Real World Experience of Daratumumab: Evaluating Lymphopenia and Adverse Events in Multiple Myeloma Patients

Multiple myeloma (MM) is an incurable disease with a limited life expectancy of five years from diagnosis. Uncontrolled disease or infections are the main causes of mortality. Daratumumab, a monoclonal antibody against CD38, is approved to treat patients with MM. Its target, CD38, is expressed not only on MM cells but also on common lymphoid precursors and subsets of normal lymphocytes. Daratumumab-induced lymphopenia is common, but its clinical significance is understudied. In this study, we report the baseline characteristics, rates of severe lymphopenia, infections, and clinical trajectory of multiple myeloma patients (n = 100) treated with daratumumab-based regimens at the Ohio State University Comprehensive Cancer Center. We discover high rates of infections, hospital utilization, and severe lymphopenia and identify risks factors for severe lymphopenia, such as low pretreatment absolute lymphocyte count (ALC) values. Severe lymphopenia persists in 23% of patients, resulting in worst survival outcomes. Our data underline the importance of monitoring ALC and consider future use of prophylactic measures or alternative regimens in subsets of MM patients.

[1]  J. Byrd,et al.  T-cell transcriptional profiling and immunophenotyping uncover LAG3 as a potential significant target of immune modulation in multiple myeloma. , 2020, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[2]  M. Mims,et al.  Safety Analysis of Five Randomized Controlled Studies of Daratumumab in Patients With Multiple Myeloma. , 2019, Clinical lymphoma, myeloma & leukemia.

[3]  T. Koru-Sengul,et al.  Hypogammaglobulinemia and Its Implications in Patients Treated with Daratumumab: A Single Institution Experience , 2019, Blood.

[4]  M. Dhodapkar,et al.  How to Train Your T Cells: Overcoming Immune Dysfunction in Multiple Myeloma , 2019, Clinical Cancer Research.

[5]  M. Fine,et al.  Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America , 2019, American journal of respiratory and critical care medicine.

[6]  N. Mahmud,et al.  Combined immune score of lymphocyte to monocyte ratio and immunoglobulin levels predicts treatment-free survival of multiple myeloma patients after autologous stem cell transplant , 2019, Bone Marrow Transplantation.

[7]  P. Sonneveld,et al.  Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study , 2019, The Lancet.

[8]  H. Goldschmidt,et al.  Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma. , 2019, The New England journal of medicine.

[9]  S. Lonial,et al.  High‐Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action , 2018, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[10]  H. Einsele,et al.  Clinical and biological characteristics of myeloma patients influence response to elotuzumab combination therapy , 2018, Journal of Cancer Research and Clinical Oncology.

[11]  F. van Rhee,et al.  Infectious and immunological sequelae of daratumumab in multiple myeloma , 2018, British journal of haematology.

[12]  G. Ippolito,et al.  ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Agents targeting lymphoid or myeloid cells surface antigens [II]: CD22, CD30, CD33, CD38, CD40, SLAMF-7 and CCR4). , 2018, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[13]  M. Caligiuri,et al.  Fratricide of NK Cells in Daratumumab Therapy for Multiple Myeloma Overcome by Ex Vivo–Expanded Autologous NK Cells , 2018, Clinical Cancer Research.

[14]  Andre H Crepaldi,et al.  Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma , 2017, The New England journal of medicine.

[15]  B. Barlogie,et al.  Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial , 2017, The Lancet.

[16]  H. Goldschmidt,et al.  Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. , 2016, The New England journal of medicine.

[17]  A. Palumbo,et al.  Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. , 2016, The New England journal of medicine.

[18]  R. Greil,et al.  An international, multicenter, prospective, observational study of neutropenia in patients being treated with lenalidomide + dexamethasone for relapsed or relapsed/refractory multiple myeloma (RR‐MM) , 2016, American journal of hematology.

[19]  Bie M. P. Verbist,et al.  Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. , 2016, Blood.

[20]  Chao Lu,et al.  Retrospective study , 2016, Medicine.

[21]  Camille Guillerey,et al.  Immune responses in multiple myeloma: role of the natural immune surveillance and potential of immunotherapies , 2016, Cellular and Molecular Life Sciences.

[22]  S. Trudel,et al.  Absolute lymphocyte count as predictor of overall survival for patients with multiple myeloma treated with single autologous stem cell transplant , 2015, Leukemia & lymphoma.

[23]  U. Mellqvist,et al.  Multiple myeloma and infections: a population-based study on 9253 multiple myeloma patients , 2015, Haematologica.

[24]  Su-Jin Shin,et al.  Prognostic Significance of Absolute Lymphocyte Count/Absolute Monocyte Count Ratio at Diagnosis in Patients with Multiple Myeloma , 2013, Korean journal of pathology.

[25]  Je-Jung Lee,et al.  Lymphocytopenia is associated with an increased risk of severe infections in patients with multiple myeloma treated with bortezomib-based regimens , 2013, International Journal of Hematology.

[26]  J. Trapani,et al.  The immunostimulatory effect of lenalidomide on NK-cell function is profoundly inhibited by concurrent dexamethasone therapy. , 2011, Blood.

[27]  D. Esseltine,et al.  Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. , 2010, Blood.

[28]  A. Dispenzieri,et al.  Prediction of survival using absolute lymphocyte count for newly diagnosed patients with multiple myeloma: a retrospective study , 2008, British journal of haematology.

[29]  R. Mesa,et al.  Absolute lymphocyte count recovery after induction chemotherapy predicts superior survival in acute myelogenous leukemia , 2005, Leukemia.

[30]  M. Naunton Lenalidomide and dexamethasone for multiple myeloma , 2013 .

[31]  D. Crivellari,et al.  A Single-Institution Experience , 2013 .

[32]  A. Palumbo,et al.  Multiple myeloma. , 2011, The New England journal of medicine.

[33]  A. Schwarer,et al.  Higher infused lymphocyte dose predicts higher lymphocyte recovery, which in turn, predicts superior overall survival following autologous hematopoietic stem cell transplantation for multiple myeloma. , 2008, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.