ASCO 2020: CELMoDs as a New Drug Class in Multiple Myeloma
A new type of myeloma treatment called CC-92480 (a CELMoD) showed benefit in a Phase I international clinical trial at the recent ASCO 2020 meeting.
This new class of drugs being developed in multiple myeloma called CELMoDs are functionally different from the immunomodulators like Revlimid and Pomalyst.
CELMoDs are larger molecules and work by quickly degrading a specific set of proteins (called Ikaros and Aiolos). They are potent modulators of the cereblon E3 ligase complex.They also stimulate the immune system and kill myeloma cells directly, even for myeloma that has become resistant to certain therapies. It is synergistic with other therapies and has "excellent tumor penetration" according to Paul Richardson, MD of the Dana Farber Cancer Institute. The other CELMoD currently in development is iberdomide.
Dr. Paul Richardson shared more information about the study on a recent Myeloma Crowd Radio program:
It’s important to not think of them as sort of again a glorified IMiD. That would be a mistake. They are really in a different category in my opinion. I think this supports that. They have a much high degradation efficiency, the induction of apoptosis is much more powerful and they overcome lenalidomide and pomalidomide resistance nicely, pre-clinically, and 220 iberdomide has been the lead CELMoD presented on that last ASCO by Dr. Sagar Lonial.
According to Dr. Richardson, the CC-92480 drug is more potent than iberdomide. In the study, 90% of patients were refractory (resistant) to lenalidomide and pomalidomide, all had received proteasome inhibitors and 70% were refractory to monoclonal antibodies (like daratumumab or isatuximab). The major side effects were neutropenia (low white blood cells) and thrombocytopenia (low platelet counts), but according to Dr. Richardson they were manageable.
Through the Phase I study, they found the Maximum Tolerated Dose was one milligram pill once a day, three weeks on, one week off, as the best schedule (after analyzing many schedules and reviewing the Ailos degradation and light chain measurements).
In those patients there was a 55% response rate (this is quite high for a single drug with patients who were this heavily pre-treated. Other recently approved drugs have been in the 30-35% range). According to Dr. Richardson:
If you look at the 55% group, seven of the 11 patients in the cohort were classically penta-refractory. Of those seven patients who were penta-refractory, one had a complete response, one had a very good partial response, and two of the patients have partial responses, and one a minimal response, so you can see why we’re excited because that’s a very nice early signal.
Even extramedullary patients (those who develop myeloma tumors outside of the bone marrow) were able to achieve a Complete Response, which for an oral drug is "really something."
Dr. Richardson said that CC-92480 worked faster, having a maximum degradation point within 5 minutes whereas pomalidomide takes about 20 minutes and lenalidomide takes 35 minutes to do the same thing.
We hope the development of this new and exciting drug class continues as myeloma patients continue to need more treatment options.