Treatment for the blood cancer multiple myeloma has changed dramatically over the past two decades, and another significant shift looks to be just around the corner.
Within the next year, a cell therapy from Bristol Myers Squibb called ide-cel could be approved by the Food and Drug Administration. Behind it and a fast-following rival treatment from Johnson & Johnson are a growing glut of antibody-based drugs aimed at the same cellular target, a protein known as BCMA. Several of them were showcased this weekend at the American Society of Hematology's virtual conference, the year's biggest meeting on blood diseases.
The encouraging results are leading multiple myeloma experts to talk hopefully about curative treatment, but could also leave them with tough choices about how best to treat their sickest patients.
"The excitement is that these new agents have extremely high response rates and longer lasting responses than we've seen with other [drugs]," said Amrita Krishnan, director of the Judy and Bernard Briskin Center for Multiple Myeloma Research at City of Hope, and an investigator in several BCMA trials. But "the biggest challenge for myeloma physicians is understanding how to best sequence these therapies."
The speed of change was made clear at ASH. Bristol Myers and partner Bluebird bio provided the latest results from ide-cel's pivotal trials, while J&J disclosed updated data for its competing cell therapy, which could soon be under FDA review, too. Poseida Therapeutics, CARSgen Therapeutics and Cellular Biomedicine Group presented new data for similar treatments they're developing.
Yet joining these cellular therapies were a batch of experimental antibody drugs from Regeneron, Amgen and others that could offer a viable alternative. These treatments home in on BCMA as well, but are simpler to make and seemingly safer. Results to date are mostly early-stage, and much remains to be proven about how effective they ultimately can be.
CAR-T sets the bar
The response rates to Bristol Myers' and J&J's treatments are very high, data presented at ASH affirmed.
Nearly all of the 97 patients treated with J&J's cilta cel, for instance, responded to treatment, with their cancer reduced or eliminated on follow-up scans. After one year, 89% were still alive and three-quarters still had not seen their disease progress.
Treatment with ide-cel, at the latest update from Bristol Myers from the Phase 1 CRB-401 study, led to a 76% response rate, with a median progression-free survival of 8.8 months.
Lee Greenberger, chief science officer of the Leukemia and Lymphoma Society, said cilta-cel "does appear to be better," though he cautioned comparing the results of two therapies that haven't been tested head to head.
Bristol Myers chief medical officer Samit Hirawat, however, noted ide-cel has been used to treat the most patients, with the longest follow-up time, of any cell therapy for multiple myeloma so far. An approval could come by March 27, which would give Bristol Myers several months to build up experience with more specialists and patients ahead of any approval for cilta-cel.
Still, the laborious process required to produce cell therapies remains a major drawback. Immune cells must be extracted from each patient, re-engineered at a central manufacturing plant and then re-infused back into the same patient.
Treatment is only administered at special centers, not the community clinics that see a majority of multiple myeloma patients. Patients must also be monitored for neurotoxicity and a potentially deadly immune reaction called cytokine release syndrome, or CRS — both common side effects to cell therapy. Most often that monitoring involves staying in a hospital.
The data from J&J, for example, showed several patients experienced severe CRS or neurotoxicity, two of whom died.
Alternatives begin to emerge
One solution to first-generation cell therapy has been the development of "off-the-shelf" products, which involve the genetic modification of immune cells from healthy donors rather than from each patient.
Allogene Therapeutics appears the furthest along and has shown data that its treatment led to a 60% response rate in a small number of patients.
Another alternative approach is quickly moving forward as well, however. Several drugmakers are developing a special type of synthetic antibody that binds to BCMA and a target on immune cells called CD3. The aim is to draw the immune cells close enough to cancerous cells to attack and kill them.
The advantage of these so-called bispecific antibodies is their potential convenience. They are off-the-shelf, enabling their use at more healthcare facilities and community clinics. And they're far less complex to manufacture and transport.
ASH included the most detailed look yet at several bispecific antibody programs. Their efficacy, while more modest than cell therapy, has been encouraging, with at least 80% of patients seeing a reduction in signs of disease at the highest doses of Amgen's AMG 701 and AbbVie and Teneobio's TNB-383B.
How long those responses last, though, is unclear and antibodies must be taken chronically, compared to a one-time cell therapy infusion.
Phase 1 data for multiple myeloma antibodies showcased at ASH
|Company||Program||Antibody type||Overall response rate at highest dose (complete response)||Safety*|
|Amgen||AMG 701||Bispecific||83% (17%)||CRS 65% (Grade 3+ CRS 9%)|
|Regeneron||REGN5458||Bispecific||63% (0%)||CRS 39% (Grade 3+ CRS 0%)|
|J&J||teclistamab||Bispecific||73% (23%)||CRS 55% (Grade 3+ CRS 0%)|
|AbbVie/Teneobio||TNB-383B||Bispecific||80% (13%)||CRS 45% (Grade 3+ CRS 0%)|
|AstraZeneca||MEDI2228||ADC||66% (2%)||Photophobia 59% (Grade 3+ photophobia 17%)|
*CRS = cytokine release syndrome SOURCE: ASH, SVB Leerink.
As with cell therapy, CRS is a side effect with many of the bispecific antibodies. While cases appear to be more mild, patients will still likely require some monitoring. That could lead bispecific antibodies to face "similar roll-out challenges" to cell therapies for other blood cancers, which have struggled commercially, wrote Geoffrey Porges, an analyst at SVB Leerink, in a note to clients.
In those cases, "patients can only receive treatments in large/tertiary centers and are treated by physicians who have experience managing CRS events," Porges added.
Krishnan acknowledged CRS could slow adoption of bispecific antibodies for multiple myeloma. "It'll be a learning curve," she said. But she expects that, if bispecifics are approved, pickup will increase as community doctors become more familiar with them.
Another antibody approach
Another strategy to go after BCMA in multiple myeloma involves what are known as antibody-drug conjugates, complex molecules that link a BCMA-targeting antibody to a toxic chemotherapy drug.
Several antibody-drug conjugate are approved for other cancers and, earlier this year, the first BCMA-targeting drug for multiple myeloma, GlaxoSmithKline's Blenrep, won FDA clearance.
ADCs, however, may be the least effective drugs of the group. Blenrep, for instance, generated a response in about a third of patients. Severe eye-related side effects are common during Blenrep treatment, requiring patients to get routine eye exams, although Greenberger described them as "manageable."
An early-stage drug from AstraZeneca, dubbed MEDI2228, appears next in line. Though its efficacy looks superior to Blenrep, that will need to be confirmed in larger trials. The drug was also assocated with frequent eye-related side effects.
While more and more BCMA-targeting drugs are advancing through development, Mark Wildgust, a J&J executive in its cancer drug division, argues there's room for many new drugs. Cell therapies and antibodies could be tested in earlier lines of treatment, for instance, or as part of drug combinations that could lead to long-term disease control or even a functional cure.
"I think there's space for the BCMA bispecifics as well as BCMA CAR-Ts," Wildgust said. "They will have their own specific spaces. In the next three to five years I don't see them overlapping."