384 results on '"Ruben Niesvizky"'
Search Results
2. A pipeline for malignancy and therapy agnostic assessment of cancer drug response using cell mass measurements
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Robert J. Kimmerling, Mark M. Stevens, Selim Olcum, Anthony Minnah, Madeleine Vacha, Rachel LaBella, Matthew Ferri, Steven C. Wasserman, Juanita Fujii, Zayna Shaheen, Srividya Sundaresan, Drew Ribadeneyra, David S. Jayabalan, Sarita Agte, Adolfo Aleman, Joseph A. Criscitiello, Ruben Niesvizky, Marlise R. Luskin, Samir Parekh, Cara A. Rosenbaum, Anobel Tamrazi, and Clifford A. Reid
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Biology (General) ,QH301-705.5 - Abstract
A pipeline for drug sensitivity testing using cell mass from sample collection to data analysis is presented.
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- 2022
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3. P870: EFFICACY AND SAFETY OF ELRANATAMAB IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA AND PRIOR B-CELL MATURATION ANTIGEN (BCMA)-DIRECTED THERAPIES: A POOLED ANALYSIS FROM MAGNETISMM STUDIES
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Salomon Manier, Alexander Lesokhin, Mohamad Mohty, Ruben Niesvizky, Christopher Maisel, Bertrand Arnulf, Sarah M. Larson, Asya Nina Varshavsky-Yanovsky, Xavier Leleu, Lionel Karlin, David H. Vesole, Nizar J Bahlis, Carlos Fernandez de Larrea, Noopur Raje, Eric Leip, Sharon T. Sullivan, Mohamed Elmeliegy, Andrea Viqueira, and Ajay Nooka
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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4. Advances in the molecular characterization of multiple myeloma and mechanism of therapeutic resistance
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Mateo Mejia Saldarriaga, Walaa Darwiche, David Jayabalan, Jorge Monge, Cara Rosenbaum, Roger N. Pearse, Ruben Niesvizky, and Mark Bustoros
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myeloma and other plasma cell dyscrasias ,resistance ,molecular subclassification ,smoldering myeloma (SMM) ,MGUS ,risk stratification ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Recent insight in the genomic landscape of newly diagnosed multiple myeloma (NDMM) and its precursor conditions, monoclonal gammopathy of uncertain significance (MGUS), and smoldering myeloma have allowed the identification of patients with precursor conditions with a high risk of progression. These cases with “progressor” MGUS/SMM have a higher average mutation burden, have higher rates of mutations in specific genes such as MAPK, DNA repair, MYC, DIS3, and are enriched for specific mutational signatures when compared to non-progressors and are comparable to those found in NDMM. The highly preserved clonal heterogeneity seen upon progression of SMM, combined with the importance of these early variables, suggests that the identification of progressors based on these findings could complement and enhance the currently available clinical models based on tumor burden. Mechanisms leading to relapse/refractory multiple myeloma (RRMM) are of clinical interest given worse overall survival in this population. An Increased mutational burden is seen in patients with RRMM when compared to NDMM, however, there is evidence of branching evolution with many of these mutations being present at the subclonal level. Likewise, alterations in proteins associated with proteosome inhibitor and immunomodulatory drugs activity could partially explain clinical resistance to these agents. Evidence of chromosomal events leading to copy number changes is seen, with the presence of TP53 deletion, mutation, or a combination of both being present in many cases. Additional chromosomal events such as 1q gain and amplification may also interact and lead to resistance.
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- 2022
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5. Gene expression profiling impacts treatment decision making in newly diagnosed multiple myeloma patients in the prospective PROMMIS trial
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Noa Biran, Binod Dhakal, Suzanne Lentzsch, David Siegel, Saad Z. Usmani, Adriana Rossi, Cara Rosenbaum, Divaya Bhutani, David H. Vesole, Cesar Rodriguez, Ajay K. Nooka, Frits vanRhee, Lisette Stork‐Sloots, Femke deSnoo, Pritish K. Bhattacharyya, Durga Prasad Dash, Sena Zümrütçü, Martin H. vanVliet, Parameswaran Hari, and Ruben Niesvizky
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clinical trials ,gene arrays ,gene expression ,multiple myeloma ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Abstract Multiple myeloma (MM) is a heterogeneous hematologic malignancy associated with several risk factors including genetic aberrations which impact disease response and survival. Thorough risk classification is essential to select the best clinical strategy to optimize outcomes. The SKY92 molecular signature classifies patients as standard‐ or high‐risk for progression. The PRospective Observational Multiple Myeloma Impact Study (PROMMIS; NCT02911571) measures impact of SKY92 on risk classification and treatment plan. Newly diagnosed MM patients had bone marrow aspirates analyzed for SKY92. Physicians completed a questionnaire for each patient capturing risk classification, hypothetical treatment plan, and physician confidence in the treatment plan, before and after unblinding SKY92. One hundred forty seven MM patients were enrolled. Before unblinding SKY92, physicians regarded 74 (50%) patients as clinical standard‐risk. After unblinding SKY92, 16 patients were re‐assigned as high‐risk by the physician, and for 15 of them treatment strategy was impacted, resulting in an escalated treatment plan. For the 73 (50%) clinical high‐risk patients, SKY92 indicated 46 patients to be standard‐risk; for 31 of these patients the treatment strategy was impacted consistent with a de‐escalation of risk. Overall, SKY92 impacted treatment decisions in 37% of patients (p
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- 2021
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6. Publisher Correction: A pipeline for malignancy and therapy agnostic assessment of cancer drug response using cell mass measurements
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Robert J. Kimmerling, Mark M. Stevens, Selim Olcum, Anthony Minnah, Madeleine Vacha, Rachel LaBella, Matthew Ferri, Steven C. Wasserman, Juanita Fujii, Zayna Shaheen, Srividya Sundaresan, Drew Ribadeneyra, David S. Jayabalan, Sarita Agte, Adolfo Aleman, Joseph A. Criscitiello, Ruben Niesvizky, Marlise R. Luskin, Samir Parekh, Cara A. Rosenbaum, Anobel Tamrazi, and Clifford A. Reid
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Biology (General) ,QH301-705.5 - Published
- 2023
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7. Lenalidomide and dexamethasone with or without clarithromycin in patients with multiple myeloma ineligible for autologous transplant: a randomized trial
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Noemi Puig, Miguel T. Hernández, Laura Rosiñol, Esther González, Felipe de Arriba, Albert Oriol, Verónica González-Calle, Fernando Escalante, Javier de la Rubia, Mercedes Gironella, Rafael Ríos, Ricarda García-Sánchez, José M. Arguiñano, Adrián Alegre, Jesús Martín, Norma. C. Gutiérrez, María J. Calasanz, María L. Martín, María del Carmen Couto, María Casanova, Mario Arnao, Ernesto Pérez-Persona, Sebastián Garzón, Marta S. González, Guillermo Martín-Sánchez, Enrique M. Ocio, Morton Coleman, Cristina Encinas, Ana M. Vale, Ana I. Teruel, María Cortés-Rodríguez, Bruno Paiva, M. Teresa Cedena, Jesús F. San-Miguel, Juan J. Lahuerta, Joan Bladé, Ruben Niesvizky, and María-Victoria Mateos
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Although case-control analyses have suggested an additive value with the association of clarithromycin to continuous lenalidomide and dexamethasone (Rd), there are not phase III trials confirming these results. In this phase III trial, 286 patients with MM ineligible for ASCT received Rd with or without clarithromycin until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). With a median follow-up of 19 months (range, 0–54), no significant differences in the median PFS were observed between the two arms (C-Rd 23 months, Rd 29 months; HR 0.783, p = 0.14), despite a higher rate of complete response (CR) or better in the C-Rd group (22.6% vs 14.4%, p = 0.048). The most common G3–4 adverse events were neutropenia [12% vs 19%] and infections [30% vs 25%], similar between the two arms; however, the percentage of toxic deaths was higher in the C-Rd group (36/50 [72%] vs 22/40 [55%], p = 0.09). The addition of clarithromycin to Rd in untreated transplant ineligible MM patients does not improve PFS despite increasing the ≥CR rate due to the higher number of toxic deaths in the C-Rd arm. Side effects related to overexposure to steroids due to its delayed clearance induced by clarithromycin in this elderly population could explain these results. The trial was registered in clinicaltrials.gov with the name GEM-CLARIDEX: Ld vs BiRd and with the following identifier NCT02575144. The full trial protocol can be accessed from ClinicalTrials.gov. This study received financial support from BMS/Celgene.
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- 2021
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8. Caspase-8 Inhibition Prevents the Cleavage and Degradation of E3 Ligase Substrate Receptor Cereblon and Potentiates Its Biological Function
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Liang Zhou, Wenjun Yu, David S. Jayabalan, Ruben Niesvizky, Samie R. Jaffrey, Xiangao Huang, and Guoqiang Xu
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cereblon ,caspase-8 ,cleavage ,TRAIL ,multiple myeloma ,lenalidomide ,Biology (General) ,QH301-705.5 - Abstract
Cereblon (CRBN), a substrate receptor of cullin 4-RING E3 ligase (CRL4), mediates the ubiquitination and degradation of constitutive substrates and immunomodulatory drug-induced neo-substrates including MEIS2, c-Jun, CLC1, IKZF1/3, CK1α, and SALL4. It has been reported that CRBN itself could be degraded through the ubiquitin-proteasome system by its associated or other cullin-RING E3 ligases, thus influencing its biological functions. However, it is unknown whether the CRBN stability and its biological function could be modulated by caspases. In this study, using model cell lines, we found that activation of the death receptor using tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) leads to the decreased CRBN protein level. Through pharmacological inhibition and activation of caspase-8 (CASP-8), we disclosed that CASP-8 regulates CRBN cleavage in cell lines. Site mapping experiments revealed that CRBN is cleaved after Asp9 upon CASP-8 activation, resulting in the reduced stability. Using myeloma as a model system, we further revealed that either inhibition or genetic depletion of CASP-8 enhances the anti-myeloma activity of lenalidomide (Len) by impairing CRBN cleavage, leading to the attenuated IKZF1 and IKZF3 protein levels and the reduced viability of myeloma cell lines and primary myeloma cells from patients. The present study discovered that the stability of the substrate receptor of an E3 ligase can be modulated by CASP-8 and suggested that administration of CASP-8 inhibitors enhances the overall effectiveness of Len-based combination therapy in myeloma.
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- 2020
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9. Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies
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David Siegel, Thomas Martin, Ajay Nooka, R. Donald Harvey, Ravi Vij, Ruben Niesvizky, Ashraf Z. Badros, Sundar Jagannath, Leanne McCulloch, Kanya Rajangam, and Sagar Lonial
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Carfilzomib, a selective proteasome inhibitor, was approved in 2012 for the treatment of relapsed and refractory multiple myeloma. Safety data for single-agent carfilzomib have been analyzed for 526 patients with advanced multiple myeloma who took part in one of 4 phase II studies (PX-171-003-A0, PX-171-003-A1, PX-171-004, and PX-171-005). Overall analyses of adverse events and treatment modifications are presented, as well as specific analyses of adverse events by organ system. Overall, the most common adverse events of any grade included fatigue (55.5%), anemia (46.8%), and nausea (44.9%). In the grouped analyses, any grade adverse events were reported in 22.1% for any cardiac (7.2% cardiac failure), 69.0% for any respiratory (42.2% dyspnea), and 33.1% for any grouped renal impairment adverse event (24.1% increased serum creatinine). The most common non-hematologic adverse events were generally Grade 1 or 2 in severity, while Grade 3/4 adverse events were primarily hematologic and mostly reversible. There was no evidence of cumulative bone marrow suppression, either neutropenia or thrombocytopenia, and febrile neutropenia occurred infrequently (1.1%). Notably, the incidence of peripheral neuropathy was low overall (13.9%), including patients with baseline peripheral neuropathy (12.7%). Additionally, the incidence of discontinuations or dose reductions attributable to adverse events was low. These data demonstrate that single-agent carfilzomib has an acceptable safety profile in heavily pre-treated patients with relapsed/refractory multiple myeloma. The tolerable safety profile allows for administration of full-dose carfilzomib, both for extended periods and in a wide spectrum of patients with advanced multiple myeloma, including those with pre-existing comorbidities.
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- 2013
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10. A phase I multidose study of dacetuzumab (SGN-40; humanized anti-CD40 monoclonal antibody) in patients with multiple myeloma
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Mohamad Hussein, James R. Berenson, Ruben Niesvizky, Nikhil Munshi, Jeffrey Matous, Ronald Sobecks, Kate Harrop, Jonathan G. Drachman, and Nancy Whiting
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
This first-in-human, phase I study evaluated the safety, maximum-tolerated dose, pharmacokinetics, and antitumor activity of dacetuzumab in 44 patients with advanced multiple myeloma. Patients received intravenous dacetuzumab, either in 4 uniform weekly doses (first 4 cohorts) or using a 5-week intrapatient dose escalation schedule (7 subsequent cohorts; the last 3 cohorts received steroid pre-medication). An initial dose of 4 mg/kg dacetuzumab exceeded the maximum-tolerated dose for uniform weekly dosing. Intrapatient dose escalation with steroid pre-medication appeared effective in reducing symptoms of cytokine release syndrome and the maximum-tolerated dose with this dosing schema was 12 mg/kg/week. Adverse events potentially related to dacetuzumab included cytokine release syndrome symptoms, non-infectious ocular inflammation, and elevated hepatic enzymes. Peak dacetuzumab blood levels increased with dose. Nine patients (20%) had a best clinical response of stable disease. The observed safety profile suggested that dacetuzumab may be combined with other multiple myeloma therapies. Two combination trials are ongoing.Clinical trials gov identifier: NCT00079716
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- 2010
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11. Immune Biomarkers of Survival and Severe Infection in Newly Diagnosed Multiple Myeloma (NDMM) Patients (pts) Treated with the Backbone Regimen Lenalidomide and Dexamethasone (Rd)
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Catarina Maia, Noemi Puig, Cristina Pérez Ruiz, Maria Teresa Cedena Romero, Camila Guerrero, Marta Larrayoz, Cirino Botta, Norma C. Gutierrez, María José Calasanz, Maria Luisa Martin-Ramos, Miguel Hernández, Laura Rosinol Dachs, Esther González Garcia, Felipe De Arriba, Albert Oriol, Veronica Gonzalez-Calle, Fernando Escalante, Javier de la Rubia, Mercedes Gironella Mesa, Rafael Rios, Ricarda Belen Garcia Sanchez, Jose Maria Arguiñano PEREZ, Adrian Alegre, Jesus Martin, María del Carmen Couto Caro, Maria Casanova, Mario Arnao Herraiz, Ernesto Pérez, Sebastián Garzón López, Marta Sonia Gonzalez Perez, Guillermo Martín-Nuñez, Adriana Rossi, Morton Coleman, Cristina Encinas, Ana M. Vale, Ana Isabel Teruel, María Cortés Rodríguez, Jose A. Martinez-Climent, Juan-José Lahuerta, Joan Bladé Creixenti, Ruben Niesvizky, Jesús San-Miguel, Maria-Victoria Mateos, and Bruno Paiva
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
12. Phase 1/2 study of ixazomib with cyclophosphamide and dexamethasone in newly diagnosed AL amyloidosis
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Cara A. Rosenbaum, Umut Özbek, Larysa Sanchez, Jonathan Lagdameo, Alex Abrahams, Hani Hassoun, Oscar Lahoud, Ruben Niesvizky, Heather J. Landau, and Keren Osman
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Boron Compounds ,Glycine ,Humans ,Immunoglobulin Light-chain Amyloidosis ,Hematology ,Cyclophosphamide ,Dexamethasone - Published
- 2022
13. SupplementaryTable1.xlsx from COVID-19 Infections and Clinical Outcomes in Patients with Multiple Myeloma in New York City: A Cohort Study from Five Academic Centers
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Ola Landgren, Gareth J. Morgan, Suzanne Lentzsch, Ruben Niesvizky, Sundar Jagannath, Faith E. Davies, Ying Taur, Ran Reshef, Christian Gordillo, Marc J. Braunstein, David Kaminetzky, Ajai Chari, Deepu Madduri, Roger N. Pearse, Adriana Rossi, Benjamin Diamond, Andriy Derkach, Francesco Maura, Carlyn Tan, Hani Hassoun, Alexander M. Lesokhin, Urvi A. Shah, Sham Mailankody, Sydney X. Lu, Neha Korde, Eric L. Smith, Dhwani Patel, Cara A. Rosenbaum, Joshua Richter, and Malin Hultcrantz
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Supplementary Table 1
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- 2023
14. Data from COVID-19 Infections and Clinical Outcomes in Patients with Multiple Myeloma in New York City: A Cohort Study from Five Academic Centers
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Ola Landgren, Gareth J. Morgan, Suzanne Lentzsch, Ruben Niesvizky, Sundar Jagannath, Faith E. Davies, Ying Taur, Ran Reshef, Christian Gordillo, Marc J. Braunstein, David Kaminetzky, Ajai Chari, Deepu Madduri, Roger N. Pearse, Adriana Rossi, Benjamin Diamond, Andriy Derkach, Francesco Maura, Carlyn Tan, Hani Hassoun, Alexander M. Lesokhin, Urvi A. Shah, Sham Mailankody, Sydney X. Lu, Neha Korde, Eric L. Smith, Dhwani Patel, Cara A. Rosenbaum, Joshua Richter, and Malin Hultcrantz
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Patients with multiple myeloma have a compromised immune system, due to both the disease and antimyeloma therapies, and may therefore be particularly susceptible to COVID-19. Here, we report outcomes and risk factors for serious disease in patients with multiple myeloma treated at five large academic centers in New York City in the spring of 2020, during which it was a global epicenter of the SARS-CoV-2 pandemic. Of 100 patients with multiple myeloma (male 58%; median age 68) diagnosed with COVID-19, 75 were admitted; of these, 13 patients (17%) were placed on invasive mechanical ventilation, and 22 patients (29%) expired. Of the 25 nonadmitted patients, 4 were asymptomatic. There was a higher risk of adverse outcome (intensive care unit admission, mechanical ventilation, or death) in Hispanics/Latinos (n = 21), OR = 4.7 (95% confidence interval, 1.3–16.7), and African American Blacks (n = 33), OR = 3.5 (1.1–11.5), as compared with White patients (n = 36). Patients who met the adverse combined endpoint had overall higher levels of inflammatory markers and cytokine activation. None of the other studied risk factors were significantly associated (P > 0.05) with adverse outcome: hypertension (n = 56), OR = 2.2 (0.9–5.4); diabetes (n = 18), OR = 0.9 (0.3–2.9); age >65 years (n = 63), OR = 1.8 (0.7–4.6); high-dose melphalan with autologous stem cell transplant n = 7), OR = 0.9 (0.2–5.4); and immunoglobulin G n = 42), OR = 0.9 (0.3–2.2). In this largest cohort to date of patients with multiple myeloma and COVID-19, we found the case fatality rate to be 29% among hospitalized patients and that race/ethnicity was the most significant risk factor for adverse outcome.Significance:Patients with multiple myeloma are immunocompromised, raising the question whether they are at higher risk of severe COVID-19 disease. In this large case series on COVID-19 in patients with multiple myeloma, we report 29% mortality rates among hospitalized patients and identify race/ethnicity as the most significant risk factor for severe outcome.See related video: https://vimeo.com/486246183/559a80cfaeSee related commentary by Munshi and Anderson, p. 218.This article is highlighted in the In This Issue feature, p. 215
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- 2023
15. Supplementary Figure 1 from Overcoming the Response Plateau in Multiple Myeloma: A Novel Bortezomib-Based Strategy for Secondary Induction and High-Yield CD34+ Stem Cell Mobilization
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Maureen E. Lane, Morton Coleman, Selina Chen-Kiang, Donna Skerret, Scott Ely, Zhaoying Xiang, Karen Pekle, Faiza Zafar, Tsiporah B. Shore, Lena Mathews, Paul J. Christos, Jessica Stern, Megan Manco, Roger N. Pearse, David S. Jayabalan, Maureen Ward, Tomer M. Mark, and Ruben Niesvizky
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PDF file - 58K, Study design and patient flow by intent to treat (ITT).
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- 2023
16. Supplementary Table S1 from Germline Lysine-Specific Demethylase 1 (LSD1/KDM1A) Mutations Confer Susceptibility to Multiple Myeloma
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Steven M. Lipkin, Leandro Cerchietti, Haiyuan Yu, Robert J. Klein, Kenneth Offit, Nicola J. Camp, Charles G. Mullighan, Henry T. Lynch, Charles Dumontet, Robert G. Roeder, Mark J. Daly, Kenneth C. Anderson, Judy E. Garber, Jane Churpek, Lucy A. Godley, Susan L. Slager, Ola Landgren, Ruben Niesvizky, Djordje Atanackovic, Mohamed Salama, Karen Curtin, Selina Chen-Kiang, Jude Phillip, Jayeshkumar Patel, Agnes Viale, Mykyta Artomov, Rosalie G. Waller, Dina Becirovic, Lauren M. Jacobs, David S. Jayabalan, Shu-Ping Wang, James D. McKay, Celine M. Vachon, Carrie Snyder, Vijai Joseph, Kim E. Nichols, Michael F. Walsh, Jinghui Zhang, Jian Sun, Maria V. Revuelta, Gang Wu, Siwei Chen, M. Nieves Calvo-Vidal, and Xiaomu Wei
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Clinical characteristics of familial myeloma probands who were studied with germline whole exome sequencing.
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- 2023
17. Supplementary Figure S1 from Germline Lysine-Specific Demethylase 1 (LSD1/KDM1A) Mutations Confer Susceptibility to Multiple Myeloma
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Steven M. Lipkin, Leandro Cerchietti, Haiyuan Yu, Robert J. Klein, Kenneth Offit, Nicola J. Camp, Charles G. Mullighan, Henry T. Lynch, Charles Dumontet, Robert G. Roeder, Mark J. Daly, Kenneth C. Anderson, Judy E. Garber, Jane Churpek, Lucy A. Godley, Susan L. Slager, Ola Landgren, Ruben Niesvizky, Djordje Atanackovic, Mohamed Salama, Karen Curtin, Selina Chen-Kiang, Jude Phillip, Jayeshkumar Patel, Agnes Viale, Mykyta Artomov, Rosalie G. Waller, Dina Becirovic, Lauren M. Jacobs, David S. Jayabalan, Shu-Ping Wang, James D. McKay, Celine M. Vachon, Carrie Snyder, Vijai Joseph, Kim E. Nichols, Michael F. Walsh, Jinghui Zhang, Jian Sun, Maria V. Revuelta, Gang Wu, Siwei Chen, M. Nieves Calvo-Vidal, and Xiaomu Wei
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PCA and gene based rare synonymous variant comparison analyses of European ancestry Multiple Myeloma cases and controls
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- 2023
18. Supplementary Table 3 from Overcoming the Response Plateau in Multiple Myeloma: A Novel Bortezomib-Based Strategy for Secondary Induction and High-Yield CD34+ Stem Cell Mobilization
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Maureen E. Lane, Morton Coleman, Selina Chen-Kiang, Donna Skerret, Scott Ely, Zhaoying Xiang, Karen Pekle, Faiza Zafar, Tsiporah B. Shore, Lena Mathews, Paul J. Christos, Jessica Stern, Megan Manco, Roger N. Pearse, David S. Jayabalan, Maureen Ward, Tomer M. Mark, and Ruben Niesvizky
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PDF file - 53K, Validation of gene expression data using QPCR compared to microarray values (data reported as fold change).
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- 2023
19. Data from Overcoming the Response Plateau in Multiple Myeloma: A Novel Bortezomib-Based Strategy for Secondary Induction and High-Yield CD34+ Stem Cell Mobilization
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Maureen E. Lane, Morton Coleman, Selina Chen-Kiang, Donna Skerret, Scott Ely, Zhaoying Xiang, Karen Pekle, Faiza Zafar, Tsiporah B. Shore, Lena Mathews, Paul J. Christos, Jessica Stern, Megan Manco, Roger N. Pearse, David S. Jayabalan, Maureen Ward, Tomer M. Mark, and Ruben Niesvizky
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Purpose: This phase II study evaluated bortezomib-based secondary induction and stem cell mobilization in 38 transplant-eligible patients with myeloma who had an incomplete and stalled response to, or had relapsed after, previous immunomodulatory drug-based induction.Experimental Design: Patients received up to six 21-day cycles of bortezomib plus dexamethasone, with added liposomal doxorubicin for patients not achieving partial response or better by cycle 2 or very good partial response or better (≥VGPR) by cycle 4 (DoVeD), followed by bortezomib, high-dose cyclophosphamide, and filgrastim mobilization. Gene expression/signaling pathway analyses were conducted in purified CD34+ cells after bortezomib-based mobilization and compared against patients who received only filgrastim ± cyclophosphamide. Plasma samples were similarly analyzed for quantification of associated protein markers.Results: The response rate to DoVeD relative to the pre-DoVeD baseline was 61%, including 39% ≥VGPR. Deeper responses were achieved in 10 of 27 patients who received bortezomib-based mobilization; postmobilization response rate was 96%, including 48% ≥VGPR, relative to the pre-DoVeD baseline. Median CD34+ cell yield was 23.2 × 106 cells/kg (median of 1 apheresis session). After a median follow-up of 46.6 months, median progression-free survival was 47.1 months from DoVeD initiation; 5-year overall survival rate was 76.4%. Grade ≥3 adverse events included thrombocytopenia (13%), hand–foot syndrome (11%), peripheral neuropathy (8%), and neutropenia (5%). Bortezomib-based mobilization was associated with modulated expression of genes involved in stem cell migration.Conclusion: Bortezomib-based secondary induction and mobilization could represent an alternative strategy for elimination of tumor burden in immunomodulatory drug-resistant patients that does not impact stem cell yield. Clin Cancer Res; 19(6); 1534–46. ©2013 AACR.
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- 2023
20. Supplementary Table 2 from Overcoming the Response Plateau in Multiple Myeloma: A Novel Bortezomib-Based Strategy for Secondary Induction and High-Yield CD34+ Stem Cell Mobilization
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Maureen E. Lane, Morton Coleman, Selina Chen-Kiang, Donna Skerret, Scott Ely, Zhaoying Xiang, Karen Pekle, Faiza Zafar, Tsiporah B. Shore, Lena Mathews, Paul J. Christos, Jessica Stern, Megan Manco, Roger N. Pearse, David S. Jayabalan, Maureen Ward, Tomer M. Mark, and Ruben Niesvizky
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PDF file - 72K, Most common all-grade and grade ≥3 AEs during DoVeD induction and bortezomib-based stem cell mobilization.
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- 2023
21. Data from Germline Lysine-Specific Demethylase 1 (LSD1/KDM1A) Mutations Confer Susceptibility to Multiple Myeloma
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Steven M. Lipkin, Leandro Cerchietti, Haiyuan Yu, Robert J. Klein, Kenneth Offit, Nicola J. Camp, Charles G. Mullighan, Henry T. Lynch, Charles Dumontet, Robert G. Roeder, Mark J. Daly, Kenneth C. Anderson, Judy E. Garber, Jane Churpek, Lucy A. Godley, Susan L. Slager, Ola Landgren, Ruben Niesvizky, Djordje Atanackovic, Mohamed Salama, Karen Curtin, Selina Chen-Kiang, Jude Phillip, Jayeshkumar Patel, Agnes Viale, Mykyta Artomov, Rosalie G. Waller, Dina Becirovic, Lauren M. Jacobs, David S. Jayabalan, Shu-Ping Wang, James D. McKay, Celine M. Vachon, Carrie Snyder, Vijai Joseph, Kim E. Nichols, Michael F. Walsh, Jinghui Zhang, Jian Sun, Maria V. Revuelta, Gang Wu, Siwei Chen, M. Nieves Calvo-Vidal, and Xiaomu Wei
- Abstract
Given the frequent and largely incurable occurrence of multiple myeloma, identification of germline genetic mutations that predispose cells to multiple myeloma may provide insight into disease etiology and the developmental mechanisms of its cell of origin, the plasma cell (PC). Here, we identified familial and early-onset multiple myeloma kindreds with truncating mutations in lysine-specific demethylase 1 (LSD1/KDM1A), an epigenetic transcriptional repressor that primarily demethylates histone H3 on lysine 4 and regulates hematopoietic stem cell self-renewal. In addition, we found higher rates of germline truncating and predicted deleterious missense KDM1A mutations in patients with multiple myeloma unselected for family history compared with controls. Both monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma cells have significantly lower KDM1A transcript levels compared with normal PCs. Transcriptome analysis of multiple myeloma cells from KDM1A mutation carriers shows enrichment of pathways and MYC target genes previously associated with myeloma pathogenesis. In mice, antigen challenge followed by pharmacologic inhibition of KDM1A promoted PC expansion, enhanced secondary immune response, elicited appearance of serum paraprotein, and mediated upregulation of MYC transcriptional targets. These changes are consistent with the development of MGUS. Collectively, our findings show that KDM1A is the first autosomal-dominant multiple myeloma germline predisposition gene providing new insights into its mechanistic roles as a tumor suppressor during post-germinal center B-cell differentiation.Significance: KDM1A is the first germline autosomal dominant predisposition gene identified in multiple myeloma and provides new insights into multiple myeloma etiology and the mechanistic role of KDM1A as a tumor suppressor during post-germinal center B-cell differentiation. Cancer Res; 78(10); 2747–59. ©2018 AACR.
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- 2023
22. Supplementary Figures S1-S3 from MAGE-A Inhibits Apoptosis in Proliferating Myeloma Cells through Repression of Bax and Maintenance of Survivin
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Hearn Jay Cho, Selina Chen-Kiang, Lloyd J. Old, Nina Bhardwaj, David S. Jayabalan, Morton Coleman, Roger Pearse, Ruben Niesvizky, Scott Ely, Rebecca Wasserstrum, Valéria C.C. Andrade, Ania Dabrowski, Xiangao Huang, Maurizio DiLiberto, Anna Mei, Achim A. Jungbluth, and Tricia Nardiello
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Supplementary Figures S1-S3 from MAGE-A Inhibits Apoptosis in Proliferating Myeloma Cells through Repression of Bax and Maintenance of Survivin
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- 2023
23. Supplementary Figure 2 from Overcoming the Response Plateau in Multiple Myeloma: A Novel Bortezomib-Based Strategy for Secondary Induction and High-Yield CD34+ Stem Cell Mobilization
- Author
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Maureen E. Lane, Morton Coleman, Selina Chen-Kiang, Donna Skerret, Scott Ely, Zhaoying Xiang, Karen Pekle, Faiza Zafar, Tsiporah B. Shore, Lena Mathews, Paul J. Christos, Jessica Stern, Megan Manco, Roger N. Pearse, David S. Jayabalan, Maureen Ward, Tomer M. Mark, and Ruben Niesvizky
- Abstract
PDF file - 60K, Kaplan-Meier estimates of (A)PFS and (B)OS in patients in the ITT population (N-38).
- Published
- 2023
24. Data from MAGE-A Inhibits Apoptosis in Proliferating Myeloma Cells through Repression of Bax and Maintenance of Survivin
- Author
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Hearn Jay Cho, Selina Chen-Kiang, Lloyd J. Old, Nina Bhardwaj, David S. Jayabalan, Morton Coleman, Roger Pearse, Ruben Niesvizky, Scott Ely, Rebecca Wasserstrum, Valéria C.C. Andrade, Ania Dabrowski, Xiangao Huang, Maurizio DiLiberto, Anna Mei, Achim A. Jungbluth, and Tricia Nardiello
- Abstract
Purpose: The type I Melanoma Antigen GEnes (MAGEs) are commonly expressed in cancers, fueling speculation that they may be therapeutic targets with oncogenic potential. They form complexes with RING domain proteins that have E3 ubiquitin ligase activity and promote p53 degradation. MAGE-A3 was detected in tumor specimens from patients with multiple myeloma and its expression correlated with higher frequencies of Ki-67+ malignant cells. In this report, we examine the mechanistic role of MAGE-A in promoting survival of proliferating multiple myeloma cells.Experimental Design: The impact of MAGE-A3 expression on survival and proliferation in vivo was examined by immunohistochemical analysis in an independent set of tumor specimens segregated into two groups: newly diagnosed, untreated patients and patients who had relapsed after chemotherapy. The mechanisms of MAGE-A3 activity were investigated in vitro by silencing its expression by short hairpin RNA interference in myeloma cell lines and primary cells and assessing the resultant effects on proliferation and apoptosis.Results: MAGE-A3 was detected in a significantly higher percentage of relapsed patients compared with newly diagnosed, establishing a novel correlation with progression of disease. Silencing of MAGE-A showed that it was dispensable for cell cycling, but was required for survival of proliferating myeloma cells. Loss of MAGE-A led to apoptosis mediated by p53-dependent activation of proapoptotic Bax expression and by reduction of survivin expression through both p53-dependent and -independent mechanisms.Conclusions: These data support a role for MAGE-A in the pathogenesis and progression of multiple myeloma by inhibiting apoptosis in proliferating myeloma cells through two novel mechanisms. Clin Cancer Res; 17(13); 4309–19. ©2011 AACR.
- Published
- 2023
25. Supplementary Table 1 from Overcoming the Response Plateau in Multiple Myeloma: A Novel Bortezomib-Based Strategy for Secondary Induction and High-Yield CD34+ Stem Cell Mobilization
- Author
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Maureen E. Lane, Morton Coleman, Selina Chen-Kiang, Donna Skerret, Scott Ely, Zhaoying Xiang, Karen Pekle, Faiza Zafar, Tsiporah B. Shore, Lena Mathews, Paul J. Christos, Jessica Stern, Megan Manco, Roger N. Pearse, David S. Jayabalan, Maureen Ward, Tomer M. Mark, and Ruben Niesvizky
- Abstract
PDF file - 59K, Responses rates after DoVeD induction, bortezomib- or non-bortezomib-based mobilization, and SCT.
- Published
- 2023
26. Supplementary Data from Germline Lysine-Specific Demethylase 1 (LSD1/KDM1A) Mutations Confer Susceptibility to Multiple Myeloma
- Author
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Steven M. Lipkin, Leandro Cerchietti, Haiyuan Yu, Robert J. Klein, Kenneth Offit, Nicola J. Camp, Charles G. Mullighan, Henry T. Lynch, Charles Dumontet, Robert G. Roeder, Mark J. Daly, Kenneth C. Anderson, Judy E. Garber, Jane Churpek, Lucy A. Godley, Susan L. Slager, Ola Landgren, Ruben Niesvizky, Djordje Atanackovic, Mohamed Salama, Karen Curtin, Selina Chen-Kiang, Jude Phillip, Jayeshkumar Patel, Agnes Viale, Mykyta Artomov, Rosalie G. Waller, Dina Becirovic, Lauren M. Jacobs, David S. Jayabalan, Shu-Ping Wang, James D. McKay, Celine M. Vachon, Carrie Snyder, Vijai Joseph, Kim E. Nichols, Michael F. Walsh, Jinghui Zhang, Jian Sun, Maria V. Revuelta, Gang Wu, Siwei Chen, M. Nieves Calvo-Vidal, and Xiaomu Wei
- Abstract
Additional methods, statistical and resource information to assist readers about how experiments and analyses were conducted.
- Published
- 2023
27. Supplementary Figures 1-2, Table 1 from A Novel Orally Active Small Molecule Potently Induces G1 Arrest in Primary Myeloma Cells and Prevents Tumor Growth by Specific Inhibition of Cyclin-Dependent Kinase 4/6
- Author
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Selina Chen-Kiang, Malcolm A.S. Moore, Scott Ely, Hearn Cho, Ruben Niesvizky, Rachel Gottschalk, Tracey Louie, Peter L. Toogood, Kaida Wu, Maurizio Di Liberto, and Linda B. Baughn
- Abstract
Supplementary Figures 1-2, Table 1 from A Novel Orally Active Small Molecule Potently Induces G1 Arrest in Primary Myeloma Cells and Prevents Tumor Growth by Specific Inhibition of Cyclin-Dependent Kinase 4/6
- Published
- 2023
28. Data from A Novel Orally Active Small Molecule Potently Induces G1 Arrest in Primary Myeloma Cells and Prevents Tumor Growth by Specific Inhibition of Cyclin-Dependent Kinase 4/6
- Author
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Selina Chen-Kiang, Malcolm A.S. Moore, Scott Ely, Hearn Cho, Ruben Niesvizky, Rachel Gottschalk, Tracey Louie, Peter L. Toogood, Kaida Wu, Maurizio Di Liberto, and Linda B. Baughn
- Abstract
Cell cycle deregulation is central to the initiation and fatality of multiple myeloma, the second most common hematopoietic cancer, although impaired apoptosis plays a critical role in the accumulation of myeloma cells in the bone marrow. The mechanism for intermittent, unrestrained proliferation of myeloma cells is unknown, but mutually exclusive activation of cyclin-dependent kinase 4 (Cdk4)-cyclin D1 or Cdk6-cyclin D2 precedes proliferation of bone marrow myeloma cells in vivo. Here, we show that by specific inhibition of Cdk4/6, the orally active small-molecule PD 0332991 potently induces G1 arrest in primary bone marrow myeloma cells ex vivo and prevents tumor growth in disseminated human myeloma xenografts. PD 0332991 inhibits Cdk4/6 proportional to the cycling status of the cells independent of cellular transformation and acts in concert with the physiologic Cdk4/6 inhibitor p18INK4c. Inhibition of Cdk4/6 by PD 0332991 is not accompanied by induction of apoptosis. However, when used in combination with a second agent, such as dexamethasone, PD 0332991 markedly enhances the killing of myeloma cells by dexamethasone. PD 0332991, therefore, represents the first promising and specific inhibitor for therapeutic targeting of Cdk4/6 in multiple myeloma and possibly other B-cell cancers. (Cancer Res 2006; 66(15): 7661-7)
- Published
- 2023
29. Angioimmunoblastic T‐cell lymphoma presenting with severe plasmacytosis mimicking plasma cell leukemia
- Author
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Mateo Mejia Saldarriaga, Mohammad Alhomoud, Gail Roboz, John N. Allan, Jia Ruan, Madhu M. Ouseph, Paul D. Simonson, Mark Bustoros, and Ruben Niesvizky
- Subjects
Hematology - Published
- 2023
30. Efficacy and Safety of Elranatamab in Patients with Relapsed/Refractory Multiple Myeloma Naïve to B-Cell Maturation Antigen (BCMA)-Directed Therapies: Results from Cohort a of the Magnetismm-3 Study
- Author
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Nizar Jacques Bahlis, Michael H. Tomasson, Mohamad Mohty, Ruben Niesvizky, Ajay K. Nooka, Salomon Manier, Christopher Maisel, Yogesh Jethava, Joaquin Martinez-Lopez, H Miles Prince, Bertrand Arnulf, Paula Rodriguez Otero, Guenther Koehne, Cyrille Touzeau, Noopur Raje, Shinsuke Iida, Marc-Steffen Raab, Eric Leip, Sharon Sullivan, Umberto Conte, Andrea Viqueira, and Alexander M Lesokhin
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
31. High Ex Vivo Response Rates to CD38/CD28xCD3 Trispecific T Cell Engager in Patients Relapsed after Anti-CD38 and Anti-BCMA Targeted Immunotherapies
- Author
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Alana Keller, Olivia Perez De Acha, Lauren T Reiman, Zachary J Walker, David S Jayabalan, Ruben Niesvizky, Peter A Forsberg, Peter Kim, Kamlesh Bisht, Hongfang Wang, Helgi van de Velde, and Daniel W. Sherbenou
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
32. Sea-BCMA Mono- and Combination Therapy in Patients with Relapsed/Refractory Multiple Myeloma: Updated Results of a Phase 1 Study (SGNBCMA-001)
- Author
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James E. Hoffman, Brea Lipe, Jason Melear, Michaela Liedtke, Mark A. Schroeder, Ruben Niesvizky, Christopher Strouse, Christopher A. Yasenchak, Damian J. Green, Jeremy Sauer, Yinghui Wang, Phoenix Ho, and Al-Ola Abdallah
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
33. Consensus guidelines and recommendations for infection prevention in multiple myeloma: a report from the International Myeloma Working Group
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Noopur S Raje, Elias Anaissie, Shaji K Kumar, Sagar Lonial, Thomas Martin, Morie A Gertz, Amrita Krishnan, Parameswaran Hari, Heinz Ludwig, Elizabeth O'Donnell, Andrew Yee, Jonathan L Kaufman, Adam D Cohen, Laurent Garderet, Ashutosh F Wechalekar, Evangelos Terpos, Navin Khatry, Ruben Niesvizky, Qing Yi, Douglas E Joshua, Tapan Saikia, Nelson Leung, Monika Engelhardt, Mohamad Mothy, Andrew Branagan, Ajai Chari, Anthony J Reiman, Brea Lipe, Joshua Richter, S Vincent Rajkumar, Jesús San Miguel, Kenneth C Anderson, Edward A Stadtmauer, Rao H Prabhala, Phillip L McCarthy, and Nikhil C Munshi
- Subjects
Consensus ,Humans ,Hematology ,Infections ,Multiple Myeloma - Abstract
Infection remains the leading cause of morbidity and mortality in patients with multiple myeloma because of the cumulative effect of disease, treatment, and host-related factors. Given that infectious risk is cumulative through the course of the disease, preventing infections is paramount. Optimal preventive strategies include vaccination against common pathogens, antimicrobial prophylaxis, infection control measures, and immunoglobulin replacement in a small subset of patients; however, there are no universally accepted guidelines for infection prevention. This Review provides a consensus statement from a panel of 36 experts with global representation, which was convened by The International Myeloma Society to review existing literature and current guidelines, address issues associated with the risk of infection and prevention of infectious complications in multiple myeloma in the context of emerging therapies, and offer recommendations for preventing these complications.
- Published
- 2022
34. Gene expression profiling impacts treatment decision making in newly diagnosed multiple myeloma patients in the prospective PROMMIS trial
- Author
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Lisette Stork-Sloots, David S. Siegel, Martin H. van Vliet, David H. Vesole, Cara A. Rosenbaum, Femke A. de Snoo, Ajay K. Nooka, Durga Prasad Dash, Adriana C Rossi, Ruben Niesvizky, Parameswaran Hari, Cesar Rodriguez, Sena Zümrütçü, Frits van Rhee, Suzanne Lentzsch, Pritish K. Bhattacharyya, Binod Dhakal, Saad Z. Usmani, Divaya Bhutani, and Noa Biran
- Subjects
Clinical trial ,Gene expression profiling ,Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Gene expression ,medicine ,Treatment decision making ,Newly diagnosed ,business ,medicine.disease ,Multiple myeloma - Abstract
Multiple myeloma (MM) is a heterogeneous hematologic malignancy associated with several risk factors including genetic aberrations which impact disease response and survival. Thorough risk classification is essential to select the best clinical strategy to optimize outcomes. The SKY92 molecular signature classifies patients as standard- or high-risk for progression. The PRospective Observational Multiple Myeloma Impact Study (PROMMIS; NCT02911571) measures impact of SKY92 on risk classification and treatment plan. Newly diagnosed MM patients had bone marrow aspirates analyzed for SKY92. Physicians completed a questionnaire for each patient capturing risk classification, hypothetical treatment plan, and physician confidence in the treatment plan, before and after unblinding SKY92. One hundred forty seven MM patients were enrolled. Before unblinding SKY92, physicians regarded 74 (50%) patients as clinical standard-risk. After unblinding SKY92, 16 patients were re-assigned as high-risk by the physician, and for 15 of them treatment strategy was impacted, resulting in an escalated treatment plan. For the 73 (50%) clinical high-risk patients, SKY92 indicated 46 patients to be standard-risk; for 31 of these patients the treatment strategy was impacted consistent with a de-escalation of risk. Overall, SKY92 impacted treatment decisions in 37% of patients (
- Published
- 2021
35. A phase 1b study of once‐weekly carfilzomib combined with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma
- Author
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Amy S. Kimball, Belle Fang, Melissa Alsina, Ola Landgren, David S. Siegel, William I. Bensinger, Noopur Raje, Ruben Niesvizky, Tibor Kovacsovics, David H. Vesole, and Jesus G. Berdeja
- Subjects
Oncology ,medicine.medical_specialty ,Dexamethasone ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,In patient ,Adverse effect ,Lenalidomide ,Multiple myeloma ,Research Articles ,business.industry ,Hematology ,medicine.disease ,Carfilzomib ,Regimen ,chemistry ,030220 oncology & carcinogenesis ,Cohort ,business ,Multiple Myeloma ,Oligopeptides ,030215 immunology ,medicine.drug ,Research Article - Abstract
Twice‐weekly carfilzomib with lenalidomide‐dexamethasone (Rd) is an effective regimen for newly diagnosed multiple myeloma (NDMM). Here we evaluated once‐weekly carfilzomib with Rd (once‐weekly KRd) in NDMM patients. The NDMM patients were enrolled regardless of transplant eligibility. Patients received carfilzomib on days 1, 8, and 15; lenalidomide 25 mg on days 1‐21; and dexamethasone 40 mg on carfilzomib days (also day 22 for cycles 1‐8) for ≤18, 28‐day cycles. Enrollment initiated in a carfilzomib 20/70 mg/m2 (20 mg/m2 on cycle one, day 1; 70 mg/m2 thereafter) NDMM dose‐expansion arm, which was suspended because of serious adverse events. After evaluation of dose‐limiting toxicities in a two‐step‐up dose‐evaluation cohort, an NDMM dose‐expansion arm (carfilzomib 20/56 mg/m2) was opened. Fifty‐one NDMM patients were enrolled in dose‐finding and dose‐expansion cohorts. Results are presented for the carfilzomib 56 mg/m2 NDMM dose‐expansion arm (n = 33). The grade ≥ 3 treatment‐emergent AE (TEAE) rate was 63.6%. Twenty‐five patients underwent stem cell collection; 18 proceeded to auto stem cell transplant, and five resumed KRd on study after autoSCT. The overall response rate (ORR) based on best overall response by cycle four was 97.0% (≥very good partial response [VGPR], 69.7%) in the NDMM 20/56 mg/m2 cohort. In patients who did not receive autoSCT (n = 15), the median number of cycles was 16.0; ORR was 93.3% (≥VGPR, 80.0%). At a median follow‐up of 8.1 months, median progression‐free survival was not reached. Once‐weekly KRd (carfilzomib 56 mg/m2) had a favorable safety profile and promising activity in NDMM, supporting the use of this regimen in this setting.
- Published
- 2020
36. Young Adults with Multiple Myeloma Have Distinct Clinical and Molecular Characteristics Compared to Older Patients
- Author
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Mateo Mejia Saldarriaga, Aubrie Sowa, David S Jayabalan, Cara A. Rosenbaum, Roger Pearse, Jorge Monge, Ruben Niesvizky, and Mark Bustoros
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
37. Clinical and Genomics Characteristics of Multiple Myeloma with Extramedullary Disease in the Mmrf Registry
- Author
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Mateo Mejia Saldarriaga, David S Jayabalan, Aubrie Sowa, Jorge Monge, Cara A. Rosenbaum, Roger Pearse, Ruben Niesvizky, Sanjay Patel, and Mark Bustoros
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
38. Plasma Cell Myeloma Presenting With Amyloid-Laden Crystal-Negative Histiocytosis
- Author
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Duane C. Hassane, John Postley, Steven P. Salvatore, Ruben Niesvizky, Kseniya Petrova-Drus, David Jayabalan, Julia T. Geyer, Marc Braunstein, Yuliya Jhanwar, Roger N. Pearse, Adriana C Rossi, Karen L. Rech, and Cara A. Rosenbaum
- Subjects
0301 basic medicine ,Amyloid ,Pathology ,medicine.medical_specialty ,Plasma cell ,Dexamethasone ,Bortezomib ,Diagnosis, Differential ,03 medical and health sciences ,0302 clinical medicine ,Langerhans cell histiocytosis ,Bone Marrow ,Antineoplastic Combined Chemotherapy Protocols ,Plasma Cell Myeloma ,medicine ,Humans ,Cyclophosphamide ,Rosai–Dorfman disease ,Multiple myeloma ,business.industry ,Amyloidosis ,Remission Induction ,General Medicine ,Middle Aged ,medicine.disease ,Histiocytosis ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,Crystallization ,Multiple Myeloma ,business ,Stem Cell Transplantation ,medicine.drug - Abstract
Objectives Crystal-storing histiocytosis (CSH) is rare in plasma cell dyscrasias, with only 3 cases reported in the setting of amyloid. No cases of crystal-negative histiocytosis coincident with multiple myeloma and amyloidosis have been reported previously. Methods A 58-year-old woman presented with pain due to destructive bone lesions and was found to have plasma cell myeloma (PCM) and marrow amyloid deposition associated with crystal-negative histiocytosis. Differential diagnoses included Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai Dorfman disease. BRAF mutations were negative, and there was no evidence of paraprotein crystals, arguing against typical CSH. Results The patient was treated with bortezomib, cyclophosphamide, and dexamethasone, and she subsequently underwent autologous stem cell transplant and ixazomib maintenance. She achieved complete remission with improvement of her symptoms and preserved remission after following up at 60 months. Conclusions We describe a case of crystal-negative histiocytosis associated with PCM. CSH is a rare disorder associated with paraprotein-producing conditions in which immunoglobulins aggregate as intracellular crystals in the lysosomes of organ-specific phagocytic macrophages. Light chain tropism in PCM can also lead to the development of amyloid deposition in organs and, in rare cases, is associated with light chain aggregation as intracellular crystals in macrophages.
- Published
- 2020
39. Different MAF translocations confer similar prognosis in newly diagnosed multiple myeloma patients
- Author
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Krzysztof Jamroziak, Artur Jurczyszyn, Chor Sang Chim, Monika Długosz-Danecka, Deepu Madduri, Julia Kelman, Max Bittrich, Michel Delforge, Klaus Martin Kortüm, Gabor Mikala, Ariel Kleman, Jorge J. Castillo, Maria-Victoria Mateos, Adam J. Olszewski, Saurabh Chhabra, Pawel Robak, Lidia Usnarska-Zubkiewicz, Anna Waszczuk-Gajda, Iwona Hus, Sarah Goldman-Mazur, David Jayabalan, Julio Davila Valls, Irit Avivi, Rebecca Silbermann, Norbert Grząśko, Stuart L. Goldberg, David H. Vesole, Yael C Cohen, Ruben Niesvizky, Piotr Mazur, Anna Suska, Verónica González-Calle, Laura Rosiñol, Alessandro Gozzetti, Łukasz Szukalski, Jacek Czepiel, Jakub Radocha, Parameswaran Hari, Daniel Coriu, Izabela Kozłowska, Aimee Chappell, Peter Barth, and Massimo Gentile
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Translocation ,Chromosomal translocation ,Newly diagnosed ,Transplantation, Autologous ,survival ,Disease-Free Survival ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Humans ,Medicine ,Multiple myeloma ,Retrospective Studies ,16) ,MAF ,myeloma ,t(14 ,20) ,business.industry ,Hematopoietic Stem Cell Transplantation ,Small sample ,Hematology ,Prognosis ,medicine.disease ,Treatment Outcome ,030220 oncology & carcinogenesis ,Multiple Myeloma ,business ,Large group ,030215 immunology - Abstract
The MAF translocations, t(14;16) and t(14;20), are considered as adverse prognostic factors based on few studies with small sample sizes. We report on their prognostic impact in a large group of 254 patients - 223 (87.8%) with t(14;16) and 31 (12.2%) with t(14;20). There were no intergroup differences in survival estimates. Median progression-free survival was 16.6 months for t(14;16) and 24.9 months for t(14;20) (
- Published
- 2020
40. Final analysis of a phase 1/2b study of ibrutinib combined with carfilzomib/dexamethasone in patients with relapsed/refractory multiple myeloma
- Author
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Ruben Niesvizky, Saurabh Chhabra, Chatchada Karanes, Robert F. Cornell, Yihua Lee, Saad Z. Usmani, Jeffrey Matous, Robert K. Stuart, Larry D. Anderson, Jason Valent, Cristina Gasparetto, Zeena Salman, Emily Liu, Ajai Chari, Matthew A. Lunning, Chaim Shustik, and Saulius Girnius
- Subjects
Male ,Oncology ,Cancer Research ,Bruton's tyrosine kinase inhibitor ,Dexamethasone ,chemistry.chemical_compound ,0302 clinical medicine ,Piperidines ,Original Research Articles ,Antineoplastic Combined Chemotherapy Protocols ,Original Research Article ,Multiple myeloma ,Aged, 80 and over ,education.field_of_study ,carfilzomib ,Bortezomib ,Hematology ,General Medicine ,Middle Aged ,Prognosis ,Survival Rate ,multiple myeloma ,030220 oncology & carcinogenesis ,Ibrutinib ,Female ,Oligopeptides ,medicine.drug ,Adult ,medicine.medical_specialty ,Population ,03 medical and health sciences ,Refractory ,ibrutinib ,Internal medicine ,medicine ,Humans ,education ,Adverse effect ,Aged ,Salvage Therapy ,business.industry ,Adenine ,medicine.disease ,Carfilzomib ,Pyrimidines ,chemistry ,Drug Resistance, Neoplasm ,Pyrazoles ,Neoplasm Recurrence, Local ,business ,Follow-Up Studies ,030215 immunology - Abstract
Patients with multiple myeloma (MM) inevitably relapse on initial treatment regimens, and novel combination therapies are needed. Ibrutinib is a first‐in‐class, once‐daily inhibitor of Bruton's tyrosine kinase, an enzyme implicated in growth and survival of MM cells. Preclinical data suggest supra‐additivity or synergy between ibrutinib and proteasome inhibitors (PIs) against MM. This phase 1/2b study evaluated the efficacy and safety of ibrutinib plus the PI carfilzomib and dexamethasone in patients with relapsed/refractory MM (RRMM). In this final analysis, we report results in patients who received the recommended phase 2 dose (RP2D; ibrutinib 840 mg and carfilzomib 36 mg/m2 with dexamethasone), which was determined in phase 1. The primary efficacy endpoint was overall response rate (ORR). Fifty‐nine patients with RRMM received the RP2D (18 in phase 1 and 41 in phase 2b). These patients had received a median of three prior lines of therapy; 69% were refractory to bortezomib, and 90% were refractory to their last treatment. ORR in the RP2D population was 71% (stringent complete response and complete response: 3% each). Median duration of clinical benefit and median duration of response were both 6.5 months. Median progression‐free survival (PFS) was 7.4 months, and median overall survival (OS) was 35.9 months. High‐risk patients had comparable ORR and median PFS (67% and 7.7 months, respectively) to non–high‐risk patients, whose ORR was 73% and median PFS was 6.9 months, whereas median OS in high‐risk patients was 13.9 months and not reached in non–high‐risk patients. The most common grade ≥3 hematologic treatment‐emergent adverse events (TEAEs) were anemia and thrombocytopenia (17% each); the most common grade ≥3 non‐hematologic TEAE was hypertension (19%). In patients with RRMM treated with multiple previous lines of therapy, ibrutinib plus carfilzomib demonstrated anticancer activity within the expected efficacy range. No new safety signals were identified and the combination was well‐tolerated.
- Published
- 2020
41. P-090: Immune biomarkers of survival and infectionrelated mortality in multiple myeloma (MM) patients treated with lenalidomide and dexamethasone (Rd)
- Author
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Catarina Maia, Noemí Puig, Maria-Teresa Cedena, Norma Gutiérrez, María-J Calassanz, Maria-L Martín-Ramos, Miguel Teodoro Hernandez Garcia, Laura Rosiñol, Mª Esther González, Felipe de Arriba de la Fuente, Albert Oriol, Verónica González, Fernando Escalante, Javier De la Rubia, Mercedes Gironella Mesa, Rafael Ríos, Ricarda García-Sánchez, José-M Arguiñano, Adrián Alegre, Jesus San-Miguel, Juan José Lahuerta Palacios, Joan Blade, Ruben Niesvizky, María-Victoria Mateos, and Bruno Paiva
- Subjects
Cancer Research ,Oncology ,Hematology - Published
- 2022
42. P-033: Patient multiple myeloma cells do not express targetable levels of CD38 when in remission on daratumumab
- Author
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Lauren Reiman, Olivia Perez de Acha, David Jayabalan, Zachary Walker, Grace Bosma, Diana Abbott, Drew Ribadeneyra, Ruben Niesvizky, Tomer Mark, Peter Forsberg, and Daniel Sherbenou
- Subjects
Cancer Research ,Oncology ,Hematology - Published
- 2022
43. Carfilzomib and dexamethasone induction with lenalidomide, clarithromycin and dexamethasone consolidation and lenalidomide maintenance for newly diagnosed multiple myeloma
- Author
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Kari Flicker, Angelique Boyer, Roger N. Pearse, Morton Coleman, Stephanie Lakritz, Adriana C Rossi, Ruben Niesvizky, Drew Ribadeneyra, John N. Allan, Karen Pekle, David Jayabalan, Tomer M Mark, Leora Boussi, Scott Ely, Brielle Liotta, and Peter A. Forsberg
- Subjects
Oncology ,Adult ,Male ,medicine.medical_specialty ,medicine.drug_class ,Phases of clinical research ,Dexamethasone ,Maintenance Chemotherapy ,chemistry.chemical_compound ,Internal medicine ,Clarithromycin ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Lenalidomide ,Multiple myeloma ,Aged ,Aged, 80 and over ,business.industry ,Hematology ,Induction Chemotherapy ,Middle Aged ,medicine.disease ,Carfilzomib ,Regimen ,Treatment Outcome ,chemistry ,Corticosteroid ,Female ,business ,Multiple Myeloma ,Oligopeptides ,medicine.drug - Abstract
Combination treatment regimens including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD) and a corticosteroid are standards of care for initial treatment of multiple myeloma (MM). We aimed to evaluate if a sequential treatment program using PI induction followed by IMiD based consolidation and maintenance could achieve similar outcomes with reduced toxicities. This phase 2 study was designed to assess the safety and efficacy of the Car-BiRd regimen: carfilzomib and dexamethasone (Kd) induction until maximum response, followed by lenalidomide, clarithromycin and dexamethasone (BiRd) consolidation until next maximum response, then lenalidomide maintenance in patients with newly diagnosed MM. Seventy-two patients, including both transplant eligible and ineligible patients, were enrolled and evaluated for response. The overall response rate to the Car-BiRd regimen was 94% with 83% of patients achieving a ≥ VGPR and 35% achieving a CR/sCR. The rate of CR/sCR increased from 7% with Kd induction to 21% with BiRd consolidation and 35% with lenalidomide maintenance. These results did not meet the study's target endpoint of a CR rate of 55%. The median PFS using this deferred transplant approach was 37.3 months (95% CI 27.9, 52.7) and median OS was not reached with a median follow-up of 60 months. Toxicities were primarily low grade and manageable. Hematologic toxicities were lower than those expected with a combination PI/IMiD protocol. The sequential Car-BiRd regimen is an effective and safe approach for the upfront treatment of MM including patients unfit for transplant.
- Published
- 2021
44. Genomic Basis of Multiple Myeloma Subtypes from the MMRF CoMMpass Study
- Author
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Hearn Jay Cho, Jennifer Stumph, Sara Nasser, Kyle McBride, Saad Z. Usmani, David Craig, Andrea Donnelly, Norma C. Gutiérrez, John D. Carpten, Christophe Legendre, Sagar Lonial, Megan Washington, Kimberly Collison, Austin Christofferson, Mattia D'Agostino, Shari Kyman, David S. Siegel, Darla K. Liles, Jeffrey L. Wolf, Jesus G. Berdeja, Barbara Zaugg, Jessica Aldrich, Ahmet Kurdoglu, Scott D. Jewell, Jonathan J Keats, Ruben Niesvizky, Adrienne Helland, Rebecca Reiman, Mary Derome, Brooks Benard, Andrzej Jakubowiak, Brianne Docter, Meghan Kirchhoff, Moshe Yair Levy, Kristi Stephenson, Bryce Turner, Ajai Chari, Jackie McDonald, Pam Kidd, Daniel Penaherrera, Ravi Vij, Martin Boateng, Winnie S. Liang, Daniel Auclair, Sheri Skerget, Maureen Toone, Jennifer Yesil, Venkata Yellapantula, Lori Cuyugan, Alex Blanski, Gregory Orloff, Sundar Jagannath, Erica Tassone, Manuela Gamella, Jonathan Adkins, Chase Miller, Daniel C. Rohrer, and Kenneth C. Anderson
- Subjects
Oncology ,medicine.medical_specialty ,Transition (genetics) ,business.industry ,medicine.medical_treatment ,Immunotherapy ,medicine.disease ,Precision medicine ,Genome ,Internal medicine ,Cohort ,medicine ,business ,Exome ,Gene ,Multiple myeloma - Abstract
Multiple myeloma is a treatable, but currently incurable, hematological malignancy of plasma cells characterized by diverse and complex tumor genetics for which precision medicine approaches to treatment are lacking. The MMRF CoMMpass study is a longitudinal, observational clinical study of newly diagnosed multiple myeloma patients where tumor samples are characterized using whole genome, exome, and RNA sequencing at diagnosis and progression, and clinical data is collected every three months. Analyses of the baseline cohort identified genes that are the target of recurrent gain- and loss-of-function events. Consensus clustering identified 8 and 12 unique copy number and expression subtypes of myeloma, respectively, identifying high- risk genetic subtypes and elucidating many of the molecular underpinnings of these unique biological groups. Analysis of serial samples showed 25.5% of patients transition to a high-risk expression subtype at progression. We observed robust expression of immunotherapy targets in this subtype, suggesting a potential therapeutic option.
- Published
- 2021
45. Caspase-8 Regulates the Antimyeloma Activity of Bortezomib and Lenalidomide
- Author
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Liang Zhou, Guoqiang Xu, Ruben Niesvizky, Zhongjian Pu, and Xiangao Huang
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Combination therapy ,Angiogenesis Inhibitors ,Antineoplastic Agents ,Caspase 8 ,Bortezomib ,hemic and lymphatic diseases ,medicine ,Humans ,Lenalidomide ,Multiple myeloma ,Pharmacology ,business.industry ,Cereblon ,medicine.disease ,Caspase Inhibitors ,HEK293 Cells ,Proteasome ,Proteasome inhibitor ,Cancer research ,Molecular Medicine ,Drug Therapy, Combination ,business ,K562 Cells ,Multiple Myeloma ,medicine.drug - Abstract
Proteasome inhibitors and immunomodulatory drugs (IMiDs) are two major types of drugs for the treatment of multiple myeloma. Although different combination therapies for myeloma have been developed and achieved high responsive rate, these strategies frequently result in drug resistance. Therefore, it is necessary to explore new molecular mechanisms and therapeutic approaches to fulfill this unmet medical need. Here, we find that proteasome inhibitor bortezomib (Btz) causes cereblon (CRBN) cleavage and that caspase-8 (CASP-8) is responsible for this cleavage. Either inhibition or genetic depletion of CASP-8 decreased the CRBN cleavage upon Btz treatment, which could potentiate the antimyeloma activity of IMiD lenalidomide (Len). This work suggests that administration of CASP-8 inhibitors might enhance the overall effectiveness of Btz/Len-based therapeutic treatment of patients with myeloma. SIGNIFICANCE STATEMENT: Caspase-8 activation upon bortezomib treatment results in the cleavage of cereblon, a substrate receptor of the cullin-4 RING E3 ligase, which is responsible for the degradation of two transcription factors, Ikaros family zinc finger protein (IKZF) 1 and IKZF3, in the presence of immunomodulatory drugs including lenalidomide. The administration of caspase-8 inhibitor may enhance the antimyeloma activity of the combination therapy with bortezomib and lenalidomide.
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- 2021
46. High-dose bendamustine and melphalan conditioning for autologous stem cell transplantation for patients with multiple myeloma
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Paul J. Christos, Morton Coleman, Tomer M Mark, June Greenberg, Ruben Niesvizky, Tsiporah B. Shore, Adriana C Rossi, Jingmei Hsu, Sebastian Mayer, Roger N. Pearse, Danielle Guarneri, Usama Gergis, Adrienne A. Phillips, Koen van Besien, and Alexandra Gomez-Arteaga
- Subjects
Melphalan ,Bendamustine ,Transplantation ,medicine.medical_specialty ,Transplant Conditioning ,business.industry ,Urology ,Phases of clinical research ,Hematology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Autologous stem-cell transplantation ,Refractory ,030220 oncology & carcinogenesis ,medicine ,business ,Multiple myeloma ,030215 immunology ,medicine.drug - Abstract
High-dose melphalan (MEL200) followed by autologous stem cell transplantation (ASCT) remains a standard of care for multiple myeloma (MM). Bendamustine induces responses in MM resistant to other alkylators. Our prior Phase I trial adding bendamustine to MEL200 transplant conditioning resulted in no additional toxicity. We now report a single-arm, phase II study that evaluated the efficacy of bendamustine 225 mg/m2 with MEL200 conditioning for ASCT in 18 patients with newly diagnosed MM (NDMM) and 17 with relapsed or refractory MM (RRMM). The primary end point was the complete response (CR/sCR) rate at day+ 100. Sample size was determined according to Simon's two-stage design. At stage 1, sixteen patients entered the study. As there were eight patients with CR/sCR, enrollment increased to 28 patients. Sixteen out of the first 28 evaluable patients achieved CR/sCR, meeting the design criteria. Enrollment was then expanded to a total of 35 patients. 51% achieved a CR/sCR. After a median follow-up of 65 months, 21 patients progressed, including 7 deaths. The median PFS for NDMM and RRMM was 48 and 45 months, respectively. Bendamustine/MEL200 conditioning resulted in excellent overall and depth of response as well as PFS, particularly in the RRMM patients, and is worthy of further investigation (NCT00916058).
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- 2019
47. Carfilzomib or bortezomib with melphalan-prednisone for transplant-ineligible patients with newly diagnosed multiple myeloma
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Philippe Moreau, Artur Jurczyszyn, Bruno Paiva, Zandra Klippel, Meletios A. Dimopoulos, Ludek Pour, Ruben Niesvizky, Muhtarjan Osman, Roman Hájek, Jesús F. San-Miguel, Anita Zahlten-Kumeli, Lugui Qiu, Jae Hoon Lee, and Thierry Facon
- Subjects
Adult ,Male ,Melphalan ,medicine.medical_specialty ,Immunology ,Population ,Biochemistry ,Gastroenterology ,Bortezomib ,chemistry.chemical_compound ,Prednisone ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Progression-free survival ,education ,Multiple myeloma ,Aged ,Aged, 80 and over ,education.field_of_study ,business.industry ,Hazard ratio ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Carfilzomib ,Progression-Free Survival ,Transplantation ,Treatment Outcome ,chemistry ,Female ,Multiple Myeloma ,business ,Oligopeptides ,medicine.drug - Abstract
The phase 3 CLARION study compared carfilzomib-melphalan-prednisone (KMP) with bortezomib-melphalan-prednisone (VMP) in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. Patients were randomized 1:1 to KMP or VMP for nine 42-day cycles (C). Patients received carfilzomib on days (D) 1, 2, 8, 9, 22, 23, 29, 30 (20 mg/m2: C1D1, C1D2; 36 mg/m2 thereafter) or bortezomib on D1, 4, 8, 11, 22, 25, 29, 32 (1.3 mg/m2; D4, 11, 25, 32 omitted for C5-9). Melphalan (9 mg/m2) and prednisone (60 mg/m2) were administered on D1-4. The primary endpoint was progression-free survival (PFS). Nine hundred fifty-five patients were randomized (intention-to-treat population: KMP, n = 478; VMP, n = 477). Median PFS was 22.3 months with KMP vs 22.1 months with VMP (hazard ratio [HR], 0.906; 95% confidence interval [CI], 0.746-1.101; P = .159). Median overall survival was similar and not reached in either group (HR, 1.08; 95% CI, 0.82-1.43). Overall response rate was 84.3% for KMP and 78.8% for VMP. Complete response rate was 25.9% for KMP and 23.1% for VMP. Minimal residual disease–negative rates were 15.7% (KMP) and 15.5% (VMP). Adverse events (AEs) of interest (any grade) occurring with a ≥5% higher patient incidence in the KMP arm were acute renal failure (13.9% [KMP] vs 6.2% [VMP]) and cardiac failure (10.8% vs 4.3%). Grade ≥3 AE rates were 74.7% (KMP) and 76.2% (VMP). Grade ≥2 peripheral neuropathy was lower for KMP vs VMP (2.5% vs 35.1%). Treatment with KMP in CLARION did not yield a statistically significant difference in PFS vs VMP. This trial was registered at www.clinicaltrials.gov as #NCT01818752.
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- 2019
48. Carfilzomib vs bortezomib in patients with multiple myeloma and renal failure: a subgroup analysis of ENDEAVOR
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Amy S. Kimball, Ralph V. Boccia, Darrell White, Ruben Niesvizky, Meletios A. Dimopoulos, Zhao Yang, Khalid Mezzi, Karim Iskander, Heinz Ludwig, and David S. Siegel
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Male ,medicine.medical_specialty ,Clinical Trials and Observations ,Immunology ,Population ,Urology ,Renal function ,Biochemistry ,Dexamethasone ,Bortezomib ,chemistry.chemical_compound ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Prospective Studies ,Renal Insufficiency ,Prospective cohort study ,education ,Survival rate ,Aged ,education.field_of_study ,business.industry ,Hazard ratio ,Cell Biology ,Hematology ,Prognosis ,Carfilzomib ,Confidence interval ,Survival Rate ,chemistry ,Drug Resistance, Neoplasm ,Female ,Neoplasm Recurrence, Local ,Multiple Myeloma ,business ,Oligopeptides ,Follow-Up Studies ,medicine.drug - Abstract
In ENDEAVOR, carfilzomib (56 mg/m2) and dexamethasone (Kd56) demonstrated longer progression-free survival (PFS) over bortezomib and dexamethasone (Vd) in patients with relapsed/refractory multiple myeloma (RRMM). Here we evaluated Kd56 vs Vd by baseline renal function in a post hoc exploratory subgroup analysis. The intent-to-treat population included 929 patients (creatinine clearance [CrCL] ≥15 to
- Published
- 2019
49. Initial safety results for MagnetisMM-3: A phase 2 trial of elranatamab, a B-cell maturation antigen (BCMA)-CD3 bispecific antibody, in patients (pts) with relapsed/refractory (R/R) multiple myeloma (MM)
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Alexander M. Lesokhin, Bertrand Arnulf, Ruben Niesvizky, Mohamad Mohty, Nizar J. Bahlis, Michael H. Tomasson, Paula Rodríguez-Otero, Hang Quach, Noopur S. Raje, Shinsuke Iida, Marc-Steffen Raab, Akos Czibere, Sharon Sullivan, Eric Leip, Andrea Viqueira, and Xavier Leleu
- Subjects
Cancer Research ,Oncology - Abstract
8006 Background: Elranatamab (PF-06863135) is a humanized bispecific antibody that targets both BCMA-expressing MM cells and CD3-expressing T cells. MagnetisMM-3 (NCT04649359) is an open-label, multicenter, non-randomized, phase 2 study to evaluate the safety and efficacy of elranatamab monotherapy in pts with R/R MM. Initial safety results are presented. Methods: MagnetisMM-3 enrolled pts who are refractory to at least 1 proteasome inhibitor, 1 immunomodulatory drug, and 1 anti-CD38 antibody. Pts were assigned to 1 of 2 independent, parallel cohorts: those naïve to BCMA-directed therapies (Cohort A) and those with previous exposure to BCMA-directed antibody-drug conjugates or CAR-T cells (Cohort B). Pts received subcutaneous elranatamab 76 mg QW on a 28-d cycle with a 2-step-up priming dose regimen administered during the first week. Dose modifications were permitted for toxicity. Treatment-emergent adverse events (TEAEs) were graded by CTCAE (v5.0), and cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) by ASTCT criteria. Results: As of the data cutoff on Dec 31, 2021, 60 pts in Cohort A had received ≥1 dose of elranatamab; the last pt’s first dose was ̃2 months prior to the cutoff. Median age was 69.0 y (range, 44−89), 48.3% were male, 63.3% were white, 18.3% were Asian and 11.7% were Black/African American. At baseline, 60.0% of pts had an ECOG performance status 1−2 and pts had received a median of 5 (range, 2−12) prior therapies. Median duration of elranatamab treatment was 9.57 wks (range, 0.1−46.1); median relative dose intensity was 87.4% (range, 23.1−101.4). TEAEs were reported in 100% (Grade [G] 3/4, 75.0%) of pts. Most common (≥30%) hematologic TEAEs were neutropenia (36.7% [G3/4, 35.0%]), anemia (36.7% [G3/4, 30.0%]) and thrombocytopenia (30.0% [G3/4, 21.7%]). Among pts who received the 2-step-up priming regimen (n = 56), CRS and ICANS, respectively, were reported in 58.9% (G3/4, 0%) and 3.6% (G3/4: 0%); of those pts, 57.6% (n = 19/33) and 100% (n = 2/2) received tocilizumab and/or steroids. Most common (≥30%) non-hematologic TEAE, other than CRS/ICANS, was fatigue (31.7% [G3/4, 3.3%]). Infections were reported in 46.7% (G3/4: 18.3%) of pts; most frequently reported were upper respiratory tract infections (11.7% [G3/4: 0%]). Discontinuations due to adverse events were reported in 5.0% of pts. No pts permanently discontinued treatment due to CRS or ICANS. There were 10 deaths; causes were MM progression (n = 8), septic shock (n = 1) and unknown (n = 1). Data will be updated at the time of presentation to include ̃90 pts. Conclusions: Preliminary results of MagnetisMM-3 in pts with R/R MM and no prior BCMA-targeted treatment suggest that 76 mg QW elranatamab with a 2-step-up priming regimen is well tolerated, with no G ≥3 CRS or ICANS observed. Clinical trial information: NCT04649359.
- Published
- 2022
50. MM-392: Belantamab Mafodotin (Belamaf; GSK2857916) US Expanded Access Program (EAP) for Heavily Pre-Treated Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Baseline Characteristics
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Larry D. Anderson, Cristina Gasparetto, Faiz Anwer, Stephanie Petrone, Eric Lewis, Mehmet H. Kocoglu, Eben I. Lichtman, Malin Hultcrantz, Jonathan L. Kaufman, Hong Li, Ruben Niesvizky, Sofia Paul, and Clifton C. Mo
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Cancer Research ,medicine.medical_specialty ,education.field_of_study ,business.industry ,Population ,Context (language use) ,Hematology ,Pomalidomide ,Clinical trial ,Oncology ,Internal medicine ,Expanded access ,medicine ,Medical history ,business ,education ,Adverse effect ,medicine.drug ,Lenalidomide - Abstract
Context The belamaf US EAP (NCT03763370) provided medicine access to patients unable to participate in a clinical trial prior to regulatory agency approval. Objective To obtain insight from the belamaf EAP on patient types potentially eligible for belamaf treatment in a real-world setting. Methods The EAP included patients with RRMM who received ≥3 prior lines of therapy and were refractory to proteasome inhibitors, immunomodulatory agents, and anti-CD38 monoclonal antibody. Patients received belamaf 2.5 mg/kg Q3W. Safety was closely monitored, and dose delays/reductions were permitted to manage adverse events. Treating physicians re-evaluated eligibility to continue belamaf at each treatment cycle; patients could withdraw at any time. The EAP closed following US FDA approval of belamaf. We report baseline characteristics from included patients. Results In this preliminary analysis (as of 3 Feb 2021), 263 patients were screened; 235 were treated with ≥1 dose of belamaf and were included in this analysis. The most common reasons for withdrawal were lack of continued clinical benefit (n=37) and death (n=21); 23 patients continued therapy beyond closure of the program. Of 235 treated patients, 137 (58.3%) were male. Median age was 66 years, with 106 patients (45.1%) aged 75 years. Two hundred eighteen patients had further medical history available; 61 (26.0%) had prior treatment-related toxicities, 10 (4.3%) had active renal disease, and 5 (2.1%) had undergone allogeneic stem cell transplant. Two hundred twenty-one patients had ocular baseline characteristics reported; these included prior glaucoma diagnosis (single-eye, n=16 [6.8%]), prior cataract diagnosis (single, n=124 [52.8%]), history of cataract surgery (single, n=66 [28.1%]), and prior dry eye diagnosis (n=46 [19.6%]). The most common prior anticancer therapies included bortezomib, lenalidomide, pomalidomide, and carfilzomib. Data cleaning is ongoing for this study. Conclusions This EAP provides insights from a real-world population of US belamaf-treated patients, which, in addition to data from the pivotal DREAMM-2 study, may help practitioners identify patients potentially eligible for belamaf treatment. Funding GlaxoSmithKline (213304). Drug linker technology licensed from Seagen Inc.; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa.
- Published
- 2021
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