Mezigdomnide Preliminary Results Multiple Myeloma from the Dose-Expansion Phase of the CC-92480-MM-001
By Paul Richardson, MD
How can Mezigdomide (CC-92480) help patients with multiple myeloma? The important point is that Mezigdomide (CC-92480) is an oral therapy that is a, what we call a new class of drugs called cell mods. These are highly potent small molecules which work by targeting the degradation of Ikaros and Aiolos, which are key transcription factors for multiple myeloma pathobiology. They’re also very important in lymphoma as well, actually. But in myeloma, they’re a key target.
These the engagement or the degradation of these particular transcription part pathways or, partners is particularly important in the context not only of triggering apoptosis in the myeloma cell, but also having downstream effects on the immune system with quite remarkable effects on T-cells and NK cells. So there’s a number of features to the way this drug works that are quite compelling.
The other point to share is that they’re quite distinct from the immunomodulators. They are much more potent in what they do, and they engage what’s called the Cereblon E3 Ligase pocket in a far more tight and decisive fashion. It emits, for example, will engage about 50% of the pocket. Mezigdomide (CC-92480) is a hundred percent and it will bind right in and activate that pocket. So it’s a, it is a different drug. They’re, we’re really able to think of it more of as a degrader than the necessary immunomodulator. The good thing is they have the same immune effects, if not more potently, which they are. But they have this profound effect directly on the tumor.
So that’s Mezigdomide (CC-92480) pre-clinically it’s synergistic in the lab with steroids, proteasome inhibitors CD38 monoclonal antibodies (mAbs) and so forth. So what was this study? This study was. An expand a preliminary results of our expansion cohort of our phase 1/2 study of Mezigdomide (CC-92480) plus or minus Dexamethasone in relapse refractory myeloma was established in the phase 1 component that you could give Mezigdomide (CC-92480) 1 milligram three weeks on a one week off and combine it with dexamethasone very safely, and it was very active, even in high refractory patients, the response rate, in our phase 1 was 55%. Now, in this expansion cohort, we enrolled over a 100 patients, they were all triple class refractory. In other words, three major classes of drugs had failed them and they were also enriched for high risk with high-risk cytogenetics, extra medullary disease, and high stage.
Importantly, also, about a third, were BCMA exposed. In other words, they’d been exposed to a BCMA targeted therapy and it had failed them. So with all of that in mind, we were particularly encouraged when we saw that we got about a 40% response rate overall. It was actually 41% to be precise. And when we looked at the BCMA exposed patients, we were even more excited it was over 50%. And interestingly enough, in the patients with extra medullary disease, the response rate was 30%. So this was really quite remarkable, and then this was coupled with a very nice safety signal with no weird or strange things in that context and above all, in during the COVID-19 pandemic. Cause we were enrolling over the last 18 months, 2 years, we were able to show.
That this drug was not associated with increased mortality signal from COVID-19, in fact, we only had one death of 101 patients, so this was quite important. In terms of other side effects, we know was a slightly increased risk of infections seen, which we see all the time in relapse refractory disease anyway, but much less than you see, for example, with bispecific CAR-Ts (t cells)and so on and above all, what we did also see was cytopenias, neutropenic phenomena was seen, which is very much expected, but we did not see non hematologic toxicity to any major degree. So in some, very promising response activity for an all oral, approach in a very refractory vulnerable population.
What is the Current SOC for Pts with Triple Refractory Multiple Myeloma?
Yeah, the standard of care, frankly, for triple class refractory BCMA exposed patients is participation in a clinical trial or trying to resurrect the activity of old agents that have been used previously.
So you might, for example, offer a patient a Bortezomib based platform combined with say, a chemotherapy. And, the likelihood of a meaningful response as unfortunately is very low. So to see this kind of activity in such a vulnerable population was very exciting.
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Common Questions From Your Colleagues
I think really the tolerability and the fact that it’s all oral is very exciting to my colleagues and particularly to community colleagues as well. Cause of patients referred don’t have to go into the hospital, it’s an outpatient regimen and that it’s generally well tolerated.
I think what’s also striking to people is that as an all oral therapy, it has a real world value because it’s there to be given in a true off-the-shelf setting. You don’t come into the hospital. It’s, as I mentioned, oral therapy that’s generally well tolerated. I think that’s the excitement from community colleagues.
5 Key Takeaways About the Mezigdomide (CC-92480) Study
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Mezigdomide ((MEZI) (CC-92480)), a novel oral CELMoD® agent with higher tumoricidal and immune-stimulating actions compared to immunomodulatory medications (IMiDs®), stimulates maximal degradation of Ikaros and Aiolos, resulting in increased (multiple) myeloma cells (mm cells) death.
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Triple-class refractory (multiple myeloma) was present in all patients (refractory to an IMiD medication [LEN/POM], a PI, and an anti-CD38 mAb), and 39.6% of patients were refractory to LEN, POM, 2 PIs, and an anti-CD38 mAb.
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As of May 24, 2022, 101 points at the RP2D had received MEZI + DEX. At study enrollment, 20.8% of patients had ISS stage III disease. Median age was 67 (range 42–85) years, median time since initial diagnosis was 7.4 (1.1–37.0) years, and median time since initial diagnosis was 7.4 (1.1–37.0) years.
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MEZI + DEX indicated encouraging efficacy in patients with triple-class refractory (multiple myeloma) RRMM, including those who had received earlier BCMA-targeted treatments, with an ORR of 40% and 50%, respectively.
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Despite the paucity of complete data, the preliminary median duration of response was 8.3 (95% confidence interval [CI]: 5.4–not reached) months and the median progression-free survival was 4.6 (95% CI: 3.2–6.3) months. The median period of follow-up was 5.8 (range: 0.5–19.0) months, and 23 (22.8%) patients stayed on treatment. The leading cause of discontinuation was progressive disease (50.5%).
What Are the Key Takeaways from this Trial?
Oh, I think key takeaways are we are continuing to see lots of exciting advances in multiple myeloma therapeutics. We need them because myeloma is not curable and it remains a deadly hematologic malignancy with relapse refractory disease, having dismal outcomes.
So this constitutes a very important new addition building on what we have also already and what we have coming. But what I love most about Mezigdomide (CC-92480) is that it’s an oral real world practical opportunity for patients to enjoy better disease control for some time.
Paul G. Richardson, MD – About The Author, Credentials, and Affiliations
Dr. Paul Richardson is the R.J. Corman Professor, Medicine, Harvard Medical School, currently at the Dana-Farber Cancer Institute, he joined the Jerome Lipper Myeloma Center in 1999, became Clinical Director in 2001, and developed numerous first-generation new multiple myeloma medications, including bortezomib, lenalidomide, and pomalidomide. Panobinostat and second-generation proteasome inhibitors like ixazomib have been studied since. Elotuzumab, daratumumab, isatuximab, antibody drug conjugates as belantamab mafotetin, and other immunotherapeutic techniques have been developed for untreated and relapsed myeloma. He is also developing the targeted cytotoxic melflufen, the first-in-class small molecule inhibitor selinexor, which inhibits XPO-1, a critical nuclear export protein, and first-in-human investigations of cereblon E3 ligase modulators (CELMoDs) for relapsed and refractory myeloma. He has spent the past decade developing lenalidomide, bortezomib, and dexamethasone (RVD) and incorporating it into the Intergroup Francophone Myelome (IFM)/DFCI clinical trial for newly diagnosed patients candidates for a stem cell transplant who are treated with RVD.
This regimen had an unprecedented response rate, which led to its adoption in this multinational study and additional US and foreign investigations. Genetic and proteomic analyses will create a platform for individualized therapy and optimal stem cell transplant location in 2021-22. RVD also supports next-generation drugs including elotuzumab, daratumumab, isatuximab, and panobinostat.
Over 400 original publications and 330 peer-reviewed reviews, chapters, and editorials are his. He was the Chairman of the Multiple Myeloma Research Consortium (MMRC) Clinical Trials Core for five years and continues to participate on the Steering and Project Review Committees. He sat on the ASCO Hematologic Malignancies Subcommittee and Internet Cancer Information Committee for one year each in 2017. He is Alliance Myeloma Committee chairman since 2011. The George Canellos Award for Excellence in Clinical Research and Patient Care, Tisch Outstanding Achievement Award for Clinical Research, and Royal College of Physicians (UK) Honorary Fellowship for international contributions to multiple myeloma and stem cell transplantation are among his honors. Therapeutic targeting of the ubiquitin-proteasome system earned him the 2012 Warren Alpert Foundation Prize.
He co-won the 2009 and 2017 Research Center of the Year Awards and the Accelerator Award for clinical research and patient enrolment in MMRC studies. Thomson Reuters Science Watch named him one of DFCI’s 19 most cited researchers in 2016. He received the 2015 ASH Ernest Beutler Prize for clinical science and translational research in the development of proteasome inhibition as an effective treatment for multiple myeloma, the 2016 COMY Award for MM research (Paris, France), the 2017 IMF Robert A. Kyle Lifetime Achievement Award, and the 2019 Morse Research Award.