Hard-to-treat multiple myeloma responds to novel CELMoD agent
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Researchers observed an overall response rate of 21% among heavily pretreated relapsed/refractory multiple myeloma targeted with CC-92480, a novel cereblon E3 ligase modulator, or CELMoD, agent, in combination with dexamethasone as part of a large multicenter international phase 1 study, according to preliminary results presented at ASCO20 Virtual Scientific Program.
CC-92480, designed for rapid and maximal degradation of a specific set of target proteins (Ikaros and Aiolos), has profound immune stimulatory effects and tumoricidal activity in resistant myeloma cell lines, Paul G. Richardson, MD, clinical program leader and director of clinical research, Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute and RJ Corman Professor of Medicine at Harvard Medical School, told Healio.
“It’s been sometimes coined ‘CAR T-therapy in a pill’ – that’s in humor of course, but it’s a bit like that because CC-92480 is synergistic with other therapies and it’s very potent,” he said. “The reason it’s such an interesting molecule is because it really has highly efficient substrate degradation and excellent tumor penetration by virtue of its pharmacologic characteristics.”
Richardson explained that CC-92480 achieves a maximum degradation point within 5 minutes in preclinical models; in comparison, pomalidomide takes about 20 minutes and lenalidomide takes 35 minutes to do the same thing. However, it isn’t “just another immunomodulatory drug,” he said. “It belongs to a new class described as a CELMoD, which have distinct features that distinguish them from other immunomodulatory agents.”
In an ongoing, multicenter, phase 1 study, Richardson and colleagues from Denmark, Britain, Canada, Spain and the U.S. examined the maximum tolerated dose, recommended phase 2 dose, safety, tolerability and pharmacokinetics of CC-92480 plus dexamethasone in 76 heavily pretreated patients with relapsed/refractory multiple myeloma.
All the subjects had relapsed/refractory disease and median of 6 prior lines of therapy, 37% had extramedullary disease, 74% were lenalidomide-refractory, 79% were pomalidomide-refractory, 74% were refractory to proteasome inhibitors and 70% were refractory to monoclonal antibody treatment, according to Richardson. At least half of the patients were penta-exposed and triple class refractory.
The researchers looked at a continuous schedule – either 10 days off out of 14, twice a month, or 21 out of 28 days – and an intensive schedule – either 3 out of 14 days, twice a month, or 7 out of 14 days, twice a month.
Richardson and colleagues determined that the recommended phase 2 dose should be 1 mg of the drug daily, 3 weeks on and 1 week off. For 76 patients, the overall response rate (ORR) was 21%, according to the findings.
“Whilst this may seem modest, it’s key to remember that it’s a phase 1 study where we started at just 0.1 mg,” Richardson said. “If you look at maximum-tolerated dose, which was 1 mg, the response rate jumped to 40% in patients who got 10 out of 14 days across each month. If you looked at the recommended phase 2 dose, our overall response rate just for CC-92480 combined with dexamethasone jumped to 55%, which is very encouraging.”
So far, 11 patients have received this maximum tolerated dose and best schedule, according to Richardson. Of the seven triple-class refractory patients in this group, five patients had responses, with one patient achieving complete remission, one achieving very good partial remission, two achieving partial remission and one achieving minimal response.
Of the 37% of patients with extramedullary disease who received the 1 mg dose, the researchers observed two very good partial responses, one complete remission and two partial responses.
“That’s compelling and reflects the tissue penetrated I mentioned before. If this proves sustained, this is an important advance for our patients – and the platform is just a pill, 3 weeks on and 1 week off,” Richardson told Healio.
Further, the overall adverse event profile was manageable, according to Richardson.
Currently, one-third of the 76 patients are still on treatment and, so far, dose reductions were required in 22% of the treated patients. No deaths related to treatment occurred and no patients discontinued CC-92480 due to toxicity. Neutropenia, thrombocytopenia and pneumonitis were manageable with dose-reduction schedule change and treatment-emergent adverse events were low. Overall, there were four cases of mild peripheral neuropathy and one case and is of deep vein thrombosis. About one-third of patients had significant infections and about 15% had pneumonia, which is typical for this population
Richardson and colleagues also found that both pharmacokinetic and pharmacodynamic effects were dose-dependent – systemic exposure improved when the dose of CC-92480 increased.
“What’s really nice in this study is that the trial was truly translational. We made observations in the laboratory, came to the bedside, treated patients, performed correlative science and got the best dosing schedule to go forward with,” he said. “We’re very hopeful that this can represent a really new and important class of drugs (the so called CELMoD’s) to complement what has already been achieved with other drugs, and meaningfully further improve patient outcome.”
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Richardson PG, et al. Abstract 8500. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
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