer Research, 2014Co-Authors: Jooeun Bae, Paul G. Richardson, Kenneth C Anderson, Rao Prabhala, Ruben D Carrasco, Glen Dranoff, Nikhil C MunshiAbstract:Introduction: Lenalidomide is an agent with immunomodulatory properties with demonstrated direct effects on the immune system and tumor microenvironment. The unfolded protein response (UPR) is a primary cellular adaptive mechanism that allows tumor cell survival under endoplasmic reticulum stress conditions by increasing its protein folding capacity. Thus, targeting the UPR is a rational approach for selective cancer cell killing. Here, we provide the basis for a novel immunotherapeutic approach by combining the antigen specific CTL against XBP1, an important transcriptional activator of the UPR, in combination with Lenalidomide, to boost the immune targeting against a variety of solid tumor cancer cells that over-express XBP1. Methods: XBP1 peptides-specific CTL (XBP1-CTL) were generated ex vivo from HLA-A2+ normal donors’ CD3+ T cells by repeated stimulation using a cocktail of heteroclitic XBP1 unspliced (US)184-192 (YISPWILAV) and XBP1 spliced (SP)367-375 (YLFPQLISV) peptides. XBP1-CTL were then incubated with or without Lenalidomide (5 µm), and evaluated for their immune responses and anti-tumor activities against breast, colon or pancreatic cancer cells. In addition, we characterized the XBP1-CTL, following lenalidamide treatment, for their enhanced expression of key T cell markers and transcriptional regulators, which are critical for immune function of effector and memory T cells. Results: An increased number of CD45RO+ memory CD3+CD8+ T cells, but not CD45RO- non-memory CD3+CD8+ T cells nor total CD3+CD8+ T cells, was observed within XBP1-CTL by Lenalidomide treatment. The combination of XBP1-CTL with Lenalidomide consistently enhanced the frequency and anti-tumor activity of the central memory CTL subset (CM: CD45RO+CCR7+/CD3+CD8+ T cells) as compared to the effector memory CTL subset (EM: CD45RO+CCR7-/CD3+CD8). In addition, Lenalidomide increased the expression of critical T cell surface markers including CD28, CD38, CD40L, CD69 and 41BB, but not ICOS nor TCRαβ. Lenalidomide treatment also enhanced anti-tumor activities of XBP1-CTL by increasing the frequencies of T-bet+/IFN-γ+, Eomes+/IFN-γ+, and Akt+ CD3+CD8+ T cells within both CM and EM subsets in response to HLA-A2+ breast (MB231), colon (LS180) or pancreatic (Panc1) cancer cell lines. Finally, the memory CD3+CD8+ T cells of XBP1-CTL displayed increased cytotoxicity (Granzyme B+) and IFN-γ production against the respective solid tumor cells when the XBP1-CTL were treated with Lenalidomide. Conclusions: This study provides the framework for using heteroclitic XBP1 US184-192 and XBP1 SP367-375 peptides as a vaccine to generate XBP1-CTL targeting a variety of solid tumors. Finally, it provides support for combination of the XBP1-based peptides vaccine with immunomodularoty drug Lenalidomide to improve patient outcome. Citation Format: Jooeun Bae, Rao Prabhala, Ruben Carrasco, Paul Richardson, Glen Dranoff, Kenneth C. Anderson, Nikhil C. Munshi. Lenalidomide treatment enhances the anti-tumor activities of XBP1 specific cytotoxic T lymphocytes by increasing the frequency and tumor-specific response of central memory CD3+CD8+ T cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 638. doi:10.1158/1538-7445.AM2014-638
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assessment of drug toxicity in patients with and without renal impairment receiving Lenalidomide at a large academic institution
Blood, 2013Co-Authors: Houry Leblebjian, Robert L Schlossman, Paul G. Richardson, Nikhil C Munshi, Irene M Ghobrial, Wanling Xie, Christy Harris, Claudia Pabaprada, Sylvia Bartel, Kenneth C AndersonAbstract:Background/Rationale Approximately 20-40% of multiple myeloma (MM) patients have renal impairment (RI) at diagnosis (Kyle et al. Mayo Clin Proc. 2003). Immediate initiation of interventions aimed at restoring renal function including but not limited to anti-MM chemotherapy is critical in such patients. Lenalidomide can be used in this context as a component of chemotherapy, but requires close monitoring and adherence to manufacturer recommendations to avoid toxicity given the impact of impaired renal function on Lenalidomide pharmacokinetics (Chen et al. J Clin Pharmacol. 2007). The purpose of this study is to evaluate the impact of Lenalidomide dosing on the agent’s toxicity profile in patients with and without RI. Objective The primary objective of this study is to assess the impact of initial Lenalidomide dose administered to newly diagnosed and relapsed/refractory MM patients with and without RI, and to evaluate the incidence of dose reductions, temporary drug discontinuations, and adverse events in these two groups. The secondary objective is to assess patients’ anticoagulation use and the development of venous thromboembolic events (VTE). Methods Data was collected retrospectively on 62 myeloma patients who filled a prescription for Lenalidomide at a single institution outpatient pharmacy from January 2010 to May 2012. Data collected included the initial dose and schedule of Lenalidomide, dose reductions due to toxicities, types of toxicities and number of days of temporary discontinuations of Lenalidomide. Renal impairment was defined as creatinine clearance (CrCl) less then 60ml/min. The manufacturer’s label recommends a dose of 25 mg for patients with CrCl ≥60ml/min QD, 10mg QD for those with CrCl 30 – 59 ml/min, and either 15 mg QOD or 5 mg QD for patients with CrCl Results Sixty two patients were included in this study, 40 of whom had normal CrCl and 22 who had RI. Thirty (48.4%) patients had newly diagnosed MM, 25 (40.3%) had relapsed/refractory disease and the remainder of patients (N=7) were on maintenance therapy either post transplant or post induction. Lenalidomide was most frequently partnered with dexamethasone (N=52; 84%) and/or bortezomib (N=24; 39%). Among the 22 patients with RI, 11 (50%) received a starting dose of Lenalidomide that was greater than the manufacturer recommended one. Dose reductions and/or temporary discontinuation occurred in 49 (79%) of the 62 patients: 30 (75%) in the normal CrCl patients and 19 (86%) among those with RI (difference=11%, 95% CI:-11%, 31%). Amongst the RI patients, dose reductions and/or temporary discontinuation occurred in 72.7% (8/11) of patients in whom an initial dose adjustments was made for RI, and in 100% (11/11) of patients in whom dose adjustment of Lenalidomide based on renal function was not made (difference=27%, 95% CI:-5%, 62%). The most common adverse events (any grade, according to CTCAE version 3) leading to dose reductions and/or temporary discontinuations included neutropenia (N=15), rash (N=10), worsening renal function (N=10), VTEs (N=9), GI intolerance (N=8), and thrombocytopenia (N=5). Among patients with RI, no difference in the type of adverse events was observed based on whether or not an initial dose adjustment for Lenalidomide was made. Aspirin or warfarin was initiated as prophylaxis in 57 of the 62 (92%) patients evaluated. Nine (15%) patients had a documented thrombotic event, all of whom were receiving aspirin prophylaxis. As of data retrieval, 23 patients are still on Lenalidomide either as treatment for relapsed disease or maintenance. For the remaining 39 patients who discontinued Lenalidomide, the most common reason for Lenalidomide discontinuation was progressive disease (16/39) or toxicities (9/39). Conclusion This analysis suggests that in the setting of RI, dose reductions and/or discontinuations were less common in patients who received the recommended renally-dose adjusted Lenalidomide at time of treatment initiation. However, the type of adverse events leading to dose reduction and/or discontinuation were similar between the two groups. The rate of thrombotic events was higher than expected and thrombotic events occurred exclusively in patients receiving aspirin prophylaxis. Disclosures: Richardson: Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Schlossman: Celgene: Consultancy. Anderson: Celgene: Membership on an entity’s Board of Directors or advisory committees.
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Lenalidomide after stem cell transplantation for multiple myeloma
The New England Journal of Medicine, 2012Co-Authors: Philip L Mccarthy, Paul G. Richardson, Kouros Owzar, Craig C Hofmeister, David D Hurd, Hani Hassoun, Sergio A Giralt, Edward A Stadtmauer, Daniel J Weisdorf, Jan S MorebAbstract:Background Data are lacking on whether Lenalidomide maintenance therapy prolongs the time to disease progression after autologous hematopoietic stem-cell transplantation in patients with multiple myeloma. Methods Between April 2005 and July 2009, we randomly assigned 460 patients who were younger than 71 years of age and had stable disease or a marginal, partial, or complete response 100 days after undergoing stem-cell transplantation to Lenalidomide or placebo, which was administered until disease progression. The starting dose of Lenalidomide was 10 mg per day (range, 5 to 15). Results The study-drug assignments were unblinded in 2009, when a planned interim analysis showed a significantly longer time to disease progression in the Lenalidomide group. At unblinding, 20% of patients who received Lenalidomide and 44% of patients who received placebo had progressive disease or had died (P<0.001); of the remaining 128 patients who received placebo and who did not have progressive disease, 86 crossed over to ...
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Lenalidomide melphalan and prednisone followed by Lenalidomide maintenance improves health related quality of life in newly diagnosed multiple myeloma patients aged 65 years or older results of a randomized phase iii trial
Haematologica, 2013Co-Authors: Meletios A. Dimopoulos, Martin Kropff, Maria Teresa Petrucci, Michel Delforge, Roman Hajek, Philip Lewis, Annabel Nixon, Jingshan Zhang, Antonio PalumboAbstract:The MM-015 trial assessed the effect of Lenalidomide-based therapy on health-related quality of life. Patients (n=459) with newly diagnosed multiple myeloma aged 65 years or over were randomized 1:1:1 to nine 4-week cycles of Lenalidomide, melphalan, and prednisone, followed by Lenalidomide maintenance; or Lenalidomide, melphalan, and prednisone, or melphalan and prednisone, with no maintenance therapy. Patients completed health-related quality of life questionnaires at baseline, after every third treatment cycle, and at treatment end. Health-related quality of life improved in all treatment groups during induction therapy. Patients receiving Lenalidomide maintenance had the most pronounced improvements, Global Health Status/Quality of Life ( P <0.05), Physical Functioning ( P <0.01), and Side Effects of Treatment ( P <0.05) out of 6 pre-selected health-related quality of life domains. More patients receiving Lenalidomide maintenance achieved minimal important differences ( P <0.05 for Physical Functioning). Therefore, Lenalidomide, melphalan, and prednisone, followed by Lenalidomide maintenance, improves health-related quality of life in patients with newly diagnosed multiple myeloma. ( [Clinicaltrials.gov][1] identifier [NCT00405756][2]). [1]: http://Clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00405756&atom=%2Fhaematol%2F98%2F5%2F784.atom
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Lenalidomide melphalan and prednisone followed by Lenalidomide maintenance improves health related quality of life in newly diagnosed multiple myeloma patients aged 65 years or older results of a randomized phase iii trial
Haematologica, 2013Co-Authors: Meletios A. Dimopoulos, Martin Kropff, Maria Teresa Petrucci, Michel Delforge, Roman Hajek, Philip Lewis, Annabel Nixon, Jingshan Zhang, Jay Mei, Antonio PalumboAbstract:The MM-015 trial assessed the effect of Lenalidomide-based therapy on health-related quality of life. Patients (n=459) with newly diagnosed multiple myeloma aged 65 years or over were randomized 1:1:1 to nine 4-week cycles of Lenalidomide, melphalan, and prednisone, followed by Lenalidomide maintenance; or Lenalidomide, melphalan, and prednisone, or melphalan and prednisone, with no maintenance therapy. Patients completed health-related quality of life questionnaires at baseline, after every third treatment cycle, and at treatment end. Health-related quality of life improved in all treatment groups during induction therapy. Patients receiving Lenalidomide maintenance had the most pronounced improvements, Global Health Status/Quality of Life (P<0.05), Physical Functioning (P<0.01), and Side Effects of Treatment (P<0.05) out of 6 pre-selected health-related quality of life domains. More patients receiving Lenalidomide maintenance achieved minimal important differences (P<0.05 for Physical Functioning). Therefore, Lenalidomide, melphalan, and prednisone, followed by Lenalidomide maintenance, improves health-related quality of life in patients with newly diagnosed multiple myeloma. (Clinicaltrials.gov identifier NCT00405756).
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melphalan prednisone and Lenalidomide treatment for newly diagnosed myeloma a report from the gimema italian multiple myeloma network
Journal of Clinical Oncology, 2007Co-Authors: Antonio Palumbo, Francesco Di Raimondo, Patrizia Falco, Paolo Corradini, Antonietta Falcone, Nicola Giuliani, Claudia Crippa, Giovannino Ciccone, Paola Omede, Maria Teresa AmbrosiniAbstract:Purpose Lenalidomide has shown significant antimyeloma activity in clinical studies. Oral melphalan, prednisone, and thalidomide have been regarded as the standard of care in elderly multiple myeloma patients. We assessed dosing, efficacy, and safety of melphalan, prednisone, and Lenalidomide (MPR) in newly diagnosed elderly myeloma patients. Patients and Methods Oral melphalan was administered in doses ranging from 0.18 to 0.25 mg/kg on days 1 to 4, prednisone at a 2-mg/kg dose on days 1 to 4, and Lenalidomide at doses ranging from 5 to 10 mg on days 1 to 21, every 28 days for nine cycles, followed by maintenance therapy with Lenalidomide alone. Aspirin was given as a prophylaxis for thrombosis. Results Fifty-four patients were enrolled and evaluated after completing the assigned treatment schedule. The maximum tolerated dose was defined as 0.18 mg/kg melphalan and 10 mg Lenalidomide. With these doses, 81% of patients achieved at least a partial response, 47.6% achieved a very good partial response, and ...