Cilta-Cel Leads to 100% MRD-Negativity Rate in High-Risk Smoldering Multiple Myeloma

Smoldering Myeloma | stock.adobe.com

Ciltacabtagene autoleucel (cilta-cel; Carvykti) elicited a 100% complete response (CR) rate in patients with high-risk smoldering multiple myeloma, according to results of a single-arm, phase 2 trial (NCT05767359) presented during the 2024 ASH Annual Meeting and Exposition.¹

At a median follow-up of 10.5 months in the safety run-in cohort, all 6 enrolled patients experienced a CR. The minimal residual disease (MRD)–negativity rate (10^-6) was 100%. Additionally, stem cell collection was successful in all eligible patients, demonstrating an average stem cell yield of 8.94 x 10⁶ CD34-positive cells/kg.

Data also showed that the responses deepened over time. Lead study author Omar Nadeem, MD, clinical director of the Center for Early Detection and Interception of Blood Cancers, and of the Myeloma Immune Effector Cell Therapy Program, at Dana-Farber Cancer Institute in Boston, Massachusetts, noted in a presentation during the meeting that MRD negativity occurred early before achieving best serological response.

“The first 3 patients have sustained MRD negativity after 1 year of follow-up. The remainder of patients remain MRD negative at the time of their last follow-up,” said Nadeem, noting that there were no patients who developed biochemical or SLIM-CRAB progression to date.

International Myeloma Working Group (IMWG) risk score is used to predict risk of progression in smoldering myeloma, which is a heterogenous disease, to multiple myeloma. Prior phase 2 and 3 studies have evaluated early intervention with patients with high-risk smoldering multiple myeloma; however, CAR-PRISM marks the first trial of a CAR T-cell therapy being evaluated for this patient population.

In April 2024, the FDA approved cilta-cel for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 1 prior line of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), and who are refractory to lenalidomide (Revlimid).² This followed an earlier indication granted for the treatment of adult patients with relapsed/refractory multiple myeloma after at least 4 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 monoclonal antibody.³

For the CAR-PRISM study, investigators hypothesized that cilta-cel could be used to achieve MRD-negative disease without induction therapy. Nadeem explained that this is because the immune system is less altered in patients with smoldering multiple myeloma, allowing CAR T-cell therapy to potentially provide even greater benefit compared with patients with relapsed/refractory myeloma. Additionally, the tumor burden in smoldering multiple myeloma is generally lower and less genomically complex, allowing for potentially greater efficacy and reduced toxicity.

In CAR-PRISM, patients underwent apheresis after screening and then received lymphodepletion with cyclophosphamide at 300 mg/m² and fludarabine at 30 mg/m² on days –5 to –3. Cilta-cel was then infused at a target dose of 0.5 or 0.75 x 10⁶ CAR+ viable T cells/kg on day 1. Post-infusion assessments for safety, efficacy, pharmacokinetics, pharmacodynamics, and biomarkers were done on days 1 to 100. Post-treatment assessments for the above outcome measures were done on days 101 up to end of cohort, and follow-up continued thereafter.

The first 3 patients were treated at a lower target dose of 0.5 x 10⁶ CAR+ viable T cells/kg, with an FDA review of safety prior to the dose escalation. Enrollment was staggered with 1 patient dosed every 60 days.

To be eligible for enrollment, patients had to have IMWG high-risk disease defined as having two of the following criteria: serum M spike of at least 2 gm/dL; an involved to uninvolved free light chain ratio of at least 20; and bone marrow plasma cells of at least 20%.

Patients were also eligible if they had an IMWG total score of 9 using the following scoring system:

• Free light chain ratio: >10-25 = 2; >25-40 = 3; >40 = 5
• Serum M protein (g/dL): >1.5-3 = 3; >3 = 4
• Bone marrow plasma cell percentage: >15-20 = 2; >20-30 =3; >30-40 = 5; >40 = 6
• Fluorescence in situ hybridization (FISH) abnormality t(4,14), t(14,16), 1q gain, or del13q = 2

Patients also could be eligible to enroll if there was presence of at least 10% bone marrow plasma cells and at least 1 of the following criteria: evolving pattern; abnormal plasma cell immunophenotype at least 95% of bone marrow plasma cells are clonal and reduction of at least 1 uninvolved immunoglobulin isotype; and high-risk FISH, which could include presence of t(4;14), t(14;16), t(14;20), 17p deletion, TP53 mutation, or 1q gain.

Patients could not have SLIM-CRAB criteria present for active multiple myeloma, have bone marrow plasmacytosis greater than 40%, be diagnosed or treated for another malignancy within 2 years of enrollment, receive prior directed therapy for smoldering multiple myeloma within 6 months of beginning study treatment, or experience a stroke or seizure within 6 months. Patients could also not have an uncontrolled intercurrent illness, including but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or any psychiatric illness/social situations that would limit compliance with study requirements.

Baseline characteristics were reported for the first 6 enrolled patients. The median age was 55 years (range, 53-66), half of patients were male, 4 patients had IgG as their heavy-chain type, and 5 patients had high-risk FISH. FISH abnormalities were comprised of monosomy 13 (n = 4), 1q gain (n = 3), t(4;14; n = 2), t(11;14; n = 1), t(14;20; n = 1), and t(14;16; n = 1).

The primary end point was safety; secondary end points were overall response rate, CR rate, MRD negativity, and progression-free survival, as well as incidence and severity of adverse effects.

Regarding safety, no dose-limiting toxicities were observed in the safety run-in cohort. Cytokine release syndrome occurred in all 6 patients but was grade 1 (n = 4) or grade 2 (n = 2). Four patients received tocilizumab (Actemra), and the other 2 received dexamethasone.

Additionally, 1 patient experienced grade 1 Bell’s palsy that was found to be self-limiting and resolved within 2 weeks. There was 1 case of grade 4 immune-related thrombocytopenia, which also resolved within 2 weeks.

Hematologic toxicities included grade 3 neutropenia, which was transient without any febrile neutropenia. One patient experienced transient grade 3 increased aspartate aminotransferase and alanine aminotransferase levels, which resolved. Additionally, there were no grade 3 infections nor any secondary malignancies to date.

Further findings showed that variable CAR+ T-cell expansion and persistence were observed in this patient population. Nadeem added that at peak expansion, the majority of T cells were CAR+ T cells at a mean of 83% (SD, 14; range, 57-97). Also, when CAR+ CD4+ and CAR+ CD8+ T cells expanded following infusion of cilta-cel, there was a preferential expansion of CAR+ CD4+ T cells; this also occurred at the time of peak expansion.

Nadeem also discussed an individual patient who was treated with cilta-cel on study. This was a 54-year-old active male diagnosed with kappa light chain high-risk smoldering multiple myeloma in 2023. The patient experienced a rise in kappa light chains and an increase in bone marrow plasmacytosis in 2024. The patient had high-risk disease per 20-2-20 criteria with evolving pattern.

Disclosures: Nadeem cited honoraria from Pfizer; research funding from JNJ, Bristol Myers Squibb, Takeda, and Janssen; membership on an entity’s board of directors or advisory committees with Sanofi, GPCR Therapeutics, Bristol Myers Squibb, Takeda, and Janssen.

References

1. Nadeem O, Nikiforow S, DeBraganca K, et al. Early safety and efficacy of CAR T-cell therapy in precursor myeloma: results of the CAR-PRISM study using ciltacabtagene autoleucel in high-risk smoldering myeloma. Blood. 2024;144(supplement 1):1027. doi:10.1182/blood-2024-202676
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 lease one prior line of therapy. News release. Johnson & Johnson. April 5, 2024. Accessed April 5, 2024. 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. FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. News release. FDA. February 28, 2022. Accessed December 10, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ciltacabtagene-autoleucel-relapsed-or-refractory-multiple-myeloma