GPRC5D is a very selective antigen that is highly expressed on malignant plasma cells and not so much, or hardly, on any other cell in the human body. It is expressed on the skin and especially the hair follicles but with the selective expression it makes it an ideal target for anti-immune therapy focussed therapies in relapsed/refractory multiple myeloma and perhaps in future also in newly diagnosed patients.
What was the design of the study?
We started with a first in human phase I design. So we were looking for the maximum tolerated dose and after that looking for efficacy, safety and tolerability. So it’s a classic phase I design. In the end we could not find the maximum tolerated dose so we stopped at the recommended phase II dose and two different doses were selected as our P2Ds.
What were the key findings?
Our key findings were that both doses, and one is 405 µg/kg every week dosing and the other one was 800μg/kg every other week dosing, that they had a comparable efficacy and also safety profile. In the end we extended the programme so 30 patients were in the first cohort and 44 patients were in the second, the every other week, cohort dosing. With that we saw also longer duration of responses, they were between 10-30 months median.
What were the side effects?
The most common side effects were cytokine release syndrome, dysgeusia and skin and nail related events as non-haem adverse events. CRS was mostly grade 1, some grade 2 and only one grade 3 CRS and that was managed very easily with one dose of tocilizumab or some corticosteroids. The other side effects were dysgeusia and skin related events and they passed away after longer dosing or we had to delay dosing or delay the dose intensity in the treatment of the patients. As haem adverse events we saw some pancytopenia, cytopenias, but they were mostly on the step-up dosing and cycle 1 or 2. They resolved spontaneously, so they were higher grade but did not seem to be a problem at all. Also we did not see much more infections; we did see infections in 40-50% of patients but no treatment related deaths occurred.
What was the conclusion of the study and what is the next step?
We are concluding that we have a novel targeting antigen in multiple myeloma, so next to CD38, BCMA we now have GPRC5D that can be targeted. These results are very encouraging because this is a single drug activity and to see these numbers as efficacy between 64-70% overall response rate is really, really astonishing. At the moment we are looking at some other dosing frequencies, we are looking at combination therapies and the future will be that this will be a very active drug, already as single agent, for relapsed and refractory multiple myeloma patients.
