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A novel protein-degrading agent exhibited promising activity in patients with relapsed/refractory multiple myeloma, results of a preliminary clinical trial showed.

Among 101 patients who received the recommended phase II dose of oral mezigdomide in combination with dexamethasone, the objective response rate was 41%. All of the patients had triple class-refractory disease, and 30% had prior exposure to therapy targeting B-cell maturation antigen (BCMA).

Neutropenia and infection occurred in most patients treated with mezigdomide, but the side effects were mild or moderate in most cases, reported Paul G. Richardson, MD, of Dana-Farber Cancer Institute in Boston, and co-authors in the .

"This study aimed to determine the therapeutic window and achieve rapid, prolonged, and maximal substrate degradation for rapid disease response while mitigating hematologic toxic effects," the authors wrote in conclusion. "Mezigdomide plus dexamethasone showed promising preliminary efficacy in this heavily pretreated population, with myelosuppression and infection as the main toxic effects."

The evolution of mezigdomide represents "the latest chapter of a story that started with clinical infamy more than 60 years ago," wrote Jake Shortt, MBChB, PhD, of Monash University in Clayton, Australia, in an . Mezigdomide targets cereblon, the long-sought binding partner for thalidomide, which failed notoriously as a sedative for use during pregnancy but found a home as the first highly active treatment for myeloma. As discovered in 2010, cereblon plays a crucial role in protein degradation but also was the culprit in thalidomide-associated teratogenicity.

The response rate for an all-oral regimen was encouraging, but the relatively brief median progression-free survival (PFS) of 4.4 months showed that more work is required, he added.

"Although mezigdomide is active in cells with low levels of cereblon, it cannot work in the complete absence of cereblon or overcome cereblon-independent resistance mechanisms," Shortt continued. "Further studies will determine the safety and efficacy of mezigdomide concomitant with other antimyeloma therapies."

"Concurrently, the myeloma field is being revolutionized by immunotherapies, such as bispecific antibodies and chimeric antigen receptor T cells," he noted. "Because mezigdomide bears the same immunostimulatory hallmarks as its IMiD [immunomodulatory drug] forebears, it may also partner well with these immune effector cell-based approaches."

Despite the plethora of effective new therapies for myeloma, almost all patients eventually relapse, develop refractory disease, or both, Richardson and co-authors noted in their introduction. Each remission becomes briefer than the one before. A need persists for alternative medications with favorable safety and ease of administration.

Mezigdomide is one of two cereblon E3 ligase modulators under development, the other being iberdomide (CC-220). Mezigdomide was designed to target Ikaros and Aiolos, key transcription factors in hematopoietic cell development and differentiation, the authors continued. In vitro studies showed the mezigdomide-induced degradation of the two factors enhanced cytotoxic effects in myeloma cells, including cells resistant to IMiDs lenalidomide (Revlimid) and pomalidomide (Pomalyst) and with cereblon down-regulation.

Following encouraging results with mezigdomide in ex vivo models, investigators conducted a phase I/II multicenter, dose-escalation, dose-expansion clinical study. Phase I included 77 patients and 13 dose levels of mezigdomide, administered with dexamethasone. A fourth of the patients had objective responses, including one complete response.

Eligibility for phase II included disease refractory to an IMiD, a glucocorticoid, a proteasome inhibitor, and an anti-CD38 antibody. A response rate of ≤12% would be considered a negative outcome.

The 101 patients included in data analysis had received a median of six prior lines of therapy, and three-fourths of the patients had undergone stem-cell transplantation. The most common adverse events (AEs, all grades) were neutropenia (77%), infection (65%), anemia (52%), and thrombocytopenia (43%). Febrile neutropenia occurred in 15% of patients. The most common grade 3/4 AEs were neutropenia (22% grade 3 and 54% grade 4), infection (29% and 6%), and anemia (35% and 1%). Grade 3 febrile neutropenia occurred in 13% of patients and grade 4 in 2%.

AEs led to mezigdomide dose reduction in 29% of patients and treatment discontinuation in 6%. Three-fourths of the patients received growth factor support. The 41 objective responses had a median duration of 7.6 months. The overall response rate was 30% for patients with plasmacytomas and 50% for patients with prior exposure to anti-BCMA therapy. A third of patients with high-risk cytogenetics responded to mezigdomide.

"This study represents the culmination of discoveries made over the past decade related to the mechanism of action of immunomodulatory agents in multiple myeloma," the authors wrote in their discussion of the findings. "Lenalidomide and pomalidomide were developed empirically on the basis of clinical observations."

"The understanding that they act as molecular glues to co-opt cereblon to target Ikaros and Aiolos for ubiquitination and proteasomal degradation came after their approval," they continued. "This finding also led to novel insights into mechanisms of resistance, including cereblon dysregulation. Mezigdomide was designed on the basis of these insights to achieve deep and sustained Ikaros and Aiolos degradation and overcome cereblon down-regulation and mutations observed in some patients."

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