Early Infection Incidence After Cilta-Cel Shows Importance of Toxicity Monitoring in Myeloma

Infection Incidence After Cilta-Cel in

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Severe and fatal infections typically occurred early after CAR T-cell therapy ciltacabtagene-autoleucel (cilta-cel; Carvykti) infusion or standard-of-care (SOC) treatment initiation in patients with multiple myeloma, with increased risk within the first few months according to findings from a safety analysis of the phase 3 CARTITUDE-4 trial (NCT04181827) that were presented at the 50th Annual Oncology Nursing Society Congress.1

At a median follow-up of 21.5 months (range, 0.1-32.8), 61.5% of patients in the cilta-cel arm (n = 128/208) and 75.7% of patients in the SOC arm (n = 157/208) experienced treatment-emergent infections of any grade. Specifically, viral infections occurred in 29.8% and 43.3% of patients, respectively; bacterial infections in 16.8% and 10.6% of patients, respectively; and fungal infections in 5.8% and 9.6% of patients, respectively. Of note, in the cilta-cel arm, 4 cases of invasive fungal infections were reported, 2 of which were grade 3 or 4; 5 patients from the SOC arm experienced invasive fungal infections, with 2 cases being grade 3 or 4.

Grade 3 or greater treatment-emergent infections were reported in 27.4% and 26.9% of patients in the cilta-cel and SOC arms, respectively. In the cilta-cel arm, rates of treatment-emergent infections were highest in the first 6 months after infusion. However, in the SOC arm, these rates were highest within the first 9 months of initiating study treatment.

Treatment-emergent fatal infections were observed in 9 and 6 patients from the cilta-cel and SOC arms, respectively, with most fatal infections occurring within the first 9 months after starting study treatment. Fatal COVID-19 pneumonia occurred in 7 and 5 patients, respectively; most of these cases were reported during the omicron variant wave of the pandemic. However, none of the patients who died from COVID-19 pneumonia were fully vaccinated, and none of the related deaths occurred after implementation of protocol-specified COVID-19 mitigation strategies.

Either treatment-emergent hypogammaglobulinemia or post-baseline IgG levels lower than 500 mg/dL were observed in 90.9% and 71.6% of patients from the cilta-cel and SOC arms, respectively. Additionally, intravenous immunoglobulin was administered to 68.3% and 15.9% of patients from these respective arms.

“After the first 6 months, grade 3 or greater infection rates were generally higher in the SOC arm than in the cilta-cel arm,” lead study author Jeanie Esselman, RN, of the Medical College of Wisconsin in Milwaukee, and colleagues wrote in a poster. “These [overall] results underscore the importance of monitoring, vaccination, COVID-19 mitigation, infection prophylaxis, and supportive care after cilta-cel infusion.”

Background and CARTITUDE-4 Design

In April 2024, the FDA approved cilta-cel for the treatment of patients with relapsed/refractory multiple myeloma who have received at least 1 prior line of therapy—including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD)—and are refractory to lenalidomide (Revlimid).2 This regulatory decision was based on data from the CARTITUDE-4 trial, which determined that cilta-cel reduced the risk of disease progression or death by 59% vs SOC among patients with multiple myeloma who were previously treated with 1 to 3 lines of therapy.

Data from the study, which were published in The New England Journal of Medicine, demonstrated that at a median follow-up of 15.9 months (range, 0.1-27.3), cilta-cel significantly improved progression-free survival vs SOC (HR, 0.26; 95% CI, 0.18-0.38; P < .001).3 Updated data from the study revealed that at a median follow-up of 34 months, cilta-cel increased overall survival vs SOC (HR, 0.55; P = .0009).4

The randomized trial included patients aged 18 years or older with multiple myeloma who had received 1 to 3 prior lines of therapy—including a PI and an IMiD, were refractory to lenalidomide, and had an ECOG performance status of 0 or 1.1 Previous CAR T-cell therapy or BCMA-targeting therapy was not permitted. Patients were randomly assigned 1:1 to be treated with cilta-cel (n = 208), or physician’s choice of SOC with pomalidomide (Pomalyst) plus bortezomib (Velcade) and dexamethasone (PVd) or daratumumab (Darzalex) plus pomalidomide and dexamethasone (DPd; n = 211). Patients were stratified based on physician’s choice of PVd or DPd; international staging system (ISS) stage; and number of prior lines of therapy.

Of note, treatment-emergent adverse effects (TEAEs)—including infections—were defined as AEs that occurred at or after the first dose of study treatment up to and including 112 days after cilta-cel infusion, up to and including 30 days after the last dose of SOC, or up to the start of subsequent antimyeloma therapy—whichever came first. Regardless of the start date, any on-study treatment-related AEs—including delayed AEs in the cilta-cel arm—were considered TEAEs. Delayed AE reporting in the cilta-cel arm collected all grade 3 or greater infections from the time of infusion through the duration of the study, regardless of causality or seriousness. Furthermore, infections were assessed in all patients who received either cilta-cel or SOC on the study. Lymphocyte counts were evaluated over time by flow cytometry in patients who received cilta-cel; serum antibody levels were established by immunoturbidimetry (LabCorp).

Baseline Patient Characteristics

In the cilta-cel and SOC arms, respectively, the median ages were 62 years (range, 27-78) and 61 years (range, 35-80). Patients had ISS stage I (cilta-cel, 65%; SOC, 63%), II (29%; 31%), and III (6%; 7%) disease. Bone marrow plasma cell levels greater than 60% were observed in 20% and 21% of patients in the cilta-cel and SOC arms, respectively; the presence of soft tissue plasmacytomas was observed in 21% and 17% of patients in these respective arms. Patients in both arms had lived a median of 3 years since multiple myeloma diagnosis (range, 0.3-18; 0.4-22). Patients in both arms had received a median of 2 prior lines of therapy (range, 1-3 each). In total, 33% and 32% of patients in the cilta-cel and SOC arms, respectively, had received 1 prior line of therapy; 67% and 68% of patients in these respective arms had received 2 to 3 prior lines of therapy. Notably, 26% of patients in both arms were triple-class exposed, and 5% and 7% of patients, respectively, were penta-drug exposed. Types of multiple myeloma included IgG (54%; 51%), IgA/IgM (18% each), and light chain (23%; 27%).

Treatment-Emergent Infections and Immune Recovery

Among the 176 patients who were treated with cilta-cel, 30.7% experienced grade 3 or greater treatment-emergent and non–treatment-emergent infections, which most often occurred during the first 6 months after infusion. Fatal treatment-emergent and non–treatment-emergent infections were reported in 11 patients treated with cilta-cel, which included 7 patients in the safety set who died from COVID-19.

“For patients receiving CAR T-cell therapy for multiple myeloma, additional risk factors for infection include lymphodepletion, toxicity management with corticosteroids, and immune suppression exerted by CAR T cells,” the poster authors wrote.

In the cilta-cel population, by day 60, 89.2% of patients who had experienced grade 3 or 4 neutropenia had recovered to grade 2 or lower neutropenia. At approximately month 4, B-cell counts in the blood were reported to begin to return to baseline levels. By approximately 9 months, blood B-cell counts had recovered to baseline levels, and plasma cell counts had also recovered to baseline levels in the blood and bone marrow. IgM and IgA levels returned to baseline at approximately 1 year and 2 years, respectively, following cilta-cel infusion. Starting on day 168, the median CD4-positive T-cell counts began to exceed the lower limit of normal, which was defined as 200 x 106/µL.

“Patients in both the cilta-cel and SOC arms were at risk for severe and fatal infections, and most severe and fatal infections occurred early after treatment started, with a higher risk in the first few months,” the poster authors concluded. “Timing of immune recovery in patients who received cilta-cel as study treatment corresponds with a reduction in infection risk; however, immune recovery may take longer in some patients, underscoring the importance of tailored infection prophylaxis.”

References

1. Esselman J, Davis A, Kruyswijk S, Florendo E, Plaks V, van de Donk NWCJ. Incidence of infection and immune recovery in the CARTITUDE-4 trial of ciltacabtagene autoleucel versus standard of care for treatment of multiple myeloma. Presented at: 50th Annual Oncology Nursing Society Congress; April 9-13, 2025; Denver, Colorado. Abstract I23.
2. Carvykti is the first and only BCMA-targeted treatment approved by the US FDA for patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy. News release. Johnson & Johnson. April 5, 2024. Accessed April 10, 2025. https://www.jnj.com/media-center/press-releases/carvykti-is-the-first-and-only-bcma-targeted-treatment-approved-by-the-u-s-fda-for-patients-with-relapsed-or-refractory-multiple-myeloma-who-have-received-at-least-one-prior-line-of-therapy
3. San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med. 2023;389(4):335-347. doi:10.1056/NEJMoa2303379
4. Mateos MV, San-Miguel J, Dhakal B, et al. Overall survival (OS) with ciltacabtagene autoleucel (cilta-cel) versus standard of care (SOC) in lenalidomide (len)-refractory multiple myeloma (MM): phase 3 CARTITUDE-4 study update. Presented at: 2024 International Myeloma Society Annual Meeting; September 25-28, 2024; Rio de Janeiro, Brazil. Abstract OA-65.