From CARs to Trispecifics, More Choices to Come in Multiple Myeloma

As choices and combinations in multiple myeloma proliferate, it’s good news for both patients and physicians, according to Ajai Chari, MD, professor of medicine at the University of California, San Francisco, who opened Friday’s symposium on immunotherapy at the International Myeloma Society 2024 Annual Meeting & Exposition, held in Rio de Janeiro, Brazil.

Ajai Chari MD | Image credit: UCSF

“I think anybody who's treating myeloma patients today is so gratified to see the improvement in their outcomes with these T-cell–redirection therapies,” Chari said. He highlighted results from recent trials involving bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapies, which have seen responses of 60% to 98% and progression-free survival (PFS) ranging from 11 months to 3 years.

Nonetheless, he said, “We have a lot of unmet needs.”

Chari noted positive news heard earlier during IMS 2024 regarding several high-risk conditions, such as treatment of extramedullary disease and patients with prior T-cell redirection, “And, of course, global access to all these agents.”

“So how do we improve upon what we have?” Chari asked. “Targeting more than 1 antigen is one approach for the T cell with CARs. There’s efforts to change the binding domains, the T-cell populations, and the source of T cells, including allogeneic [T cells],” he said.

Other strategies call for moving treatment into earlier lines of care. And then, Chari said, there are the many studies looking at taking bispecific antibodies and working in a third target, creating trispecifics.

In what one panel chair called a “whirlwind,” Chari took the audience on a rapid tour of both recent approvals in myeloma and a view of what’s in the pipeline. With CAR T cells, for example, improvements will come not just through new products but also through alternative manufacturing processes that could save time and cut costs.

There are also new types of CARs: human single-chain variable fragments and allogeneic CARs. Chari showed early results from small studies with strong overall response rates and promising, if immature, PFS results. The question, he said, is how to “contextualize” what’s occurring compared with current therapies.

“It’s hard to make too many comparisons from single-arm small studies,” he said. “But we're already seeing some interesting results.”

He compared recent phase 3 studies involving combinations of anti-CD38 therapies, pomalidomide, dexamethasone, and B-cell maturation antigen (BCMA)-targeting products. At the recent meeting of the American Society of Clinical Oncology, the DREAMM-7 and DREAMM-8 studies showed the benefits of adding the BCMA-targeting antibody-drug conjugate belantamab mafodotin to backbone regimens, and Chari once again urged caution when comparing PFS with earlier trials.

“We're looking at anywhere from 1 to 3 lines of prior therapy,” he said, noting a more meaningful metric are HRs. Of note, he said, “We should commend all of these studies of moving away from the doublet comparisons of yesteryear. We're now moving to triplet comparisons, and in spite of that, we're getting very impressive hazard ratios.”

Improvements in adverse event (AE) profiles are important, too. Chari noted that results for CARTITUDE-4 answered questions “that we were concerned about.” Neurotoxicity AEs were seen in 30% of patients, but there was only a single case of Parkinsonism, which had been a lingering issue.

Coming in CAR T

“We have novel targets,” he said, including non-BCMA targets such as GPRC5D and CD70, and dual targets, including the combinations of BCMA with CD19 and GPRC5D.

“We have really exciting in vivo CARS, which are viral injections directly into the patient to avoid the leukapheresis manufacturing,” Chari said. “At UCSF, we’ll soon be having a CRISPR nonviral CAR,” referring to the gene-editing technology, clustered regularly interspaced short palindromic repeats, that allows scientists to modify living organism DNA.

Some clinical data for the GPRC5D is coming in, he said, and responses are exciting, but again, he cautioned that numbers are small. Of concern, Chari said, so far the durability of PFS is suboptimal.

CAR T-cell combinations are also being studied, but Chari said this concept removes one of the chief advantages of the CAR T approach, which is to give patients a break from treatment.

He reviewed a series of bispecific and trispecific engagers under development, including JNJ-7965322, which combines BCMA and GPRC5D targeting. As was explained the following day in a session on emerging therapies, this treatment essentially does the job of the talquetamab-teclistamab combination being studied in the RedirecTT-1 trial by Yael C. Cohen, MD; however, since it’s a trispecific, it does so with far less toxicity.

Chari concluded with some data on the use of prophylactic tociluzumab with bispecific antibodies; this is being studied in community practice due to the interest in bringing these therapies to a broader patient population.

“Overall,” Chari said, early results show this strategy reduces rates of cytokine release syndrome (CRS), “but what you see is a bigger drop in the grade 1s than the grade 2s. So, what remains to be worked up further is we’re going to be moving this to outpatient.” Also, he said, the drop in CRS comes with “a hint” of more neutropenia.