Preliminary Efficacy, Safety Data Drive Further Exploration of Mezigdomide-Based Combinations in R/R Myeloma

Preliminary findings from the phase 1/2 CA057-003 trial (NCT05372354), which showed signals of clinical activity and safety with 3 novel, all-oral, mezigdomide (CC-92480)–based triplet regimens, provide a robust rationale for further exploration of mezigdomide in combination with tazemetostat (Tazverik) and other novel agents for heavily pretreated patients with relapsed/refractory multiple myeloma, according to David S. Siegel, MD, PhD.

In a presentation at the 2024 ASH Annual Meeting & Exposition, results from CA057-003 showed that mezigdomide in combination with either the EZH2 inhibitor tazemetostat (n = 16), the BET inhibitor BMS-986158 (n = 20), or the MEK inhibitor trametinib (Mekinist; n = 20) elicited overall response rates of 50%, 35% or 75%, respectively. Notably, trends towards deeper responses, evidenced by the rates of very good partial response or better, were observed with the 1.0 mg dose of mezigdomide in the tazemetostat and BMS-986158 cohorts. In the trametinib cohort, deeper responses were reported at mezigdomide doses of 0.6 mg or higher; 11 patients at the 1.0 mg dose level (n = 13) continued treatment. No new safety signals were identified across all cohorts.

“This particular trial utilized some partner drug candidates that aren’t typically used in myeloma,” said Siegel, chief of the Division of Multiple Myeloma at John Theurer Cancer Center, Hackensack University Medical Center, New Jersey. “[Based on the data], we were very encouraged to move forward, not just with the combinations that were tested in this particular trial, but with mezigdomide as a staple drug in future myeloma management.”

In an interview with OncLive®, Siegel discussed how mezigdomide builds on the therapeutic properties of earlier thalidomide derivatives; shared early findings from the CA057-003 trial supporting the continued evaluation of mezigdomide-based triplets; and outlined the potential role for mezigdomide in the multiple myeloma treatment arsenal.

OncLive: How does mezigdomide differ from earlier thalidomide (Thalomid) derivatives, and what is the rationale for investigating its use in combination therapies for multiple myeloma?

Siegel: Mezigdomide, which is the centerpiece of this trial, is a newer derivative of thalidomide. Thalidomide derivatives are probably the most important drugs that have been developed in myeloma over the past couple of decades. Mezigdomide is a molecule that seems to maximize the qualities of thalidomide and the other thalidomide derivatives, both in terms of having direct tumoricidal effects, but also in terms of modulating immune responses [to] tumors in general. Early work with mezigdomide identified several pathways that seemed to be particularly amenable to intervention. This trial is an effort to maximize interactions with mezigdomide by targeting some of these other pathways.

What initial efficacy and safety results from CA057-003 were reported at the 2024 ASH Annual Meeting?

This was a relatively straightforward phase 1/2 trial [consisting of a] heavily pretreated patient population. One of the stipulations of the trial is that there were no available conventional alternatives for these patients, so this was a group of patients who had very little in the way of therapeutic opportunities.

The results have been encouraging thus far. The [data with] some combinations are a little bit more mature than others, and the [more mature] data is what we presented. [The results] show that these combinations are both well tolerated. That is not to say that there are no toxicities—these thalidomide derivatives, mezigdomide in particular, can cause hematologic toxicities—but there were no surprising [safety] signals in terms of [having to limit] these combinations due to unforeseen toxicities.

In this patient population, [for whom we] would not expect [to see] durable responses, we are seeing them [with these mezigdomide combinations]. [Furthermore,] we’re seeing [benefit] without costing the patients in terms of unacceptable hematologic or subjective toxicities. [None of these toxicities were] intolerable to an extent that that we felt we could not move forward with those combinations.

What role do you envision for mezigdomide in the current multiple myeloma treatment paradigm? How might this evolve in tandem with novel approaches?

Mezigdomide is going to be a staple drug much the way its predecessors were. Those predecessors were lenalidomide [Revlimid] and pomalidomide [Pomalyst], which have been ubiquitously used in myeloma. We’re getting to the point where we can now maximize this synergy between those thalidomide derivatives and other drugs that we use.

[Mezigdomide may be effective] in combination with CAR T-cell therapy, T-cell engagers, or other agents that have yet to be identified. Of all the drugs that we talk about right now in the myeloma space, the only one that’s going to [remain relevant] 10 years from now is going to be mezigdomide. We will have replacements [for current] T-cell engagers, CAR T-cell therapies, proteasome inhibitors and whatnot, but mezigdomide is going to [remain a] central drug in the management of myeloma in the future.

As much as we have improved outcomes for patients with myeloma, there’s still a need for further improvement. We have every reason to [believe] that we’re continuing on that path, not just with mezigdomide, but with novel CAR T-cell therapies, new T-cell engagers, and all kinds of developments that [will allow] our patients to get better care, [achieve] better outcomes, and have better quality of life.

Reference

Costa LJ, Schjesvold F, Popat R, et al. Mezigdomide (MEZI) in novel-novel combinations for relapsed or refractory multiple myeloma (RRMM): preliminary results from the CA057-003 trial. Blood. 2024;144(suppl 1):677. doi:10.1182/blood-2024-198403