The all-oral combination of mezigdomide – a cereblon E3 ubiquitin ligase modulator – and dexamethasone showed early efficacy in patients with heavily pretreated relapsed or refractory (R/R) multiple myeloma (MM), according to results of a phase I/II trial recently published in New England Journal of Medicine.
Mezigdomide is in a class of small molecule protein degraders known as CELMods that co-opt cereblon to degrade Ikaros and Aiolos rapidly and deeply, according to study researcher and principal investigator Paul G. Richardson, MD, director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute in Boston.
“It is important to recognize that mezigdomide is quite distinct from the immunomodulatory drugs (so-called IMiDs),” Dr. Richardson said. “The differences are several and include that mezigdomide much more potently degrades Ikaros and Aiolos, which are key transcription factors governing the activity of this pathway and its effect on plasma cell survival.”
Dr. Richardson said mezigdomide was designed at a molecular level to not only 100% engage the cereblon pocket – compared with IMiDs that engage less than 50% – but promote maximal substrate-binding capacity as a result.
“Moreover, it not only kills myeloma cells directly but has direct effects through this pathway on T-cell and natural killer cell activation,” Dr. Richardson said. “In a sense, it is therefore a form of T-cell activating therapy but given more simply as a pill.”
In the phase I portion of this study, 77 patients with R/R MM were enrolled. Examining a variety of dosing strengths and schedules, the researchers identified an optimal dosing strategy of 1.0 mg given orally once daily plus weekly dexamethasone for 21 days during each 28-day cycle.
Among the 11 patients in this cohort who received the recommended phase II dose (RP2D), the overall response rate (ORR) was 55% with a median duration of response (DOR) of 9.2 months.
With the RP2D established, 101 additional patients were enrolled in a dose-expansion cohort. Patients had triple-class-refractory MM; 30% of patients had also received prior BCMA-targeting treatment – including antibody-drug conjugates (22%) – and 40% had plasmacytomas.
The ORR was 41% confirmed by independent review, with a median DOR of 7.6 months and an overall median progression-free survival (PFS) of 4.4 months. Among those patients who had received previous anti-BCMA therapy, the ORR was 50% with a median DOR of 6.9 months and a median PFS of 5.4 months. Of the 15 patients with previous anti-BCMA therapy, 12 had received antibody-drug conjugates, two had received T-cell engagers, and one had received chimeric antigen receptor (CAR) T-cell therapy. The ORR for patients with plasmacytomas was 30%.
“This provides an easy-to-administer, off-the-shelf, outpatient and community-directed approach,” Dr. Richardson said, adding that this all-oral approach was especially important during the COVID-19 pandemic. “This type of treatment strategy is very important, especially given that bispecific antibodies and CAR T-cell therapy both require our patients to be hospitalized, at least initially, and it’s worth adding that this outpatient feature is especially relevant among our older patients.”
The most common adverse events (AEs) were neutropenia (77%) and infection (65%). AEs proved generally manageable, Dr. Richardson said. He also pointed out that 65% of patients experienced grade 1 or 2 infection, typically treated with oral therapy, but only 29% were grade 3 (requiring intravenous therapy), and 6% were grade 4.
“Recognizing that infection in advanced myeloma is very common and can be severe, these rates were significantly lower than we see with bispecific antibodies and CAR T-cell therapy, for example, which can be greater and especially in the context of grade 3 or higher events,” Dr. Richardson said.
Dr. Richardson also emphasized that this all-oral combination strategy was designed with the option of having other “backbone” drugs, such as proteasome inhibitors and CD38 monoclonal antibodies, added to it. In addition, strategies combining mezigdomide with BCMA-targeting treatment strategies are now in development.
“This has all proven encouraging, and we will be presenting updated results at this year’s American Society of Hematology annual meeting on the former,” Dr. Richardson said. “Previously our studies have shown durable response rates of between 70-80% when mezigdomide is combined with either a proteosome inhibitor or CD38 monoclonal antibody, as well as favorable tolerability in R/R MM, which is certainly comparable to other highly effective immunotherapeutic approaches in this setting.”
The researchers did not report any limitations to their study.
This study was funded by BMS/Celgene. Any conflicts of interest declared by the authors can be found in the original article.
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.