PS1427 THE SIGNIFICANCE OF UNEXPECTED PHARMACOKINETICS OF DARATUMUMAB DURING LONG‐TERM MONTHLY TREATMENT FOR MYELOMA
Authors: Sheldon J. , Crichlow A. , Powles R. , Little L. 
Published: June 2019

Background:

Daratumumab, a drug used in the treatment of multiple myeloma appears as a small IgGK band on serum protein electrophoresis that can be quantified alongside any monoclonal proteins that are present in a patient's serum.

Aims:

To assess the value and significance of the Daratumumab concentration over the course of treatment.

Methods:

Daratumumab concentrations have been measured in the serum in 33 patients being treated for B cell malignancies (the paraprotein types were IgG n = 15, IgA n = 11, BJP n = 5, no paraprotein n = 2). The mean duration of Daratumumab treatment was 15.8 months (range 1–31 months) and all patients were treated according to standard Daratumumab protocol. The quantifications were obtained from the densitometry of the Daratumumab peak from capillary zone electrophoresis separation peak converted into g/L using the samples serum total protein concentration.

Results:

Five of the 33 patients never shown a band of Daratumumab on the serum protein electrophoresis. Interestingly all these patients had IgG paraproteins (4 IgGK, 1IGgL) and it might be that the electrophoretic mobility of their paraprotein overlapped that of the Daratumumab. Their total IgG concentrations (measured immunochemically) were all above 12 g/L. All other patients with IgG paraproteins and comparable total IgG concentrations maintained detectable Daratumumab during their treatment.

There were 23 patients where (to date) the duration of the Daratumumab treatment is more than 6 months and who showed a quantifiable Daratumumab band during their treatment. Eight of the 23 patients (2 IgAK, 1 IgAL, 1 IgGK, 2 IgGL, 1 BJP and 1 non‐secretory) had quantifiable Daratumumab throughout their Daratumumab treatment (range 10–31 months). In fifteen patients (6 IgGk, 3 IgAk, 2 IgAl, 3 K BJP and 1 L BJP) the Daratumumab band disappeared from the serum protein electrophoresis at some point during their treatment. The mean time to loss of the Daratumumab band was 12.4 months (range 6–26 months, median 10 months). Following the recommended dose of 16 mg/kg, the Cmax value is reported to be 0.915 g/L which is consistent with our findings of Daratumumab concentrations between 0.46 and 2.01 g/L (included data from all patients with measureable concentrations).

Summary/Conclusion:

The half‐life of Daratumumab is reported to be 18–23 days so while patients are on weekly or even two‐weekly infusions at the start of Daratumumab therapy, a progressive increase in the Daratumumab may be expected but this is not reflected in our data. The concentration and duration of the Daratumumab band, particularly during the monthly infusion phase is surprising; the concentration remains comparable to the more frequent infusion phases. However, the most surprising findings are i) the disappearance of the Daratumumab band in a significance number of patients during the monthly infusion period, and ii) the wide range in the “time to disappearance” in the context of the reported 18–23 half‐life of Daratumumab. It would be expected that daratumumab would detectable in all patients throughout all treatment phases.

The turnover of IgG is complex and in addition to normal catabolic processes the neonatal Fc‐receptors recirculate IgG and prolong its half‐life when IgG concentrations fall; the interaction of Daratumumab in this process may offer some explanation for unexpected patters of Daratumumab concentrations that we have seen in a cohort of 33 patients. The presence, concentration or duration of the Daratumumab band had no correlation to patient outcome.