Bristol Myers details landmark Abecma multiple myeloma data that ASH turned down

In a tight BCMA CAR-T race, Bristol Myers Squibb has delivered the drug class’s first randomized trial win in multiple myeloma. But the detailed data, recently rejected by the American Society of Hematology (ASH) for its annual meeting, might simply not matter that much to doctors and the drug’s sales.

Detailed data from the trial, coded KarMMa-3, has been published in The New England Journal of Medicine and is being presented at the EBMT-EHA European CAR T-cell Meeting Friday.

In the study, BMS’ Abecma cut the risk of disease progression or death by a whopping 51% compared with the standard regimen in multiple myeloma patients who have tried two to four prior lines of therapy.  The Abecma arm had a median 13.3 months without disease progression, versus 4.4 months in the control group.

The trial marks “a major milestone” as the first randomized study for a CAR-T therapy in multiple myeloma, and the investigators who saw the results were “ecstatic,” Nick Leschly, CEO of BMS’ partner 2seventy bio, said in an interview with Fierce Pharma ahead of the data release.

But Rahul Banerjee, M.D., a Fred Hutch doctor who specializes in multiple myeloma and cell therapies, said he had expected Abecma to deliver a much better median progression-free survival number than the 8.6 months it posted in the original KarMMa study in a later-line setting. “It was a little bit better. Not tremendously better. It kind of got stuck,” Banerjee said in a separate interview.

Still, as BMS’ cell therapy development lead Anne Kerber pointed out, there’s actually an overlap between the two trials’ patient population in terms of lines of therapies they had received. Perhaps more importantly, the KarMMa-3 patients had tried three different classes of therapies—immunomodulatory agents such as BMS’ Revlimid, proteasome inhibitors such as Takeda’s Velcade and Johnson & Johnson’s anti-CD38 antibody Darzalex. About 66% of patients had tumors refractory to all three drug classes, which indicates more aggressive disease.

“I believe that if you’re tripe-class-exposed, it probably doesn’t matter how many prior lines you’ve had, because you will have a very poor outcome,” Kerber said.

The control arm’s 4.4-month PFS performance was also a little below Banerjee’s real-world experience, even though it matches some historical trial data. Banerjee said patients today are actually getting better outcomes based on improved care. But he shrugged off the difference, saying that he’s more focused on how Abecma itself performed.

In terms of Abecma's performance across different patient subgroups, Kerber noted that the therapy showed “very clear consistency”, including in those with high-risk cytogenetic features, who made up over 40% of all trialed patients. In patients with known high-risk cytogenetic abnormalities, Abecma cut the risk of disease progression or death by 39%, versus 56% in the others.

In another element that probably hurt Abecma’s data, some patients in the Abecma arm actually had fast progression and didn’t even get the CAR-T therapy, 2seventy chief medical officer Steve Bernstein said in the interview. The fact that some patients couldn’t get the drug on time could be related to how long it takes to manufacture CAR-T therapies.

While BMS, 2seventy and Banerjee all highlighted the transformational nature of KarMMa-3 in the development of myeloma CAR-T therapies, the data were mysteriously turned down for a late-breaking presentation at the ASH 2022 annual meeting last December, arguably the most important annual medical meeting for blood diseases. The absence triggered concerns about whether there are any weak points in the data.

Bernstein suggested that data or interest from the field aren’t the problems. The 2seventy exec noted that ASH isn’t just about myeloma or blood cancer—it covers an entire spectrum of blood disorders—so it needs some diversity in therapeutic areas. In multiple myeloma, ASH 2022 chose pivotal data from Johnson & Johnson’s potential first-in-class GPRC5D agent talquetamab for its press program, but no myeloma research was included as late breaker.

The release of the Abecma data comes as its direct rival, J&J and Legend Biotech’s Carvykti, just reported a trial success from a clinical trial that’s one line earlier than KarMMa-3. But as 2seventy’s Leschly pointed out, a comparison between the two agents simply doesn’t matter in the near future.

“What people forget is that it’s a complete supply-driven market here, and it’s about delivering the best that you can to as many patients as you can,” Leschly said.

Leschly was referring to the manufacturing bottleneck that Abecma and Carvykti share. Both therapies showed strong data in late-line myeloma, where they are approved for use after four or more lines of prior treatment. This triggered strong demand that’s far from being met. And while both teams are working to ramp up production, supply will likely remain constrained for years, Leschly noted. That means, the two therapies don’t need very impressive data to drive uptake—at least for now.

Fred Hutch’s Banerjee also raised the same question. Interest in both therapies is high, he said, but “the big issue is slots” and limited hospital beds to give these complicated therapies that require patient monitoring. The long wait lists mean that even if the FDA decides to approve the CAR-Ts in earlier lines of treatment immediately, it’s not going to change which patients doctors will put on CAR-Ts, Banerjee said.

In the meantime, over the long term, J&J-Legend and BMS are moving the CAR-Ts to even earlier lines of treatment. BMS plans to launch the phase 3 KarMMa-9 trial in patients who had an inadequate response to stem cell transplant. Kerber wouldn’t give an exact timeline for the study but said the treatment setting “truly address[es] an unmet need.” And J&J is running CARTITUDE-5 and CARTITUDE-6 in newly diagnosed patients who are ineligible and eligible for stem cell transplant, respectively. 

Editor's Note: A previous version of the story mistakenly stated that J&J's talquetamab data were part of ASH 2022's late-breaking abstract. Those results were actually included in the press program, not LBA.