BACKGROUND: Teclistamab is a T-cell-redirecting bispecific antibody that targets both CD3 expressed on the surface of T cells and B-cell maturation antigen expressed on the surface of myeloma cells. In the phase 1 dose-defining portion of the study, teclistamab showed promising efficacy in patients with relapsed or refractory multiple myeloma. METHODS: In this phase 1-2 study, we enrolled patients who had relapsed or refractory myeloma after at least three therapy lines, including triple-class exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. Patients received a weekly subcutaneous injection of teclistamab (at a dose of 1.5 mg per kilogram of body weight) after receiving step-up doses of 0.06 mg and 0.3 mg per kilogram. The primary end point was the overall response (partial response or better). RESULTS: Among 165 patients who received teclistamab, 77.6% had triple-class refractory disease (median, five previous therapy lines). With a median follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients (39.4%) having a complete response or better. A total of 44 patients (26.7%) were found to have no minimal residual disease (MRD); the MRD-negativity rate among the patients with a complete response or better was 46%. The median duration of response was 18.4 months (95% confidence interval [CI], 14.9 to not estimable). The median duration of progression-free survival was 11.3 months (95% CI, 8.8 to 17.1). Common adverse events included cytokine release syndrome (in 72.1% of the patients; grade 3, 0.6%; no grade 4), neutropenia (in 70.9%; grade 3 or 4, 64.2%), anemia (in 52.1%; grade 3 or 4, 37.0%), and thrombocytopenia (in 40.0%; grade 3 or 4, 21.2%). Infections were frequent (in 76.4%; grade 3 or 4, 44.8%). Neurotoxic events occurred in 24 patients (14.5%), including immune effector cell-associated neurotoxicity syndrome in 5 patients (3.0%; all grade 1 or 2). CONCLUSIONS: Teclistamab resulted in a high rate of deep and durable response in patients with triple-class-exposed relapsed or refractory multiple myeloma. Cytopenias and infections were common; toxic effects that were consistent with T-cell redirection were mostly grade 1 or 2. (Funded by Janssen Research and Development; MajesTEC-1 ClinicalTrials.gov numbers, NCT03145181 and NCT04557098.).
Subject(s)Antibodies, Bispecific , Antineoplastic Agents, Immunological , B-Cell Maturation Antigen , CD3 Complex , Multiple Myeloma , Antibodies, Bispecific/administration & dosage , Antibodies, Bispecific/adverse effects , Antibodies, Bispecific/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , B-Cell Maturation Antigen/antagonists & inhibitors , CD3 Complex/antagonists & inhibitors , Humans , Injections, Subcutaneous , Multiple Myeloma/drug therapy , Multiple Myeloma/immunology , Multiple Myeloma/pathology , Neoplasm Recurrence, Local/drug therapy , Recurrence , T-Lymphocytes/drug effects , T-Lymphocytes/immunology
Subject(s)BNT162 Vaccine/administration & dosage , COVID-19 , Immunity, Humoral , Immunization, Secondary , Multiple Myeloma , SARS-CoV-2/immunology , Aged , COVID-19/immunology , COVID-19/prevention & control , Female , Humans , Male , Middle Aged , Multiple Myeloma/immunology , Multiple Myeloma/therapy , Prospective Studies
Subject(s)ADP-ribosyl Cyclase 1/antagonists & inhibitors , Antineoplastic Agents, Immunological/therapeutic use , BNT162 Vaccine/therapeutic use , COVID-19/prevention & control , Multiple Myeloma/drug therapy , SARS-CoV-2/immunology , ADP-ribosyl Cyclase 1/immunology , Adult , Aged , Antineoplastic Agents, Immunological/pharmacology , BNT162 Vaccine/pharmacology , COVID-19/complications , COVID-19/immunology , Female , Humans , Immunity, Cellular , Immunity, Humoral , Immunogenicity, Vaccine , Male , Middle Aged , Multiple Myeloma/complications , Multiple Myeloma/immunology , Prospective Studies
Subject(s)Ad26COVS1/immunology , Antibodies, Viral/biosynthesis , BNT162 Vaccine/immunology , COVID-19/prevention & control , Immunoglobulin G/biosynthesis , Multiple Myeloma/immunology , SARS-CoV-2/immunology , Waldenstrom Macroglobulinemia/immunology , Asymptomatic Diseases , COVID-19/epidemiology , COVID-19 Vaccines , Female , Humans , Immunocompromised Host , Immunogenicity, Vaccine , Immunologic Tests , Male , Models, Immunological , Prospective Studies , Risk
Subject(s)COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Immunity, Cellular/drug effects , Immunogenicity, Vaccine , Multiple Myeloma/immunology , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/immunology , 2019-nCoV Vaccine mRNA-1273 , Antibodies, Viral/blood , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , B-Lymphocytes/virology , BNT162 Vaccine , COVID-19/diagnosis , COVID-19/immunology , COVID-19/virology , Case-Control Studies , Cytokines/blood , Host-Pathogen Interactions , Humans , Immunoglobulin G/blood , Lymphocyte Activation/drug effects , Multiple Myeloma/diagnosis , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/virology , Treatment Outcome , Vaccination
Patients with haematological malignancies have a high risk of severe infection and death from SARS-CoV-2. In this prospective observational study, we investigated the impact of cancer type, disease activity, and treatment in 877 unvaccinated UK patients with SARS-CoV-2 infection and active haematological cancer. The primary end-point was all-cause mortality. In a multivariate analysis adjusted for age, sex and comorbidities, the highest mortality was in patients with acute leukaemia [odds ratio (OR) = 1·73, 95% confidence interval (CI) 1·1-2·72, P = 0·017] and myeloma (OR 1·3, 95% CI 0·96-1·76, P = 0·08). Having uncontrolled cancer (newly diagnosed awaiting treatment as well as relapsed or progressive disease) was associated with increased mortality risk (OR = 2·45, 95% CI 1·09-5·5, P = 0·03), as was receiving second or beyond line of treatment (OR = 1·7, 95% CI 1·08-2·67, P = 0·023). We found no association between recent cytotoxic chemotherapy or anti-CD19/anti-CD20 treatment and increased risk of death within the limitations of the cohort size. Therefore, disease control is an important factor predicting mortality in the context of SARS-CoV-2 infection alongside the possible risks of therapies such as cytotoxic treatment or anti-CD19/anti-CD20 treatments.
Subject(s)Antigens, CD20/immunology , Antineoplastic Agents, Immunological/therapeutic use , COVID-19/complications , Hematologic Neoplasms/complications , Hematologic Neoplasms/drug therapy , Adult , Antineoplastic Agents, Immunological/adverse effects , COVID-19/etiology , COVID-19/immunology , Female , Hematologic Neoplasms/immunology , Humans , Leukemia/complications , Leukemia/drug therapy , Leukemia/immunology , Male , Multiple Myeloma/complications , Multiple Myeloma/drug therapy , Multiple Myeloma/immunology , Prospective Studies , Risk Factors
Subject(s)Immunotherapy, Adoptive , Multiple Myeloma , Receptors, Chimeric Antigen/immunology , Virus Diseases , Adult , Aged , Female , Follow-Up Studies , Humans , Male , Middle Aged , Multiple Myeloma/immunology , Multiple Myeloma/therapy , Multiple Myeloma/virology , Registries , Virus Diseases/etiology , Virus Diseases/immunology
Patients with multiple myeloma frequently present with substantial immune impairment and an increased risk for infections and infection-related mortality. The risk for infection with SARS-CoV-2 virus and resulting mortality is also increased, emphasising the importance of protecting patients by vaccination. Available data in patients with multiple myeloma suggest a suboptimal anti-SARS-CoV-2 immune response, meaning a proportion of patients are unprotected. Factors associated with poor response are uncontrolled disease, immunosuppression, concomitant therapy, more lines of therapy, and CD38 antibody-directed and B-cell maturation antigen-directed therapy. These facts suggest that monitoring the immune response to vaccination in patients with multiple myeloma might provide guidance for clinical management, such as administration of additional doses of the same or another vaccine, or even temporary treatment discontinuation, if possible. In those who do not exhibit a good response, prophylactic treatment with neutralising monoclonal antibody cocktails might be considered. In patients deficient of a SARS-CoV-2 immune response, adherence to measures for infection risk reduction is particularly recommended. This consensus was generated by members of the European Multiple Myeloma Network and some external experts. The panel members convened in virtual meetings and conducted an extensive literature research and evaluated recently published data and work presented at meetings, as well as findings from their own studies. The outcome of the discussions on establishing consensus recommendations for COVID-19 vaccination in patients with multiple myeloma was condensed into this Review.
Subject(s)COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Multiple Myeloma/complications , Practice Guidelines as Topic/standards , Consensus , Humans , Multiple Myeloma/drug therapy , Multiple Myeloma/immunology , SARS-CoV-2 , Vaccination
Subject(s)BNT162 Vaccine/therapeutic use , COVID-19/prevention & control , Immunity, Humoral , Immunoglobulin Light-chain Amyloidosis/complications , Multiple Myeloma/complications , Antibodies, Viral/immunology , COVID-19/complications , COVID-19/immunology , Female , Humans , Immunoglobulin G/immunology , Immunoglobulin Light-chain Amyloidosis/immunology , Male , Multiple Myeloma/immunology , Prospective Studies
Multiple myeloma patients are often treated with immunomodulatory drugs, proteasome inhibitors, or monoclonal antibodies until disease progression. Continuous therapy in combination with the underlying disease frequently results in severe humoral and cellular immunodeficiency, which often manifests in recurrent infections. Here, we report on the clinical management and immunological data of three multiple-myeloma patients diagnosed with COVID-19. Despite severe hypogammaglobulinemia, deteriorated T cell counts, and neutropenia, the patients were able to combat COVID-19 by balanced response of innate immunity, strong CD8+ and CD4+ T cell activation and differentiation, development of specific T-cell memory subsets, and development of anti-SARS-CoV-2 type IgM and IgG antibodies with virus-neutralizing capacities. Even 12 months after re-introduction of lenalidomide maintenance therapy, antibody levels and virus-neutralizing antibody titers remained detectable, indicating persisting immunity against SARS-CoV-2. We conclude that in MM patients who tested positive for SARS-CoV-2 and were receiving active MM treatment, immune response assessment could be a useful tool to help guide decision-making regarding the continuation of anti-tumor therapy and supportive therapy. KEY MESSAGES: Immunosuppression due to multiple myeloma might not be the crucial factor that is affecting the course of COVID-19. In this case, despite pre-existing severe deficits in CD4+ T-cell counts and IgA und IgM deficiency, we noticed a robust humoral and cellular immune response against SARS-CoV-2. Evaluation of immune response and antibody titers in MM patients that were tested positive for SARS-CoV-2 and are on active MM treatment should be performed on a larger scale; the findings might affect further treatment recommendations for COVID-19, MM treatment re-introduction, and isolation measures.
Subject(s)COVID-19/immunology , Immunity, Cellular/immunology , Immunity, Humoral/immunology , Multiple Myeloma/immunology , Multiple Myeloma/virology , SARS-CoV-2/immunology , Antibodies, Neutralizing/immunology , Humans , Immunoglobulin G/immunology , Male , Middle Aged
Patients with multiple myeloma (MM) have a suboptimal antibody response following vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and lower seroconversion rates following coronavirus disease 2019 (COVID-19) compared with healthy individuals. In this context, we evaluated the development of neutralising antibodies (NAbs) against SARS-CoV-2 in non-vaccinated patients with MM and COVID-19 compared with patients after vaccination with two doses of the BNT162b2 vaccine. Serum was collected either four weeks post confirmed diagnosis or four weeks post a second dose of BNT162b2. NAbs were measured with a Food and Drug Administration-approved enzyme-linked immunosorbent assay methodology. Thirty-five patients with COVID-19 and MM along with 35 matched patients were included. The two groups did not differ in age, sex, body mass index, prior lines of therapy, disease status, lymphocyte count, immunoglobulin levels and comorbidities. Patients with MM and COVID-19 showed a superior humoral response compared with vaccinated patients with MM. The median (interquartile range) NAb titre was 87·6% (71·6-94%) and 58·7% (21·4-91·8%) for COVID-19-positive and vaccinated patients, respectively (P = 0·01).Importantly, there was no difference in NAb production between COVID-19-positive and vaccinated patients who did not receive any treatment (median NAb 85·1% vs 91·7%, P = 0·14). In conclusion, our data indicate that vaccinated patients with MM on treatment without prior COVID-19 should be considered for booster vaccine doses.
Subject(s)Antibodies, Neutralizing/biosynthesis , Antibodies, Viral/biosynthesis , BNT162 Vaccine/immunology , COVID-19/immunology , Multiple Myeloma/immunology , SARS-CoV-2/immunology , Adult , Aged , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/complications , COVID-19/prevention & control , COVID-19 Serological Testing , Epitopes/immunology , Female , Humans , Immunization, Secondary , Immunocompromised Host , Immunogenicity, Vaccine , Male , Middle Aged , Multiple Myeloma/complications , Prospective Studies , Vaccination
The identification of discrete subclasses within the immunoglobulin G (IgG) isotype by Grey and Kunkel (1964. J. Exp. Med.https://doi.org/10.1084/jem.120.2.253) provided the framework for our current understanding of differential IgG subclass activity in protective and self-reactive immune responses.
Subject(s)Immunoglobulin G/metabolism , Antibody Formation/immunology , B-Lymphocytes/metabolism , COVID-19/immunology , Glycosylation , Humans , Multiple Myeloma/immunology , Multiple Myeloma/pathology
Subject(s)Antibodies, Neutralizing/blood , Antibodies, Viral/blood , BNT162 Vaccine/immunology , COVID-19/prevention & control , Immunoglobulin G/blood , SARS-CoV-2/immunology , Aged , Antibodies, Neutralizing/biosynthesis , Antibodies, Viral/biosynthesis , Cohort Studies , Female , Hematologic Neoplasms/immunology , Humans , Immunogenicity, Vaccine , Immunoglobulin G/biosynthesis , Kinetics , Leukemia/immunology , Lymphoma, Non-Hodgkin/immunology , Male , Middle Aged , Multiple Myeloma/immunology , Myeloproliferative Disorders/immunology , Time Factors , Vaccination
Among the hallmarks of cancer is the ability of neoplastic cells to evade and suppress immune surveillance to allow their growth and evolution. Nowhere is this as apparent as in multiple myeloma, a cancer of antibody-producing plasma cells, where a complex interplay between neoplastic cells and the immune microenvironment is required for the development and progression of disease. Decades of research has led to the discovery of a number of therapeutic agents, from cytotoxic drugs to genetically engineered cells that mediate their antimyeloma effects at least partially through altering these immune interactions. In this review, we discuss the history of immunotherapy and current practices in multiple myeloma, as well as the advances that promise to one day offer a cure for this deadly disease.
Subject(s)Immunotherapy , Multiple Myeloma/therapy , Humans , Multiple Myeloma/immunology
Recent data suggest a suboptimal antibody response to COVID-19 vaccination in patients with hematological malignancies. Neutralizing antibodies (NAbs) against SARS-CoV-2 were evaluated in 276 patients with plasma cell neoplasms after vaccination with either the BNT162b2 or the AZD1222 vaccine, on days 1 (before the first vaccine shot), 22, and 50. Patients with MM (n = 213), SMM (n = 38), and MGUS (n = 25) and 226 healthy controls were enrolled in the study (NCT04743388). Vaccination with either two doses of the BNT162b2 or one dose of the AZD1222 vaccine leads to lower production of NAbs in patients with MM compared with controls both on day 22 and on day 50 (p < 0.001 for all comparisons). Furthermore, MM patients showed an inferior NAb response compared with MGUS on day 22 (p = 0.009) and on day 50 (p = 0.003). Importantly, active treatment with either anti-CD38 monoclonal antibodies (Mabs) or belantamab mafodotin and lymphopenia at the time of vaccination were independent prognostic factors for suboptimal antibody response following vaccination. In conclusion, MM patients have low humoral response following SARS-CoV-2 vaccination, especially under treatment with anti-CD38 or belamaf. This underlines the need for timely vaccination, possibly during a treatment-free period, and for continuous vigilance on infection control measures in non-responders.
Subject(s)Antibodies, Neutralizing , Antibodies, Viral , COVID-19 Vaccines , COVID-19 , Multiple Myeloma , SARS-CoV-2 , Aged , Aged, 80 and over , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/blood , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , Female , Humans , Male , Middle Aged , Multiple Myeloma/blood , Multiple Myeloma/immunology , Prospective Studies , SARS-CoV-2/immunology , SARS-CoV-2/metabolism
Multiple myeloma (MM) patients are at higher risk for severe COVID-19. Their mRNA vaccination response against SARS-CoV-2 is unknown. Thus, we analyzed responses to mRNA vaccination against COVID-19 among these patients. Using an ELISA-based assay that detects IgG antibodies to SARS-CoV-2 spike protein, we determined serum antibody levels prior to immunization and 12-21 and 14-21 days following the first and second vaccinations, respectively, with mRNA-1273 (Moderna) or BNT162b2 (Pfizer/BioNTech) among 103 MM patients (96 and 7 with active and smoldering disease, respectively). We stratified patients into clinically relevant responders (>250 IU/mL), partial responders (50-250 IU/mL, which was above pre-COVID-19 background), and nonresponders (<50 IU/mL). Smoldering MM patients responded better than those with active disease. Only 45% of active MM patients developed an adequate response, while 22% had a partial response. Lower spike antibody levels were associated with older age, impaired renal function, low lymphocyte counts, reduced uninvolved immunoglobulin levels, > second line of treatment, and among those not in complete remission. Patients who received mRNA-1273 vaccine had higher anti-spike antibody levels than those who were vaccinated with BNT162b2. Thus, most MM patients have impaired responses to mRNA vaccination against COVID-19, and specific clinical and myeloma-related characteristics predict vaccine responsiveness.