CELMoD Drug Cuts Risk of Myeloma Progression, Death by 52% in Trial

CHICAGO — Adding a novel cereblon E3 ligase modulation (CELMoD) drug to a standard multiple myeloma regimen significantly improved progression-free survival (PFS) in a vulnerable population of patients with relapsed or refractory disease, a phase III trial showed.

In participants largely refractory to lenalidomide (Revlimid) and an anti-CD38 antibody, median PFS reached 18 months with the triplet of mezigdomide plus carfilzomib (Kyprolis) and dexamethasone, as compared with 8.3 months with the latter two drugs alone (HR 0.48, 95% CI 0.36-0.63, P<0.0001), reported Paul Richardson, MD, of the Dana-Farber Cancer Institute in Boston.

“Oral mezigdomide combined with weekly IV carfilzomib is a potential new standard of care in relapsed/refractory disease and, most importantly, can be easily used across diverse care settings, including community practice,” he said during a late-breaking presentation of the SUCCESSOR-2 trial at the American Society of Clinical Oncology (ASCO) annual meeting.

The triplet regimen substantially improved response rates, induced deeper responses, was also associated with superior second PFS, and the safety profile was manageable with dose modification and growth factors, according to Richardson.

‘Something Very Scintillating’

His presentation came as the penultimate one during a late afternoon Friday ASCO session, but Richardson guaranteed to the attendees it would be worth the wait.

“I realize we’re close to beer time here — promise to at least give you something very scintillating,” he said, pointing out that SUCCESSOR-2 is the first phase III readout involving a CELMoD drug.

The oral agent binds cereblon uniquely and more effectively than lenalidomide or pomalidomide (Pomalyst) and has been shown preclinically to enhance myeloma cell killing and to be a more potent immune stimulator compared with those immunomodulatory drugs (IMiDs), Richardson explained. It can also override resistance to IMiDs and other classes of drugs.

Mezigdomide’s efficacy in myeloma has been confirmed in a number of settings, including in triple-class refractory patients. The drug previously showed a 50% response rate in patients already exposed to B-cell maturation antigen (BCMA)-directed CAR-T products or bispecific agents.

Another oral CELMoD drug, iberdomide, in development for relapsed or refractory multiple myeloma is currently under review at the FDA, with a decision expected in August. That drug is less potent but aims to be paired with earlier in the disease course alongside IMiDs.

Patients more and more in the upfront setting are being exposed to quadruplet regimens, so when they relapse they’re anti-CD38 and lenalidomide exposed or refractory, said Richardson, which limits options. Carfilzomib-dexamethasone is a commonly used regimen in this setting.

ASCO discussant Ajai Chari, MD, of the University of California San Francisco, noted the improvement in second PFS in the triplet arm of SUCCESSOR-2 (23.6 vs 13 months; HR 0.53, 95% CI 0.39-0.72), “despite the fact that the control arm had more access to novel therapies, particularly almost 30% had a CAR or bispecific.”

In terms of sequencing, he said that as an off-the-shelf therapy, mezigdomide could be an effective option during the manufacturing period of CAR T cells.

SUCCESSOR-2 Details

Patients in the phase III SUCCESSOR-2 study had to have at least one prior line of therapy involving both lenalidomide and an anti-CD38 drug such as daratumumab (Darzalex) or isatuximab (Sarclisa). Following a dose-finding stage, the trial assigned 288 participants to mezigdomide (1 mg orally once daily on days 1-21 of 28-day cycles) plus carfilzomib and dexamethasone and 191 to carfilzomib and dexamethasone alone.

Patient characteristics were generally well balanced, said Richardson. Participants had a median age of about 68 years, a majority were men and white, with around 30% Asian. About one-fourth had extramedullary disease and roughly one-third had classical high-risk cytogenetics. Median prior lines of therapy was two (as many as nine), over 90% were triple-class exposed, almost 70% were refractory to both an anti-CD38 drug and lenalidomide, and fewer than 10% had received an anti-BCMA therapy or T cell-redirected therapy.

PFS was the primary endpoint, and Richardson noted that the benefit with mezigdomide was observed across all prespecified subgroups, including age, prior therapy, refractory status, cytogenetic risk, and presence of extramedullary disease.

In terms of secondary efficacy endpoints, the addition of the CELMoD drug improved rates of overall response (80.2% vs 53.4% in the control group) and complete response or better (26.7% vs 8.9%), with 12-month response rates of 72% versus 54%.

Overall survival data were immature but trending in the right direction. At data cutoff, deaths had occurred in 21.5% of the study arm versus 26.7% of the control arm (HR 0.79, 95% CI 0.54-1.15).

Grade 3/4 adverse events (AEs) occurred in 83.7% of the mezigdomide arm and 56.5% of those in the control group, with a particularly higher rate of neutropenia in the mezigdomide arm (61.1% vs 9.1%). Richardson pointed out that neutropenia is an expected on-target AE with mezigdomide but reversible and manageable with dose interruptions/modifications or granulocyte colony-stimulating factor. One patient discontinued the drug due to neutropenia.

Some of the other grade 3/4 AEs occurring more frequently with the CELMoD drug included thrombocytopenia (39.2% vs 22.6%), anemia (26% vs 15.1%), decreases in white blood cell counts (18.8% vs 3.8%), pneumonia (15.6% vs 5.9%), and venous thromboembolism (2.8% vs 0.5%), while grade 3/4 hypertension was less frequent (3.8% vs 9.1% in the control arm), potentially due to a lower carfilzomib dose used in the triplet arm.

Grade 3 and 4 infections were reported in 28.5% and 5.6% of the mezigdomide arm, respectively, and in 15.1% and 0.5% of the control arm.

Grade 5 AEs occurred in 7.3% of the mezigdomide group and 4.3% of the control group and were mostly in the context of disease progression, said Richardson. Fatal infections occurred in 2.4% and 1.1%, respectively.

AEs are not adjusted for time on therapy, noted Chari, “so we’re going to see more AEs with the triplet, but fortunately not major differences in discontinuation.”

Dose reductions for mezigdomide occurred in 42.4% but the relative dose intensity was high, at 83%. Overall, 9.7% in the mezigdomide arm stopped all treatment for AEs versus 5.8% in the control arm.