Cemsidomide (CFT7455), an oral cereblon-based degrader of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), has the potential to offer patients with heavily pretreated relapsed/refractory multiple myeloma a potent, all-oral treatment option, according to Sagar Lonial, MD, FACP, FASCO, and Sikander Ailawadhi, MD.
“Cemsidomide is a cereblon-based [IKZF1/3] degrader that has significant potency compared [with] other drugs that are out there, not just in terms of its ability to bind cereblon, but also the speed with which it degrades Ikaros and Aiolos, which ultimately results in 2 sets of effects on myeloma cells,” Lonial said in an exclusive interview with OncLive®. “Downregulation results in plasma cell death, and in immune cells, it does result in substantial activation of T cells [and] natural killer cells, and reverses T-cell exhaustion.”
Building on positive data from a first-in-human phase 1 CFT7455-1101 trial (NCT04756726), the ongoing phase 2 MOMENTUM trial (NCT07284758) is further evaluating the cemsidomide in combination with dexamethasone in patients with relapsed/refractory mutliple myeloma who have received at least 3 prior lines of therapy.1-3
Lonial and Ailawadhi provided insights on the development and mechanism of action of cemsidomide; expanded on the phase 1 data; and detailed what the MOMENTUM trial may mean for cemsidomide plus dexamathasone in multiple myeloma management.
Lonial is the chair and professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, as well as the chief medical officer of Winship Cancer Institute of Emory University in Atlanta, Georgia. Ailawadhi is a hematologist and medical oncologist and professor of medicine at Mayo Clinic in Jacksonville, Florida.
Why are cereblon-targeting degraders drawing interest in relapsed/refractory myeloma?
Immunomodulatory drugs (IMiDs) have anchored multiple myeloma treatment for decades, but only recently has the field pinned their activity to cereblon binding, which opened the door to a more potent generation of agents, according to Ailawadhi.
“Newer drugs have now been developed called CELMoDs that specifically bind to this cereblon protein more strongly than [IMiDs]. They alter the substrate specificity for the cereblon protein, and that leads to degradation of Ikaros and Aiolos proteins through a protein degradation pathway in the cells, leading to increased cell death,” Ailawadhi said. “[Cemsidomide has] been designed [to be] more specific, much more targeted, leading to more potency and more benefit.”
Ailawadhi emphasized that expanding the mechanistic repertoire is a practical necessity for a disease like multiple myeloma that relapses in most patients and requires a continual supply of new therapeutic options. The oral availability of the agent also adds to its intrigue.
“Having options that [are oral] is extremely helpful and beneficial,” Ailawadhi said, highlighting particular benefit for patients facing indefinite, ongoing therapy.
What did the phase 1 study of cemsidomide plus dexamethasone show?
Updated results from the CFT7455-1101 study of cemsidomide plus dexamethasone, which were presented by Lonial at the 2026 EHA Congress, showed that at a data cutoff of February 27, 2026, patients treated at the recommended phase 2 dose (RP2D) of 100 µg of cemsidomide once per day plus dexamethasone (n = 19) achieved an overall response rate (ORR) of 53% and a clinical benefit rate (CBR) of 63%.1 The ORR was 36% across all dose levels (n = 72), including 40% at the daily 75-µg dose (n = 20) and 27% at the daily 62.5-µg dose level (n = 15).
Cemsidomide Shows Promise in Heavily Pretreated R/R Myeloma
- Cemsidomide is a potent, oral, cereblon-based degrader of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) that drives plasma cell death while activating T cells and natural killer cells and reversing T-cell exhaustion.
- In the phase 1 CFT7455-1101 trial, cemsidomide plus dexamethasone produced a 53% ORR and a 63% CBR at the 100-µg RP2D in a population of patients with relapsed/refractory multiple myeloma who received a median of 7 prior lines of therapy.
- The ongoing phase 2 MOMENTUM trial is a single-arm, open-label study evaluating cemsidomide at the 100-µg dose on a 14-days-on/14-days-off schedule plus weekly dexamethasone in patients with relapsed/refractory disease after at least 3 prior lines of therapy.
At the RP2D, best responses comprised stringent complete response (sCR) at 5%, CR at 11%, very good partial response (VGPR) at 11%, PR at 26%, minor response at 11%, stable disease at 21%, and progressive disease at 16%.
The median progression-free survival (PFS) across all dose levels was 3.9 months (95% CI, 3.2-5.6), and the median duration of response (DOR) was 7.9 months (95% CI, 3.0-not evaluable). Two patients at the 100-µg dose achieved minimal residual disease (MRD)-negativity; these patients had respective best responses of sCR and CR. Responses were consistent across subgroups, including a 52.9% (95% CI, 27.8-77) ORR at the RP2D among patients with prior CAR T-cell therapy or a TCE.1
“When you begin to look at that dose and schedule for [cemsidomide], what you begin to see is ORRs of [around] 50% in a [population who received] a median of 7 prior lines of therapy,” Lonial said. “[This is] a very heavily pretreated, refractory patient population with extramedullary disease, yet we were seeing substantial responses in that patient group.”
Regarding safety, Lonial explained that neutropenia was a key adverse effect (AE) reported in phase 1 study, occurring at any grade in 62% of the safety population (n = 73); the grade 3 and grade 4 rates were 22% and 36%, respectively, with no grade 5 neutropenia reported. Neutropenia was managed via dose reductions and granulocyte-colony stimulating factor (G-CSF) when permitted; 45% of the safety population received G-CSF.
Notably, treatment-emergent AEs led to treatment discontinuation and dose reduction at respective rates of 4% and 7% across the safety population. These discontinuations or reductions all occurred in the cohorts evaluating cemsidomide at doses of 75 µg or 100 µg.
Ailawadhi noted that the addition of dexamethasone builds on a distinct pharmacokinetic signature seen with single-agent cemsidomide, in which paraprotein and serum free light chain levels tracked with drug exposure.
“With the addition of dexamethasone, which we know is an extremely effective anti-myeloma agent, it has been able to augment some of that benefit that [cemsidomide] was able to achieve on its own,” he said.
What is the importance of the ongoing MOMENTUM trial for the evaluation of cemsidomide in multiple myeloma?
The ongoing phase 2 MOMENTUM trial is a single-arm, open-label, multicenter study evaluating cemsidomide at the 100-µg RP2D on a 14-days-on/14-days-off schedule plus weekly dexamethasone, with a planned enrollment of approximately 100 patients across roughly 60 sites in the United States and Europe.2,3 The first patient was dosed in February 2026.2
“The MOMENTUM trial is trying to [use] the best dose from that early phase 1 study [and] do an expansion cohort to truly understand the efficacy of this combination with [dexamethasone] in a 14-day-on, 14-day-off schedule before we plan further phase 3 trials,” Lonial said.
Investigators are enrolling patients at least 18 years of age with documented multiple myeloma and measurable disease. At least 3 prior anti–multiple myeloma regimens are required, and they must include at least 2 consecutive cycles of an IMiD, a proteasome inhibitor, an anti-CD38 monoclonal antibody, and a T-cell engager/CAR T-cell therapy (unless not indicated or refused by the patient). Refractory disease or documented disease progression within 60 days of their last dose of prior therapy is also required.
“This is now a very contemporary, real-world problem that this trial is trying to solve,” Ailawadhi said regarding the previous treatment requirements. “All the important classes of drugs, the patients have been exposed to and are refractory to.”
Patients with myeloma detected in the central nervous system, those with nonsecretory or oligosecretory multiple myeloma, and patients who received the CELMoDs iberdomide (Zenbexus) or mezigdomide in their most recent line of therapy are being excluded.
The primary end point is ORR per International Myeloma Working Group criteria as assessed by an independent review committee; secondary end points include DOR, CR rate with MRD status, time to response, PFS, overall survival, safety, and pharmacokinetics.
“The independent role of cemsidomide vs CELMoDs vs IMiDs is an evolving question. What I think I'm most excited about cemsidomide is that it’s very potent. It had a high ORR in refractory myeloma [in the phase 1 study],” Lonial said. “It also has a pretty potent immune-stimulating piece, which I think makes it a great partner for T-cell engagers, CAR T cells, and other therapeutic approaches that require enhanced immune function or reversal of T-cell exhaustion as a potential mechanism.”
References
- Lonial S, Yee AJ, Richardson PG, et al. Updated results of a phase 1 first-in-human study of cemsidomide, a novel MonoDAC degrader, with dexamethasone (DEX) in patients with relapsed/refractory multiple myeloma (RRMM). Presented at: 2026 European Hematology Association Congress; June 11-14, 2026; Milan, Italy.
- Dhakal B, Ramasamy K, Ali A, et al. MOMENTUM: a phase 2, open-label, single-arm, multicenter study to evaluate the efficacy of cemsidomide + dexamethasone in subjects with relapsed/refractory multiple myeloma. Presented at: 2026 ASCO Annual Meeting; May 29-June 2, 2026; Chicago, IL.
- A study of cemsidomide in combination with dexamethasone in participants with relapsed/refractory multiple myeloma (mOMENTUM). ClinicalTrials.gov. Updated 2026. Accessed August 24, 2026. https://clinicaltrials.gov/study/NCT07284758
