ASH 2024 preview – multiple myeloma in focus

With Arcellx's Gilead-partnered Car-T contender anitocabtagene autoleucel seizing much of the limelight at the upcoming ASH conference, the most notable oral presentations on other BCMA-directed multiple myeloma therapies concern not Car-T but antibody formats.

Perhaps the most important among the abstracts released so far concerns ABBV-383, a T-cell engager AbbVie acquired from TeneoOne, and on which it doubled down last year. But multiple myeloma treatment is about more than just BCMA, and ASH offers key updates also on Bristol Myers Squibb's Revlimid follow-on cereblon modulators, and its anti-GPRC5D Car-T.

In BCMA blockade AbbVie already reported a 57% ORR from an ABBV-383 monotherapy trial, and now come data from a combo of this heavy-chain-only T-cell engager with Darzalex and dexamethasone, where an ASH abstracts cites a 70% ORR, or 82% with a high dose. After the TeneoOne deal AbbVie scrapped a tie-up with Harpoon (now part of Merck & Co) on a separate anti-BCMA T-cell engager, HPN217.

ASH will also have first data on another similarly acting MAb, EMB-06, which was originated by China's EpiMab, but whose ex-China rights were licensed a year ago to the private US biotech Vignette Bio, which paid $60m in up-front cash and stock. Judging by the abstract, toxicity could be a focus.

These feature among the most advanced presentations concerning clinical trial results to be discussed at ASH. Most of the meeting's regular abstracts have been unveiled, while plenary presentations remain under wraps, and late-breakers go live on 25 November.

"Almost cancers"

One perhaps surprising theme of this year's ASH will be slow-growing, precancer conditions, with an 8 December press briefing featuring "almost cancers".

Whether conditions like smouldering myeloma, which is mostly asymptomatic but can progress to active myeloma, should be treated with a procedure as dangerous as Car-T therapy is clearly contentious. One small trial of Carvykti in this setting shows all patients developing severe neutropenia, and 17% seeing grade 3 or higher liver enzyme elevation.

Smouldering myeloma is also a focus for Johnson & Johnson/Genmab’s Darzalex, which has recently been filed in this condition. An ASH abstract shows significantly improved PFS versus the current standard of care, active monitoring, with a hazard ratio of 0.49 (p<0.0001).

Sanofi is also testing its rival anti-CD38 MAb, Sarclisa, in smouldering myeloma in the Ithaca trial, but doesn't expect to be able to file until 2026 at the earliest.

Celmods and others

Meanwhile, for Bristol the development of so-called cereblon E3 ligase modulator (celmod) agents is a priority as a means of protecting its Celgene-derived multiple myeloma franchise, and three of these molecules, mezigdomide, golcadomide and iberdomide, are now in pivotal studies.

ASH will see oral presentations from two mezigdomide studies, featuring combinations with various multiple myeloma drugs. Bristol's hope is that mezigdomide could replace Pomalyst, whose patents will start expiring shortly, as an established treatment for relapsed multiple myeloma.

Separately, a cereblon binder, C4 Therapeutics' cemsidomide, which is said to degrade IKZF1/3, will feature in ASH presentations on non-Hodgkin's lymphoma, having shown a 25% ORR among 14 patients with peripheral T-cell lymphoma.

For Bristol the most impressive ASH data could come from the anti-GPRC5D Car-T project BMS-986393. This reported first phase 1 results at ASH 2023, showing an 88% response rate among 73 patients, emboldened by which Bristol unveiled the therapy's phase 3 Quintessential-2 trial, which is due to start in February.

The phase 1 dataset now includes 26 multiple myeloma subjects given the go-forward BMS-986393 dose, an ASH abstract with a May cutoff reveals, and among evaluable patients the ORR stands at 91%.

Selected oral ASH presentations on multiple myeloma

ASH will take place on 7-10 December in San Diego.