Debate: Should CAR T Best Be Used in Early MM Relapse?

HOUSTON — Chimeric antigen receptor T-cell therapy (CAR T) has emerged as a game changer for the treatment of multiple myeloma (MM), but questions remain as to how — and when — the immunotherapy will best be used for patients who experience disease relapse.
Will CAR T be best used in early relapse? Experts debated this question at the annual meeting of the Society of Hematologic Oncology (SOHO) 2024. Based on attendees’ votes, at least one side of the debate emerged victorious.
Krina Patel, MD, of The University of Texas MD Anderson Cancer Center, Houston, came out swinging with earnest support for using CAR T in early relapse. Saad Z. Usmani, of Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York City, and Cornell University, Ithaca, New York, argued in favor of being “a little more circumspect.”
Patel: Yes, Earlier Is Better
A pre-debate audience poll leaned Patel’s way, with about 59% of 73 votes favoring CAR T in early relapse, 33% favoring reserving CAR T for patients who relapse after three or more lines of therapy, and 8% undecided.
“CAR T is not just a drug — it’s an actual therapy that takes a lot of logistics, as well as bridging therapy and all these other things to take into account,” said Patel, an associate professor at MD Anderson. “And again, when I can go earlier, I have control over some of this.”
Furthermore, randomized phase 3 data from the KarMMA-3 study and the CARTITUDE-4 study showed that multiple standard therapies were not as good as CAR T in the early relapse setting, she said, pointing to the respective hazard ratios for disease progression or death with CAR T vs standard therapies of 0.49 and 0.26.
CARTITUDE-4 also suggested that manufacturing failures are more likely in later relapse — when time is already of greater essence, she said, noting that it can take an additional 3 months when restarting the process.
When it comes to toxicity, yes, it is a concern, she said.
“But we know how to decrease toxicity,” she stressed. “And again, with our second- and third-line approaches, we actually have better therapies to give for bridging.”
Quality of life is another important consideration, Patel said, noting only CAR T offers a “one and done” therapy that helps patients “truly feel better.”
“They’re not having to come into hospitals as often, and this is not just for months; it’s for years,” she said. “To be able to give that to somebody is huge, and again, we have objective data that show that compared to our standard-of-care therapies, patients do better in almost every realm of quality-of-life metrics.”
Patel also pointed to recent data from a retrospective study showing that for bridging therapy, less is more when disease is controlled, and in the early-line setting, more and safer options are available for reducing tumor burden.
Early CAR T is better for older or frail patients as well, she argued, noting that these patients don’t have time to wait, and a new study demonstrates that they tend to do well with CAR T in the early relapse setting.
The choice for early CAR T is clear in patients with high-risk disease, but Patel stressed that it shouldn’t be reserved for those patients, asking, “When has anything worked well for patients with high-risk disease and not [also] better for standard-risk patients?”
“And why give only 20%-25% of your patients [who actually reach fifth-line treatment] access to something that we know has really revolutionized myeloma therapy?” she said.
Many patients don’t have access, and that’s an issue, she acknowledged, adding: “But for those who do, we really should be giving it to them as soon as possible.”
Usmani: Reserve CAR T for Later Relapse
Not so fast, said Usmani, chief of myeloma service at Memorial Sloan Kettering and a professor at Weill Cornell.
“All of these therapies are doing wonders for our patients, and we believe in them, but we have to be a little circumspect in looking at this data more closely and not just with emotions,” he said, noting that many options exist for patients in a first or second relapse, and new options are emerging.
There is also a “harsh reality” in terms of CAR T availability, he noted, explaining that in 2021, about 180,000 people were living with MM, and about two thirds of those had relapsed disease. Meanwhile, fewer than 1000 CAR T products have been delivered each year for patients with relapsed MM since they were approved in this setting in the United States.
“So, it’s a pipe dream, seriously, that we will be able to utilize CAR T for all patients in early relapsed disease,” he said, adding that capacity will remain an issue, due to limited resources.
The existing data, including from KarMMa-3 and CARTITUDE-4, show little potential for long-term benefit with early vs later CAR T.
“There is no plateau,” he said of the survival curves in KarMMa-3, underscoring the lack of a difference in overall survival benefit based on CAR T timing.
The CARTITUDE-4 curves “look great,” and it may be that a “small plateau emerges,” but they don’t demonstrate a benefit of earlier vs later CAR T, he said.
As Patel noted, there are few treatment options for patients with anti-CD38 monoclonal antibody and immunomodulatory drug resistance at first relapse. However, that situation will soon change, Usmani stated.
“Guess what? Belamaf is coming to the rescue!” he said of the off-the-shelf and more accessible B-cell maturation antigen-targeted antibody-drug conjugate belantamab mafodotin, which has recently been evaluated in the DREAMM 7 and DREAMM 8 trials.
DREAMM 7 demonstrated improved survival vs daratumumab, bortezomib, and dexamethasone in the relapsed/refractory MM setting when used in combination with bortezomib and dexamethasone. DREAMM 8 shows similar benefit with belantamab mafodotin, pomalidomide, and dexamethasone vs pomalidomide, bortezomib, and dexamethasone in lenalidomide-exposed patients with relapsed or refractory MM.
“Belamaf combinations in the one to three lines [of prior therapy] setting look really good,” he said, noting a particular benefit for progression-free survival and a trend toward improved overall survival.
Considering these factors, as well as the risk for cytopenias and the subsequent risk for infection in most patients who undergo CAR T-cell therapy and the known potential risk for secondary malignancies, Usmani said that he will remain “in the camp of being really careful in selecting CAR T patients for early relapse” until more is known about the risks.
“CAR T for all is not the answer. I think we have to be careful in picking CAR T patients; it’s not a zero-sum game here,” he said, stressing that “there are too many unknowns with the use of early CAR T therapy.”
“It makes sense in some, but not for everyone,” he said, emphasizing the importance of including patients in the discussion.
“The great thing is we have all these options for our patients,” he said.
Usmani persuaded at least a few colleagues: The final vote showed 42% of 124 voters supported early CAR T compared with 52% who supported CAR T after three or more lines of therapy and 6% who remained undecided.
Sharon Worcester, MA, is an award-winning medical journalist based in Birmingham, Alabama, writing for Medscape Medical News, MDedge, and other affiliate sites. She currently covers oncology, but she has also written on a variety of other medical specialties and healthcare topics. She can be reached at [email protected] or on X @SW_MedReporter.
 
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