Cilta-cel demonstrated feasibility in the treatment of patients with high-risk smoldering multiple myeloma in the phase 2 CAR-PRISM trial.
Treatment with ciltacabtagene autoleucel (cilta-cel; Carvykti) led to an overall response rate (ORR) and minimal residual disease (MRD) negativity rate of 100% in patients with high-risk smoldering multiple myeloma, according to data from the phase 2 CAR-PRISM trial (NCT05767359).1,2
Findings presented at the
At a median follow-up of 15.3 months, MRD negativity at a 10–6 sensitivity per next-generation sequencing was reported in all patients, with a median time to MRD negativity of 1 month. MRD negativity at a 10–5 sensitivity was achieved by all patients at 1 month following CAR T-cell therapy infusion; all patients reached MRD negativity at the 10–6 threshold by month 2. MRD negativity was sustained at the 3-, 6-, 12-, and 24-month assessments in evaluable patients.
Regarding safety, no dose-limiting toxicities (DLTs) were reported in the safety run-in cohorts. All patients experienced cytokine release syndrome (CRS) but 85% of cases were grade 1, and the remaining 15% of cases were grade 2. All infections were grade 1 or 2; notably, all patients were administered immunoglobulin as prophylaxis.
“This is the first study of CAR T-cell therapy in a precursor cancer setting, where cilta-cel was used as a primary therapy with no induction or bridging therapy,” lead study author Omar Nadeem, MD, said in a presentation of the data. “Longer follow-up is needed to determine the durability of response and help inform the risk:benefit ratio of early use of cilta-cel in high-risk smoldering myeloma.”
Nadeem is a senior physician, clinical director of the Myeloma Immune Effector Cell Therapy Program, clinical director of the Center for Early Detection and Interception of Blood Cancers, and associate director of the Multiple Myeloma Clinical Research Program at Dana-Farber Cener Institute, as well as an assistant professor of medicine at Harvard Medical School in Boston, Massachusetts.
The BCMA-directed CAR T-cell therapy cilta-cel is
Within the smoldering myeloma setting, the first systemic therapy for select patients in this population was approved in November 2025, with
Despite the improved progression-free survival (PFS) outcomes observed with subcutaneous daratumumab vs active surveillance in the phase 3 AQUILA trial (NCT03301220) that supported the approval of the anti-CD38 monoclonal antibody for patients with high-risk smoldering myeloma, Nadeem explained during his presentation that disease progression was still reported in approximately 40% of patients at 5 years during AQUILA.1,4
As such, investigators sought to explore whether improving depth of response with smoldering multiple myeloma therapies could lead to improved outcomes.1
To enroll in CAR-PRISM, patients needed to high-risk smoldering multiple myeloma per International Myeloma Working Group (IMWG) 20-2-20 criteria, comprising the presence of 2 of the following 3 factors: a serum M spike of at least 2 gm/dL, an involved-to-uninvolved free light chain (FLC) ratio of at least 20, and a bone marrow plasma cell level of at least 20%. Patients could also enroll if they had a IMWG total score of at least 9 when accounting for factors such as FLC ratio, serum M protein level, bone marrow plasma cell percentage, and the presence of t(4;14) translocations, t(14;16) translocations, 1q gains, or 13q deletions per fluorescence in situ hybridization (FISH). Enrollment was also allowed for patients with a bone marrow plasma cell level of at least 10% and at least 1 of the following factors: evolving pattern; abnormal phenotype with at least 95% of bone marrow plasma cells being clonal and the reduction of at least 1 uninvolved immunoglobulin isotype; high-risk FISH; or a monoclonal light chain excretion of more than 200 mg per day (for those with light chain smoldering multiple myeloma).
The study did not include patients who met SLIM-CRAB criteria for active multiple myeloma or those with a bone marrow plasmacytosis level above 40%. Prior therapy for smoldering multiple myeloma within 6 months of enrollment was not permitted.
After screening, enrolled patients underwent leukapheresis and stem cell collection for preservation for a potential future autologous stem cell transplant. Bridging therapy was not allowed during the manufacturing of cilta-cel.
Cilta-Cel in High-Risk Smoldering Multiple Myeloma: CAR-PRISM Results
Patients received lymphodepleting chemotherapy comprising fludarabine at 30 mg/m2 and cyclophosphamide at 300 mg/m2 per day on days –5, –4, and –3 prior to receiving CAR T-cell therapy. Cilta-cel was administered on day 1 at target doses ranging from 0.3 x 106 to 0.5 x 106 CAR-positive T cells (n = 12) or more than 0.5 x 106 CAR-positive T cells (n = 8).
The incidence of DLTs served as the trial’s primary end point. Secondary end points included ORR, CR rate, MRD negativity rate, PFS, and adverse effects (AEs).
Among 22 eligible patients, 2 declined to participate in the study, and the remaining 20 received cilta-cel. All 20 patients remained in follow-up as of the data cutoff.
In the total population, the median age was 58 years (range, 37-78), 30% of patients were female, and 5% of patients were Black or Hispanic. All patients had an ECOG performance status of 0. Twenty percent of patients had received prior treatment for smoldering multiple myeloma. The median time from screening to apheresis was 15 days (range, 12-27), and the median time from apheresis to cilta-cel infusion was 56 days (range, 52-76).
At baseline, the median M spike level was 1.76 g/dL (interquartile range [IQR], 0.92-2.64), the median involved-to-uninvolved FLC ratio was 21.8 (IQR, 9.6-36.1), and the median bone marrow plasma cell infiltration rate was 20% (IQR, 20%-30%).
Reported cytogenetic abnormalities included 17p deletion (5%), 13q deletion (40%), t(4;14) translocation (25%), t(14;16) translocation (5%), t(14;20) translocation (5%), 1q gain or amplification (30%), hyperdiploid smoldering myeloma (50%), and t(11;14) translocation (10%). Notably, 65% of patients had IMWG 20-2-20 high-risk disease.
Findings also showed that the median PFS and overall survival (OS) were not reached, with no PFS or OS events reported. All patients remained free from biochemical or SLIM-CRAB progression.
Non–immune effector cell–associated neurotoxicity syndrome neurotoxicity (NINTs) was reported in 7 patients at a median time to onset of 21 days (range, 10-52). Four of these patients had cranial nerve palsies, which all resolved. NINTs were ongoing in 3 patients: 2 patients had grade 1 movement and neurocognitive symptoms, and 1 other patient had grade 1 intention tremor.
The most common treatment-emergent AEs included neutropenia (any-grade, 100%; grade 3/4, 90%), leukopenia (100%; 90%), CRS (100%; 0%), anemia (95%; 10%), increased alanine aminotransferase levels (85%; 10%), thrombocytopenia (80%; 15%), fatigue (80%; 0%), increased aspartate aminotransferase levels (75%; 5%), increased lymphocyte count (50%; 15%), infection (25%; 0%), lymphopenia (20%; 20%), and NINTs (35%; 0%).
Soluble BCMA levels declined following the infusion of cilta-cel, irrespective of dose level, with these levels falling below the median value for health controls by day 21. At day 56, 18 of 20 patients had soluble BCMA levels below the control median, and this improved to 19 patients at day 100. Notably, baseline soluble BCMA levels were not associated with the incidence of NINTs.
An absolute lymphocyte count (ALC) of more than 3.0 x 109/L was reported in 18 of 20 patients, and the median peak ALC across the overall population was 6.8 x 109/L (range, 2.4 x 109/L -36.4 x 109/L). Greater lymphocyte expansion was reported in patients who developed NINTs.
Additionally, effector memory T-cell levels remained high in patients who experienced NINTs; these levels declined in low-dose and NINT-negative subgroups.
Disclosures: Nadeem reported serving as a consultant for Johnson & Johnson, Bristol Myers Squibb, GPCR Therapeutics, Kite, AstraZeneca, and Sanofi; receiving grant/research support from Johnson & Johnson and Bristol Myers Squibb; and being a stockholder in Sanofi (spouse).
