ASCO: BMS hails "compelling" phase 3 celmod readout

Bristol Myers Squibb has high hopes for its celmod programme for blood cancers, and a phase 3 readout – for mezigdomide in multiple myeloma – has delivered the goods.

The cereblon E3 ligase modulator, given in combination with Amgen's Kyprolis (carfilzomib) and dexamethasone (Kd) as second-line or later treatment for relapsed or refractory multiple myeloma, cut the risk of disease progression or death by 52% compared to Kd alone in the highly-anticipated SUCCESSOR-2 study presented at ASCO today.

Median progression-free survival (PFS) came in at 18 months, more than twice the 8.3 months recorded in the Kd group, with a consistent benefit across different lines of treatment, as well as in higher-risk groups, such as elderly subjects, and those with more aggressive extramedullary disease, when malignant cells proliferate outside the bone marrow.

Among the other endpoints, the overall response rate came in at 80.2% versus 53.4% for the control group, and complete response/stringent complete responses were seen in 26.7% and 8.9% of patients, respectively.

According to Paul Richardson of Dana-Farber Cancer Institute and Harvard Medical School, who presented the data at ASCO, the efficacy was accompanied by "a consistent safety profile and the convenience of oral administration and ability to implement across diverse care settings."

Among the toxicities seen more commonly with the mezigdomide regimen were neutropenia (61.1% versus 9.1%) and infections (34% vs 15.6%).

"Maintaining durable disease control becomes an increasing challenge with each line of therapy for patients with relapsed or refractory disease and increasing resistance to therapy, so achieving extended progression-free survival of a year and a half is especially meaningful," said Richardson.

BMS had said previously that the PFS results were positive, but this was the first revelation of the data and bode well for upcoming filings for mezigdomide in relapsed/refractory multiple myeloma (RRMM).

Celmods bind more tightly to cereblon than other immunomodulatory drugs, such as BMS's Revlimid (lenalidomide) and Pomalyst (pomalidomide), producing deeper responses and overcoming drug resistance.

"There are several pivotal studies with mezigdomide in RRMM exploring its use in combination with other standard treatments, such as bortezomib and dexamethasone, to confirm its value in real-world practice, as well as providing a broad platform for regulatory approval," said Richardson.

"In addition, its ability to reverse immune exhaustion and enhance immune activity makes it an ideal partner to current immunotherapies as well as other novel oral agents, and numerous trials are now underway."

BMS filed the first drug in its celmod programme – iberdomide – for RRMM as part of a combination regimen with Johnson & Johnson and Genmab's anti-CD38 antibody Darzalex (daratumumab) and dexamethasone based on the EXCALIBER-RRMM study, and is waiting for a decision by the FDA in August.

Analysts have predicted blockbuster sales for both celmods, positioning them as successors to Revlimid and Pomalyst, for which generic competition halved combined sales last year to less than $5 billion, having been around $16.5 billion at peak.