Oral CELMoD Mezigdomide May Address Logistical Challenges Linked With R/R Myeloma Management

Paul G. Richardson, MD

Enhanced antiproliferative activity and immune responses seen with the novel CELMoD mezigdomide (CC-92480) alongside dexamethasone in heavily pretreated patients with relapsed/refractory multiple myeloma, as well as the agent’s versatility as an oral therapeutic, suggests its potential utility as salvage therapy for patients who progressed on prior anti-BCMA therapy and other poor prognostic subgroups, according to Paul G. Richardson, MD.

Findings from the dose-escalation portion of a phase 1/2 trial (NCT03374085) showed that patients experienced an overall response rate (ORR) of 25% (95% CI, 16%-36%) with the combination at a median follow-up of 6.3 months (range, 0.6-33.1). This consisted of a complete response (CR) rate of 1%, a very good partial response (VGPR) rate of 12%, and a partial response (PR) rate of 12%. The combination’s safety profile primarily consisted of myelotoxic adverse effects (AEs) and was deemed manageable.

In the phase 2 dose-expansion, mezigdomide and dexamethasone produced an ORR of 41% (95% CI, 31%-51%), including a stringent CR rate of 2%, a CR rate of 3%, a VGPR rate of 20%, and a PR rate 16%. The median duration of response (DOR) in the overall population was 7.6 months (95% CI, 5.4-9.5), although these data were immature, and the median progression-free survival (PFS) was 4.4 months (95% CI, 3.0-5.5).

“We need strategies to salvage patients after BCMA-targeted approaches have failed,” said Richardson, who is a clinical program leader and the director of Clinical Research at the Jerome Lipper Multiple Myeloma Center, as well as a physician at Dana-Farber Cancer Institute, and an RJ Corman professor of Medicine at Harvard Medical School, Boston, Massachusetts. “[Although] there are an abundance of other targets [for future drug development], mezigdomide [could still] have a very crucial role [in the myeloma treatment paradigm] if any of those approaches [do not produce responses in] a patient.”

In an interview with OncLive^®, Richardson, who is also a 2021 Giant of Cancer Care® inductee in multiple myeloma, expanded on the design and methodology of this phase 1/2 study, shared clinical findings and several case studies from the trial showcasing the encouraging activity and safety of mezigdomide in relapsed/refractory patients, and emphasized the need for more oral, outpatient treatment strategies like mezigdomide to account for the heterogeneity of this disease.

OncLive: What was the rationale for investigating the novel CELMoD mezigdomide in patients with relapsed/refractory multiple myeloma?

Richardson: Multiple myeloma is just that; it is multiple subgroups of disease under one umbrella, it's truly not 1 disease. In that spirit, the [idea that] one size does not fit all [with treatment] is clear cut, now more than ever. Fortunately, we've got a plethora of novel agents to meet that challenge. They range from immunomodulatory [IMiD] drugs, proteasome inhibitors, monoclonal antibodies, and other small molecules, to the revolution of immuno-oncology.

We have seen the advent of CAR T-cell therapy and T-cell redirection utilizing bispecifics. It's important to recognize the value of targeting immune suppression in myeloma, and doing so with off-the-shelf strategies, which can overcome some of the logistic challenges [associated] with [the regimens] I've just described. In the [myeloma] construct, we have heterogeneity of disease, multiple patient- and myeloma-related factors that can impact treatment outcomes. Immune dysfunction is fundamental, and there is high mutational burden. Newly diagnosed patients are highly diverse, but as the disease becomes relapsed/refractory, it becomes even more challenging [to manage].

Showing this construct also emphasizes the importance of translating what we see in clinical science to real-world practice. We're now seeing many patients in our practices live 10 to 15 years with their disease. [However, we need to] recognize that these are medians. Under that umbrella of progress, the high-risk group of patients, which constitutes about a third of those patients, we see still have very challenging diseases in terms of longevity of disease control, and overall survival (OS). OS in higher-risk patients can be much shorter. Conversely, standard-risk patients in whom the disease and the pathobiology that may be less aggressive and less challenging, can live many years.

With that as a backdrop, we think of oral therapies in the context of what I just alluded to, which is that we have a very substantial number of patients who are older and [reside] in communities where access to tertiary and quaternary centers may be more limited. Above all, this disease is also predominant in patients of African-American heritage. The ability to offer treatments [and make them] accessible to communities as diverse as our myeloma populations is vital. The translation of this to real-world practice is self-evident.

What is unique about the mechanism of action of mezigdomide?

In that context, we're particularly excited about the results with mezigdomide. What's so exciting about it is that it is a potent degrader. It's able to maximally degrade [Ikaros/Aiolos]. It engages as a larger molecule than the IMiDs, which are in the same broad category of CRL4CRBN E3 ligase engagers, but mezigdomide is more of a CRL4(CRBN) modulator, hence the term CELMoD. Downstream of this engagement into this key pocket in the CRL4(CRBN) E3 ligase complex, [mezigdomide can], in a targeted fashion, optimally degrade Aiolos far more powerfully than [what] we see in preclinical models [with] pomalidomide [Pomalyst] or lenalidomide [Revlimid].

This results in apoptosis inside the myeloma cell itself. The effects are quite dramatic. The antiproliferative activity [of mezigdomide] in lenalidomide- and pomalidomide- resistant cell lines in model systems is striking. It may also be seen in both parental and resistant cell lines. What's interesting is this idea that there must be some level of CRL4(CRBN) present in order for these molecules to work preclinically.

What initial safety and efficacy findings were reported with mezigdomide from the phase 1 dose-escalation portion of this study? How did preclinical data with mezigdomide compare with the agent’s performance in a clinical setting?

The publication of our work with mezigdomide [was published] in the New England Journal of Medicine. This was a phase 1/2 study, in which we evaluated mezigdomide alone and in combination with dexamethasone. Preclinically it was highly synergistic with [dexamethasone] in relapsed/refractory myeloma.

In the first part of the study, we established the recommended phase 2 dose of mezigdomide in combination with dexamethasone. This turned out to be a 1-mg dose [administered] daily for 3 weeks on and 1 week off. Then we moved into a second dose-expansion phase to establish what we did seen in the context of part 1. It's important to note that in the dose-escalation part of the trial, we documented a response rate of approximately 55% to the recommended phase 2 dose. [This was not observed] in a large number of patients, given the inherent nature of phase 1 design, but it is nonetheless compelling. The tolerability profile was exciting because we demonstrated that the primary toxicities were hematologic. Non-hematologic toxicity was much less common and challenging than we sometimes see with other approaches.

Interestingly, infection rates were relatively low and manageable despite the myelosuppression that is a critical aspect of these drugs. Above all, we didn't see the signals of COVID-19 mortality that were being seen at that time in other clinical trials, which suggested a different degree of immune suppression and compromise. This was further validated when we moved into the part 2 cohort.

Please discuss the design, key objectives, and methodology of this phase 1/2 trial.

All patients [in part 2] were steroid refractory. We dosed patients under the age of 75 with 40 mg once weekly. For patients aged 75 or older dosing of dexamethasone was less than 20 mg by protocol. This is a standard approach to minimize toxicities associated with steroid use. Patients had to have had at least 3 prior lines of treatment to qualify. Refractoriness to [IMiD]s, proteasome inhibition and anti-CD38 antibody therapy was mandatory. Patients had to be truly refractory, not only relapsing on treatment, or at least [had to be refractory] within 60 days. This was a strict requirement for entry into part 2 of the study. Finally, we allowed patients [who had progressed on and/or were refractory to prior] anti-BCMA therapies. The primary end point in the second part of the study was overall response rate [ORR], with traditional secondary end points including the DOR and PFS. [For] exploratory [end points], we looked at pharmacodynamics.

Could you expand on the patient population that was included in the study? Were there any notable baseline characteristics?

There were 101 patients in the second part of the study. The median number of prior lines of therapy was 6, and in that context, the vast majority had [prior] stem cell transplant All of them had been exposed to pomalidomide or lenalidomide, proteasome inhibition and monoclonal antibodies, and about one-third had received anti-BCMA therapy. This predominantly included antibody-drug conjugates, but also bispecific T-cell engagers and CAR T-cell therapy. Patients were classically refractory. This would not constitute a population of exquisite unmet medical need. Also, many patients in this group had extramedullary disease.

What key efficacy findings were reported in the phase 2 portion of the trial?

The takeaway from the study [is that] the ORR [produced by mezigdomide and dexamethasone], as confirmed by an independent committee, was 40.6%. [This] included CRs, VGPRs, and stringent CRs. In the extramedullary disease population, which we define as patients with plasmacytoma and systemic relapsed/refractory disease, we saw a response rate of 30%. [This is] a very poor prognostic subgroup. We were [also] impressed with the ORR in the BCMA-exposed patients. [These patients were] triple-class refractory and had other poor prognostic features, such as high-risk cytogenetics and extramedullary disease. The response rate [in this subgroup] was 50%, [which] caught our attention. We [do] have to be careful [interpreting this result] because the number of patients [in this group was] 30.

The time to first response was rapid, and the DOR in responding patients was encouraging. If, for example, you had a VGPR, DOR was a median of about 9 months. The median PFS for the group was more modest at approximately 4.5 months, but that's typical for monotherapies in this setting, especially ones that are oral and truly outpatient. Nonetheless, to see this drug performing the way that it did in this highly refractory resistant population is compelling.

Importantly, our oldest patient in the study was over 85 years old. While we're excited by the promise of CAR T-cell therapy and bispecifics, we have to recognize that they require hospitalization [and can be] potentially challenging for the octogenarian or frail patients that we see in our practice.

According to this analysis, what should be known about the pharmacokinetic profile of mezigdomide?

In the study, we looked at pharmacodynamics very comprehensively. I especially want to acknowledge my co-investigators and our former partner, BMS Celgene, because they [engaged in] a comprehensive effort to try and nail down the pharmacodynamics. In addition to the pharmacokinetics as part of the original dose escalation phase, I want to share this representative slice. It's a patient of mine who had previously come onto the study having had a great response initially, but then became refractory to the combination of isatuximab [Sarclisa], pomalidomide, and dexamethasone. In the screening of bone marrow, the immunohistochemistry was enriched for Aiolos, so clearly this pathway was breaking through. Just after a week of therapy with mezigdomide and dexamethasone, we saw [a change in Aiolos status].

If you looked across the study, we saw impressive changes in tumor Aiolos associated with their treatment. Above all, we saw peripheral blood immunophenotyping even in patients who, upon [becoming] refractory, were modulating in a favorable way. This supported the notion that mezigdomide can work when pomalidomide has failed. That sets this apart clinically from the immunomodulatory class broadly. As we move into this category of the CELMoDs, including the less-potent but still active [agent] iberdomide (CC 220), we can see real distinctions. When you've got pharmacodynamic data like these, it's very promising.

Could you share any other real-world examples of clinical activity with mezigdomide in this study?

From the original dose-escalation part in phase 1, [we have] an example of the activity of this drug in extramedullary disease. This is from my co-senior investigator, Nizar Bahlis, MD, of the University of Calgary and the Charbonneau Cancer Research Institute, who was the co-author of the paper. Prior to initiation of mezigdomide, this patient not only had aggressive triple-class refractory disease, but also had substantial extramedullary involvement in the liver. After treatment had been onboarded for a few months, there was almost complete resolution, and this patient had an outstanding response to treatment. Looking at the 1-mg dose group, we saw some consistent and exciting results in [those with] extramedullary disease.

Next, I want to [talk about] a patient of mine who was part of the phase 2 expansion group. The PET/CT scan illustrates the tumor burden that this gentleman had at the start. He was in real trouble. He had [received] multiple prior therapies, including BCMA-targeted treatment, he had extramedullary disease everywhere, and most importantly he had extramedullary disease growing across his portacath, so we couldn't access his port when we started therapy. Remarkably, after 4 months [of mezigdomide therapy], he had complete resolution on PET/CT. My nursing team was telling me how remarkable it was that they could safely access his portacath. He was delighted. This is an example of the power of this platform. I would also share that this patient could tolerate this drug remarkably well. Myelosuppression and infections matter, and we must be on top of all those things. [However], broadly speaking, we found the combination strategy with dexamethasone [to have] manageable tolerability, and [that] toxicities encountered were truly reversible with growth factor support, dose adjustment, etc.

Are any next steps planned for the investigation of mezigdomide?

One of the future directions is [looking at mezigdomide] combination strategies preclinically. We have synergy with proteasome inhibitors and antibodies, and this has gone forward very nicely. In the New England Journal of Medicine editorial, there was a comment [asking if we] would run into trouble with irreversible myelosuppression or anything of that nature. We're not seeing that. The dose going forward in combination has typically been about 0.6 mg daily at a 3-weeks-on/1-week-off schedule. [When administering mezigdomide] in combination with bortezomib [Velcade], we have response rates in relapsed/refractory disease, approaching 80%, which is quite remarkable. [Response rates are similar with] daratumumab [Darzalex] and, interestingly, with carfilzomib [Kyprolis]. We're seeing this potent platform for combination strategies in earlier disease going forward. Phase 3 studies interrogating this are now underway, and we're very pleased to be part of those together with colleagues across North America and Europe. Obviously, these are specialist centers, but we're hoping to increase access to what we believe is an important platform.

If mezigdomide continues to show efficacy in relapsed/refractory myeloma, how might this agent affect the treatment paradigm for patients who have exhausted all other BCMA-targeted therapies?

BCMA[-directed therapy] is another exciting new frontier. As was mentioned in the editorial, combining [mezigdomide] with the new BCMA platforms and cellular therapies makes great sense. Trials are planned [to investigate the viability of] combining this powerful platform with T-cell redirecting therapy, and as a post-CAR T-cell strategy. Interestingly, we saw activity with the combination of mezigdomide and elotuzumab [Empliciti], recognizing this interaction with natural killer cells. If CAR T-cell therapy fails, natural killer cells are an access point that one could legitimately exploit.

[Accordingly], my colleague Omar Nadim, MD, of Dana-Farber Cancer Institute is conducting a trial of iberdomide with elotuzumab but may be incorporating mezigdomide into that platform based on these data. [That is being done] to see how we can rationally exploit the science we're demonstrating in patients in the lab and bring safe combinations [to those in the clinic].After CAR T-cell therapy, patients are more vulnerable [to developing] cytopenia and infections.

I’d like to share an observation from one of my patients. She had inpatient stays for a variety of immunotherapies and [her] family is exhausted. Unfortunately, her bispecific ran out of steam. She said, "I don't mind what we do now, but I would like to do something outpatient where I do not have to come into the hospital." We shouldn't underestimate the power of [outpatient treatment]. This is particularly important for patients in rural or suburban communities, where it may not be easy to access tertiary/quaternary centers where immunotherapy exists or is best leveraged. Again, [mezigdomide is] not [producing] a response rate of 70%, but we are [seeing] response rates of 41% or 50%, depending on where you're landing, and that is not bad for an oral platform. There's a bright future for mezigdomide. We'll have to wait and see what the phase 3 studies show, but we've got big phase 2 [data] here that provide a body of evidence to support moving this drug forward as quickly as possible for our patients with the most unmet medical need.

What is your main takeaway message for colleagues just regarding this research?

The important message for providers and caregivers in myeloma is that we all know that we're now up to 18 potential therapeutic options in myeloma. I want to thank the regulatory authorities for making all of this possible, as well as [those pushing these] enormous investigative efforts, and above all, the participation of our patients and families.

The thing that I'm worried about is [people saying], "We've got enough [options now], surely you can cure this cancer now, can't you?" Multiple myeloma is just that, and it's not a one-size-fits-all approach. We're not curing people on any substantial scale. We're achieving disease control that lasts for much longer than it ever did in an increasing proportion of patients. My clinic specializes in relapsed/refractory disease, and we have patient subgroups who are elderly or frail, [or] in whom there is immune exhaustion. All these caveats need to be kept in mind as we [navigate] therapeutic options. We're blessed to [now] see patients now living 10, 15, even 20 and 30 years, but we must be aware that there is a substantial number [of patients] who don't even get close to that. At the same time, there are patients in whom certain treatment modalities, exciting and wonderful as they have been, are not feasible and/or safe.

With that in mind, I'm particularly excited about CELMoDs and mezigdomide. [This excitement extends to] other oral agents and strategies [directed at] different targets, different modalities that are truly outpatient. They don't require hospitalization, they can be infused in the clinic, they can be things that don't require multiple visits, etc. We need to be aware of the value of these as we go forward.

Reference

Richardson PG, Trudel S, Popat R, et al. Mezigdomide plus dexamethasone in relapsed and refractory multiple myeloma. N Engl J Med. 2023;389(11):1009-1022. doi:10.1056/NEJMoa2303194

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