[Immunosubstitution of patients with refractory multiple myeloma treated with teclistamab, a bispecific antibody]

Abstract

Multiple myeloma (MM) is the 2^nd most common haematological malignancy in France, and its treatment has been improved in recent years by the arrival of new therapies such as CAR-T cells and bispecific antibodies. Among the latter, teclistamab, indicated as a 4^th-line treatment for relapsed or refractory MM patients, targets the CD3 antigen on the surface of T lymphocytes and the BCMA antigen on the surface of malignant plasma cells. The adverse reactions to teclistamab described in the summary of product characteristics (SPC) mention hypogammaglobulinemia, leading to recurrent infections. Immunosubstitution with normal human immunoglobulin (HN-Ig) is often necessary. However, these drugs are regularly in short supply, and are subject to prioritisation recommendations. Until now, immunosubstitution in myeloma has been a "non-priority" indication, to be assessed according to the criteria of the French National Agency for the Safety of Medicines and Health Products (ANSM). The aim of this study was to analyse the management of hypogammaglobulinaemia in the context of teclistamab treatment in our institution over a one-year period during post-marketing authorisation (MA) early access (AP2). Patient characteristics and clinical data related to treatment with teclistamab and HN-Ig (dose, route of administration, frequency, and time to post-teclistamab initiation for HN-Ig, first infection and its type prior to immunosubstitution and its time to onset relative to teclistamab initiation) were extracted from patient records. In order to analyse compliance with the recommendations for prioritisation of HN Ig indications, blood Ig G levels were recorded (at the time of teclistamab initiation, one month later, 3 months later, and 6 months after the start of teclistamab treatment). The quantities in total grams of Ig HN consumed in hospital and aftercare as part of teclistamab treatment and in all DIS indications combined were also investigated. Among the 35 patients treated with teclistamab, 24 received HN Ig as a replacement after an average of 1 month of treatment. At least one infection occurred in 13 of these patients approximately 1 month after initiation of teclistamab. Bacterial infections accounted for 75 % of these infections, mainly pneumonia, bronchitis and urinary tract infections. In 96 % of patients, HN Ig was administered intravenously at a dose of 0.4g/kg each month. Only one patient was treated with weekly subcutaneous Ig HN at a dose of 0.1g/kg. Only 50 % of patients treated with HN Ig met the prioritisation criteria defined by the ANSM (latest recommendations April 2019). Despite immunosubstitution, IgG levels remained relatively stable over time, with a median of 2.6g/L at the start of teclistamab treatment. The time to initiation of immunosubstitution only shortened over time, from 3 months at the start of the study to 0 months, and then to systematic initiation of IS from the start of teclistamab. In terms of consumption, the use of HN-Ig to compensate for post-teclistamab hypogammaglobulinaemia represented 33 % of the total consumption of HN-Ig for secondary immunodeficiency. In conclusion, the systematic introduction of Ig HN immunosubstitution seems necessary to prevent infections following teclistamab treatment in patients with proven hypogamaglobulinaemia. This new practice is likely to have a major impact on the consumption of these plasma-derived medicinal products, which are already often in short supply.

Keywords: Bispecific antibody; Immunosubstitution; Myeloma; Myélome multiple; Teclistamab.