Anti-CD38 immunotherapy assay and monitoring in patients with multiple myeloma: A monocentric pilot study

Abstract

Abstract Introduction Daratumumab is a humanized monoclonal antibody targeting surface molecule CD38 on myeloma cells. It is widely used due to its favourable tolerability and proven efficacy in treating Multiple Myeloma (MM) and is currently recommended as first-line therapy for both transplant eligible and ineligible patients. It can also be used in case of relapse. Therapeutic drug monitoring (TDM) is commonly used with proven efficacy in autoimmune diseases such as inflammatory bowel disease and rheumatism to adjust treatment with recognized decision-making algorithms (Rutgeerts 2010). In hematology, therapeutic response to rituximab has been correlated with serum drug concentration in several studies ( 1998). To date, monitoring of anti-CD38 in patients with MM during maintenance therapy and its correlation with therapeutic response were not explored. We present a study assessing (1) time intra-individual variability measured with a new available assay to monitor daratumumab concentrations in cohort 1, and (2) association between daratumumab serum concentrations and clinical response in MM patients in cohort 1 and 2. Methods We conducted a monocentric biobank observational study including patients with MM receiving daratumumab (subcutaneous fixed dose, 1800mg) -based regimens. Blood samples were collected before the next injection of daratumumab. For cohort 1, patients with only one blood sample were excluded. For cohort 2, the study was offered to all patients treated in our center and the recruitment period lasted one month. Daratumumab concentrations were determined using the enzyme linked immunosorbent assay (ELISA Q-DAR, Shikari, Matriks Biotek). Responding patients were defined according to the IMWG criteria (complete, very good and partial response) and non-responding patients were identified based on disease progression (biological or clinical). Welch's t-tests were performed, and collected data was analyzed using the Stataid software. Results For cohort 1, 53 blood samples from 19 patients were analyzed (intra-individual variability cohort). A median of two measures per patient was performed (min-max: 2-7). The median age was 76 years (66-85 years), estimated glomerular filtration rate (eGFR) 56 mL/min/ 1,73 m2 (26-89 mL/min/ 1,73 m2) and body mass index (BMI) 23 kg/m² (16-32 kg/m²). Among them, 56% received daratumumab as first line therapy. Regarding daratumumab concentrations, the median intra-individual relative standard deviation was 19% (IQR 5-90%). The average daratumumab serum concentrations were compared between responders and non-responders patients. Concentrations were significantly lower in non-responders (median: 1495µg/L IQR 814-2847 µg/L) compared to responders (median: 2958 µg/L, IQR 2229-3435 µg/L; p=0,0003). For cohort 2, 38 patients, among which 28 women, were included (25 responders patients and 13 non-responders). The median age of 76 years (55-89 years). Among them, 63% received daratumumab as first line therapy. There was no significant statistical difference between the responders and non-responders groups regarding their characteristics (age, sex ratio, eGFR, BMI, treatment line of daratumumab, M-component at day 1 and bone marrow plasmacytosis). Daratumumab serum concentrations were significantly lower in non-responders, with a median of 1367µg/L (IQR 824-1488 µg/L), compared to 1733 µg/L (IQR 1429-2019 µg/L) in responders group (p =0.0055). Conclusion Our pilot study provides data supporting that higher concentrations of immunotherapy might be correlated to better treatment response. Therapeutic monitoring of daratumumab in patients treated for MM could thus help to predict the response to treatment and/or could help physicians to optimize time interval between injections. Further larger multicenter studies are needed to confirm these results.