Teclistamab for Relapsed/Refractory Multiple Myeloma: Real-World Experience in an Early Access Program

Background Teclistamab, a BCMAxCD3 bispecific antibody, has shown promising results in clinical trials for the treatment of relapsed/refractory multiple myeloma (RRMM) with an overall response rate of 63% and duration of response of 18.4 months in the phase 1-2 study with patients that had received a minimum of 3 prior lines (Moreau, et al. N Engl J Med. 2022). Beginning in July 2021 Sweden was the first country world-wide to start the early access program with subcutaneous teclistamab (Single Patient Request Program), supported by Janssen. Here we report the outcome of these patients.

Method Seventeen patients with RRMM were treated with teclistamab in 5 different hospitals in Sweden. Patients who had received at least 1 full dose of teclistamab at data cut off 30 June 2022 were included. As per guidelines all patients were hospitalized for the initial step-up doses (60 and 300 microgram per kilogram (µg/Kg)) and first full dose (1500 µg/Kg) with a median of 7 days (range 6 - 29). This was followed by 1500 µg/Kg QW (n=15) or Q2W (n=2). Three patients after achieving very good partial response (VGPR) or better switched from weekly to biweekly treatment or treatment every 3^rd week. Paracetamol, dexamethasone and antihistamine was given as cytokine release syndrome (CRS) prophylaxis during the step-up dosing.

Responses are defined in accordance with the IMWG response criteria with the addition of near complete response (nCR) defined as undetectable M protein and normal FLC ratio, but lacking bone marrow assessment. Both CRS and immune-effector cell associated neurotoxicity syndrome (ICANS) have been graded according to the ASTCT grading systems (Lee et al. Biol Blood Marrow Transplant. 2019).

Results

Of the 17 patients, 10 were male and 7 were female, with median age of 62 years (range 43 - 83). Median number of prior lines of treatment was 9 (range 3 - 14), with all patients (100%) penta-drug exposed; 88% and 41% were triple-class and penta-drug refractory, respectively. Fifteen patients (88%) had previously received high dose melphalan and autologous stem cell transplantation. Two patients had relapsed after allogeneic stem cell transplantation.

At data cut off, 15 patients were evaluable for response with an overall response rate of 60% (n=9), with 53% (n=8) reaching ≥VGPR (Figure 1). Median time to first response was 1 month (range 0.4 - 1.8) and to best repose 2 months (range 0.4 - 7.4). Progression free survival is shown in Figure 2. In 6 patients the treatment was discontinued, 4 due to progressive disease, 1 due to recurrent infections and 1 death due to myeloma shortly after commencing teclistamab treatment.

Nine patients (53%) experienced CRS; 8 grade 1 and 1 grade 2. All CRS events occurred during the pre-planned hospitalization and were treated effectively with paracetamol and/or dexamethasone. Tocilizumab was only administrated to the patient with CRS grade 2. One patient was reported to experience a suspected recurrent ICANS grade 1 (difficulties writing a sentence) during the step-up doses and the 1^st full dose, but the symptoms resolved before the next dose.

Six patients suffered from infections that required hospitalization: 3 COVID-19, 1 neutropenic fever during the step-up dosing schedule, 1 infected decubitus ulcer and 1 sepsis of unknown origin. COVID-19 infections were treated with sotrovimab, remdesivir and/or corticosteroids. All patients recovered and could resume teclistamab treatment. Several grade 1 - 2 bacterial and viral infections were managed in the outpatient clinic, including asymptomatic CMV reactivation.

Conclusions This first real-world experience supports that teclistamab is effective with manageable side effects, corresponding to the results of published clinical trials showing high response rates in heavily pretreated, penta-drug exposed patients with multiple myeloma. CRS was common but of low grade and easily manageable. Infections are a challenge in patients with B-cell defects and need to be an area of focus in teclistamab treated patients. Therefore, regular monitoring of infections including viral reactivation is important. Hypogammaglobulinemia should be treated with immunoglobulin replacement therapy and prophylaxis against herpes simplex virus/varicella zoster virus and hepatitis B (in serologically HBV positive patients without active infection) is recommended.

Uttervall:GSK: Consultancy; BMS: Other: Speaking and teaching; Janssen: Consultancy. Nahi:Genmab: Current Employment.