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CAR T cells rise to the front in multiple myeloma

Dr Sergio Giralt, Memorial Sloan Kettering Cancer Center, USA
Phase 3, KarMMa-3

Medicom interviewed Dr Sergio Giralt (Memorial Sloan Kettering Cancer Center, NY, USA) on the results of the KarMMa-3 trial, investigating the efficacy and safety of idecabtagene vicleucel (ide-cel) in patients with relapsed or refractory multiple myeloma. The findings were recently published in the New England Journal of Medicine [1].

Medicom: How did the KarMMa-3 study come into existence and why is this trial important for the management of multiple myeloma?
Source: mskcc.org

“We conducted a multi-institutional, multinational study that assessed the role of ide-cel, which is a BCMA-targeted CAR T-cell therapy, in earlier lines of myeloma therapy,” said Dr Giralt. “However, some of the included patients were triple refractory and had been exposed to a previous proteasome inhibitor, immune modulator drugs (e.g. lenalidomide), or an anti-CD38 monoclonal antibody (e.g. daratumumab).”

“It is becoming more and more frequent that patients for whom treatments are no longer working have already been exposed to the 3 major drug classes earlier in their disease journey,” continued Dr Giralt. “Ide-cel became commercially available a couple of years ago but was only approved for patients who had relapsed after 4 or more lines of treatment. We wanted to explore its role in earlier lines of therapy because the current situation does not enable patients who had only had 1 or 2 lines of treatment to receive the BCMA-targeting CAR T therapy ide-cel.”

The KarMMa-3 study (n=386) randomised patients with relapsed/refractory myeloma who had received between 1 and 3 prior lines of treatment 2:1 to ide-cel or the standard conventional treatment in the participating country. The treatments had to be given depending on what an individual patient was relapsing on. In total, 5 different standard chemotherapy combinations were used in the control group.

Medicom: What were the main outcomes of the trial?

“We observed a significant response rate benefit in the patients who were randomised to ide-cel, with 71% of the patients displaying at least a partial response and 39% of the patients achieving a complete response, compared with an overall response rate of 42% and a complete response rate of 5% in patients who received standard chemotherapy,” said Dr Giralt.

Furthermore, Dr Giralt mentioned an advantage of ide-cel over standard chemotherapy for the primary endpoint of progression-free survival. “The median progression-free survival for the ide-cel group was 13.3 months and the median progression-free survival for the control group was 4.4 months.” Dr Giralt added that the study had a crossover design, meaning that patients who had relapsed on the standard-of-care were allowed to receive ide-cel. “This is important because the survival analysis will be affected by the fact that a significant proportion of patients actually did cross over to the ide-cel arm.” Death due to disease progression occurred in 17% of the patients in the ide-cel group and 17% of the patients in the control group.

Medicom: Were there any new safety issues that came up with ide-cel treatment? Or were they consistent with previous findings?

“All CAR T-cell therapies that are commercially available have adverse events of interest, primarily cytokine release syndrome (CRS) and neurotoxicity,” explained Dr Giralt. “CRS was relatively common: grade 1 and 2 CRS occurred in about 75 to 80% of the patients. However, grade 3 and 4 CRS only occurred in 4% of the patients,” stressed Dr Giralt. “There was 1 patient who died from cytokine release; a patient who had a concomitant fungal sepsis.”

Dr Giralt said that any grade neurotoxicity occurred in approximately 15% of the patients, but grade 3–4 neurotoxicity was uncommon, occurring in only 3% of the patients. According to Dr Giralt, the most common toxicities with all CAR T-cells treatments occur from the lymphodepletion chemotherapy stage of the treatment, which in this study was fludarabine/cyclophosphamide. However, prolonged pancytopaenia, the typical problem leading to infection during this stage of the treatment, was extremely rare. “Patients usually recovered their platelet and neutrophil counts within 20 days,” he added. Dr Giralt explained that the study group reported a few deaths that were associated with infectious complications. “The included patients were heavily pre-treated and were therefore at risk for infection. This is one of the reasons why these therapies have to be delivered in specialised centres with adequate expertise and support.”

Medicom: What were some of the limitations of the trial that you aim to resolve in the future? 

“If you look at the consort diagram in the New England Journal of Medicine paper, 490 patients were screened, 386 patients were randomised, 254 were assigned to the ide-cel group, and 225 patients actually received ide-cel,” answered Dr Giralt [1]. “Thus, around 10% of patients who were scheduled to receive ide-cel, did not. This is why everybody is excited about off-the-shelf CAR T-cell therapies; patients will not have to wait. Patients with active myeloma can rapidly deteriorate in the 4–5 week time period between the moment of randomisation and the time they receive the cells.”

Next, Dr Giralt mentioned that many of the screened patients were deemed ineligible to receive ide-cel for clinical reasons. “However, the creatinine levels and haematologic parameters that were required to enroll were somewhat stringent, and, in clinical practice, many of the screened patients would in fact be getting ide-cel,” said Dr Giralt. “Therefore, I think some of the limitations of the study will probably be eliminated if the product gets a label for use in an earlier line of therapy. Other limitations are inherent to CAR T-cells treatment and will only be eliminated when we have off-the-shelf products.”

Furthermore, Dr Giralt addressed the role of CAR T-cell therapies in light of the advent of T-cell engagers, such as teclistamab and talquetamab. “We’re assuming that many of the T-cell engagers will be used before a patient gets referred for a CAR T-cell therapy because they will be available for community oncologists to utilise. T-cell engagers require hospitalisation and a certain degree of expertise to manage adverse events. These are things that community oncologists are accustomed to doing and are very well prepared to do. The question is then, will a CAR T-cell therapy work after having received another BCMA-targeted agent, such as teclistamab? There is emerging data that if the administration of the BCMA-targeted therapy was more than 6 months ago, a CAR T-cell therapy can still work. But the data is limited, and we have to wait for more data to answer this question.”

Medicom: Previously, several lymphoma trials reported that CAR T cells were effective therapeutically across all ages, with older patients doing just as well, if not better, than younger patients. How do these results compare with the findings in myeloma?

“We do not see a signal that older populations do worse,” answered Dr Giralt. “But remember, to be able to get a CAR T-cell therapy, you need to have a performance status of 80 to 90. Patients with an ECOG performance status of 2 or greater are not eligible to receive these therapies. In lymphoma, many of us have expanded that indication because we think this is an effective therapy in patients with active disease.” According to Dr Giralt, a similar trend is emerging in the management of patients with myeloma. “I think with the commercial drugs, we are starting to allow patients, who have a performance status that may not have allowed them to go on a protocol, to receive CAR T-cell therapies. Ide-cel offers a 70% response rate and improvements in quality of life. Although many of the patients relapsed, as opposed to what we observed in lymphoma, we’re not necessarily seeing a plateau on that curve. In fact, for patients who achieve a complete remission on ide-cel, the median remission duration is beyond 18 months now.”

Medicom: What’s next on the horizon in this area?

Dr Giralt stated that myeloma therapy has been revolutionised over the last 10 years with the advent of anti-CD38 monoclonal antibodies, novel proteasome inhibitors, and combination therapies. “When I started doing this 30 years ago, the life expectancy of a myeloma patient, even after transplant, was around 5 years. Now it is more than 10 years. The main limitation for many of the successful new treatments is access. Unfortunately, many myeloma patients across the United States are not getting what we would consider optimal therapy. Only 30 to 40% of patients who would benefit from transplants are being referred for transplants. Similarly, we assume that the access to CAR T-cell therapies will be limited,” Dr Giralt decided.

    1. Rodriguez-Otero P, et al. N Engl J Med 2023;388:1002–1014.


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