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COMy 2020 | CD38: a promising target for multiple myeloma antibody therapy

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Saad Usmani

Saad Usmani, MD, University of North Carolina School of Medicine, Chapel Hill, NC, discusses anti-CD38 and other new therapies in clinical trials. CD38 is a widely expressed surface marker that is found on hematopoietic cell lines, including B-cells, and in non-hematopoietic cells such as plasma cells. In order to utilize the potential target, anti-CD38 makers have been developed in combination with other therapies. Currently, they are being examined in an early phase clinical setting. The treatments in the furthest development are the antibody drugs daratumumab and isatuximab. Additionally, Dr Usmani discusses clinical trials evaluating the use of anti-CD38 antibodies in relapsed/refractory multiple myeloma, such as the CASTOR, CANDOR and IKEMA trials. This interview took place during the Controversies in Multiple Myeloma (COMy) 2020 Virtual World Congress.

Transcript (edited for clarity)

CD38 is a surface marker that’s widely expressed on hematopoietic cell lines specifically with the B-cell lineage, but it’s also expressed on non-hematopoietic cell lineages as well. It is commonly expressed on plasma cells and the scientific rationale is there to utilize this as a potential target for therapies. Several anti-CD38 monoclonal antibodies have been examined in early phase clinical trials...

CD38 is a surface marker that’s widely expressed on hematopoietic cell lines specifically with the B-cell lineage, but it’s also expressed on non-hematopoietic cell lineages as well. It is commonly expressed on plasma cells and the scientific rationale is there to utilize this as a potential target for therapies. Several anti-CD38 monoclonal antibodies have been examined in early phase clinical trials. The two that are the farthest ahead in terms of clinical development have been the antibody daratumumab, which is a humanized IgG Kappa monoclonal antibody, and isatuximab, which is a chimeric IgG kappa antibody. And I detailed the monotherapy data with daratumumab, as well as the data in the relapsed refractory setting. I did the same for isatuximab. We do have data with the pomalidomide combination as well as carfilzomib combination. So I walked through the phase I data, the phase II, III data with both of these monoclonal antibodies, highlighting which clinical populations those data will be most relevant for.

With the daratumumab based combinations, I discussed the data with the lenalidomide as well as bortezomib combinations, so namely the POLLUX and the CASTOR trial highlighting the fact that the three-drug combination with this anti-CD38 in both those trials, came up with positive results compared to the two-drug combinations in terms of depth of response, overall response, MRD negativity rates, as well as progression-free survival. And then I also discussed the data that exists with the combination of pomalidomide, dexamethasone and the most recently presented CANDOR clinical trial, which looked at daratumumab, carfilzomib, dex versus carfilzomib, dexamethasone. The populations are obviously different with each of these trials and so, it would be important to bear those in mind when picking which option may be the best for your patient. For example, with patients who would get data with Len/Dex, that clinical trial did not have patients who had prior len refractoriness, but patients with bortezomib exposure or refractoriness were included, similarly with the data of bortezomib, dex combination patients who had prior len exposure or len refractoriness where were included bortezomib refractoriness were excluded.

So, that would be the …, if you’re looking for a non-len combination, that would be something to consider. More impressive data however, are with the daratumumab combination with carfizomib dexamethasone where the median PFS has not been reached after 16 month follow up, whereas that for Krd was about 16 months and, about a third of the patients had Len exposed and refractory disease. So I think, that would be clinically meaningful, in the same way in isatuximab, Pom/Dex combination appears to be very effective, it read right out positively for patients with relapse/refractory myeloma and, Len exposed or refractory patients were enrolled on that study.

And the IKEMA data, which was the combination of isatuximab with carfilzomib, dexamethasone, compared to carfilzomib dexamethasone also read out positively. It would be interesting to see what the median PFS is for the three drug combinations with both these monoclonal antibodies, as a potential distinction, the depth of response appears to be similar. The safety profile appears to be similar. So it will be really , the clinical benefit that patients get in terms of disease control, which would probably be distinct. And then the route of administration and the schedule of administration. I did not talk about the cost of drug, but if you look at the global care of myeloma patients, I think that probably will also come into play.

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