CARVYKTI - Use in High-Risk Smoldering Multiple Myeloma

SUMMARY

• Johnson & Johnson does not recommend the use of CARVYKTI in a manner that is inconsistent with the approved labeling.
• CARVYKTI is not approved by the regulatory agencies for treatment of patients with high-risk smoldering multiple myeloma (SMM).
• CAR-PRISM (PRecision Intervention Smoldering Myeloma) is a phase 2, interventional study investigating the safety and efficacy of CARVYKTI in patients with high-risk SMM.¹
  • Nadeem et al (2026)¹ published the safety and efficacy results of 20 patients treated with CARVYKTI in the CAR-PRISM trial at a median follow-up of 15.3 months.
    • No protocol-defined dose-limiting toxicities (DLTs) were observed among patients in the safety run-in cohort.
    • All patients experienced adverse events (AEs); cytokine release syndrome (CRS) occurred in all patients, with 17 patients experiencing grade 1 CRS and 3 patients experiencing grade 2 CRS. No grade ≥3 CRS events were reported.
    • All patients achieved minimal residual disease (MRD) negativity at 10^-6 threshold at month 2 after infusion, as assessed by next-generation sequencing and an objective response (OR); 18 patients (90%) achieved a complete response or stringent complete response (CR/sCR) as best response.
  • Nadeem et al (2024)² presented the safety and efficacy results for the first 6 patients enrolled in the safety run-in cohort of CAR-PRISM at a median follow-up of 10.5 months.
    • No DLTs were observed in the safety run-in cohort.
    • All 6 patients experienced cytokine release syndrome (CRS), with 4 patients having grade 1 CRS and 2 patients having grade 2 CRS. No patients experienced grade 3 or higher CRS.
    • The overall response rate (ORR) was 100% and all 6 patients achieved a complete response (CR) as their best response. All 6 patients achieved MRD negativity at the 10^-6 threshold.

CLINICAL DATA

CAR-PRISM is a phase 2, interventional study investigating the safety and efficacy of CARVYKTI in patients with high-risk SMM.¹

Study Design/Methods

• The study design is shown in Figure: CAR-PRISM: Study Design.
• Key eligibility criteria:
  • High-risk SMM with ≤40% plasma cells in the bone marrow and with high-risk criteria defined as having any 1 of the following criteria¹:
    • International Myeloma Working Group (IMWG) high risk per “20-2-20” criteria, defined as the presence of any 2 of the following¹:
      • Serum M-protein spike of ≥2 g/dL, involved-to-uninvolved free light chain (FLC) ratio of ≥20, and bone marrow plasma cell (BMPC)% of ≥20%
    • Having an IMWG total score of 9, computed using the following scoring system¹:
      • FLC ratios: >10-25=2, >25-40=3, and >40=5
      • Serum M-protein (g/dL): >1.5-3=3 and >3=4
      • BMPC%: >15-20=2, >20-30=3, >30-40=5, and >40=6
      • Fluorescence in situ hybridization (FISH) abnormality (t(4;14), t(14;16), 1q gain, or del13q)=2
    • Presence of ≥10% BMPC and at least 1 of the following¹:
      • Evolving pattern: evolving monoclonal protein (≥10% increase in serum M-protein over a 6-month period) or evolving change in hemoglobin (≥0.5 g/dL decrease in hemoglobin over a 12-month period) or progressive increase of >10% in involved light chain over a 6-month period along with a light chain ratio of >8.
      • Abnormal plasma cell immunophenotype: ≥95% of BMPCs are clonal and reduction of ≥1 uninvolved immunoglobulin (Ig) isotype (only IgG; IgA and IgM will be considered).
      • High-risk cytogenetics: defined as the presence of t(4;14), t(14;16), t(14;20), 17p deletion, TP53 mutation, or 1q21 gain.
• Exclusion criteria: presence of SLIM-CRAB criteria for active multiple myeloma; BMPC of >40%; diagnosis of or treatment for another malignancy within 2 years of enrollment; receipt of prior SMM-directed therapy within 6 months of beginning treatment in the study; occurrence of stroke or seizure within 6 months; presence of uncontrolled intercurrent illnesses including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social circumstances that would limit compliance with study requirements.¹
• Safety run-in: patients were enrolled into either of the 2 safety run-in phases in a standard 3+3 design.¹
  • The first 3 patients were treated at a lower target dose of 0.5×10⁶ chimeric antigen receptor-positive (CAR+) viable T cells/kg, with Food and Drug Administration (FDA) review of safety prior to dose escalation.
  • The next 3 patients were treated at a target dose of 0.75×10⁶ CAR+ viable T cells/kg.
  • Enrollment was staggered, with 1 patient dosed every 60 days.
• The first 15 patients were hospitalized for post‑treatment monitoring, whereas remaining cohort of patients received CARVYKTI infusion in an outpatient setting with hospitalization only at the onset of AEs.¹

CAR-PRISM - Interim Analysis

Results

Nadeem et al (2026)¹ published the safety and efficacy results of 20 patients treated with CARVYKTI in the CAR-PRISM trial at a median follow-up of 15.3 months.

Patient Characteristics

• A total of 20 patients enrolled between April 15, 2023, and July 3, 2025, underwent leukapheresis and received a single infusion of CARVYKTI.
• The median time from initial diagnosis to enrollment was 16.1 months (IQR [interquartile range], 8.4-36.2).
• Patient characteristics are presented in Table: CAR-PRISM: Patient Characteristics and Demographics Based on Administered CAR-T Dose.

Safety: Primary Endpoint

• No protocol-defined DLTs were observed among patients in the safety run-in cohort.¹
• All patients experienced AEs.¹
• CRS occurred in all patients:
  • Grade 1 and grade 2 CRS were reported in 85% (n=17) and 15% (n=3) of patients, respectively. No grade ≥3 CRS events were observed.³
  • Tocilizumab and dexamethasone were administered at a low clinical threshold in 85% (n=17) and 65% of patients (n=13), respectively.¹
• Hematologic AEs¹:
  • Neutropenia was common, with grade 4 and grade 3 observed in 55% (n=11) and 35% (n=7) of patients, respectively. Events were predominantly short‑lived, with a median duration of 7 days (IQR, 4-13). All patients were classified as low risk by immune effector cell‑associated hematotoxicity (ICAHT) grading.
  • Severe thrombocytopenia occurred in 2 patients with features similar to immune thrombocytopenia; 1 of these patients developed hemolytic anemia, possibly due to fludarabine. These events were transient and resolved with corticosteroids and intravenous immunoglobulin (IVIG).
  • No persistent hematologic toxicities were observed.¹
  • Hematologic AEs are summarized in Table: CAR-PRISM: Hematologic AEs.
• Upper respiratory tract infection (URTI) of any grade was reported in 25% of patients (n=5). All patients received IVIG prophylaxis.¹
  • No grade 3 or 4 URTI events were reported.¹
  • Grade 1 and grade 2 URTI were reported in 5% (n=1) and 20% (n=4) of patients, respectively.³
• Other AEs are summarized in Table: CAR-PRISM: Other AEs.
• Non-immune effector cell-associated neurotoxicity syndrome (ICANS) neurotoxicity (NINT) of any grade was reported in 35% of patients (n=7).^1,3
  • No grade 3 or 4 NINT was reported.
  • Grade 1 and grade 2 NINTs were reported in 30% (n=6) and 5% (n=1) of patients, respectively.
  • NINT symptoms included facial nerve disorders, paresthesia, and events overlapping with the movement and neurocognitive AE spectrum; these events resolved within 4-8 weeks, with a median time to onset of 21 days (range, 10-52) and are summarized in Table: CAR-PRISM: NINT Events.
• No cases of immune effector cell‑associated hemophagocytic lymphohistiocytosis‑like syndrome (IEC‑HS) or secondary malignancy or immune effector cell‑associated enterocolitis (IEC-EC) were reported.¹

Efficacy: Secondary Endpoint

MRD Negativity¹

• All patients achieved MRD negativity at the 10^-6 threshold as assessed by NGS.
• The median time to MRD negativity was 1 month.
• All patients achieved MRD negativity at the 10^-5 threshold and 10^-6 threshold at month 1 and month 2 after CARVYKTI infusion, respectively.
• MRD negativity at the 10^-6 threshold persisted across subsequent assessments (month 3, 6, 12, and 24) through the data cutoff.

Response¹

• An OR was observed in all patients (n=20).
• A total of 18 patients (90%) achieved a sCR/CR as best response.
• Among the remaining 2 patients with approximately 3.5 months of follow-up, immunofixation remained positive, most likely due to delayed clearance of residual paraprotein.
• All 16 patients with a minimum follow‑up of 6 months achieved sCR/CR.
• No disease progression or deaths were reported.
• Median progression-free survival (PFS) and overall survival were not reached.
• Responses and response durability did not differ between patients with high‑risk and standard‑risk cytogenetics.

Biomarkers: Secondary Endpoint

Antimyeloma Biomarkers and Immune Activity¹

• Biomarkers associated with CARVYKTI treatment were evaluated, with analyses focusing on post‑infusion lymphocyte expansion assessed by absolute lymphocyte count (ALC), soluble B-cell maturation antigen (sBCMA), and longitudinal CAR-T cell immunophenotype, including CD4:CD8 ratios and CAR-T cell subsets.
• For ALC, laboratory kinetics were compared during the first 21 days after CARVYKTI infusion by dose group and NINT status.
  • An ALC >3.0×10⁹/L was achieved by 18 of 20 patients.
  • The median ALC in the overall cohort was 6.8×10⁹/L (range, 2.4-36.4×10⁹/L) and was numerically higher in patients receiving >0.5×10⁶ CAR+ T cells/kg (12.4 vs 6.4×10⁹/L; P=0.17) and in those who experienced NINTs (12.7 vs 6.3×10⁹/L; P=0.08).
  • Across dose groups, ALC exposure and kinetics did not differ significantly (area under the curve [AUC], P=0.12; trajectory, P=0.10).
  • Patients with NINTs exhibited greater post‑infusion lymphocyte expansion, with higher ALC exposure (AUC, P=0.006) and a distinct longitudinal ALC trajectory compared with those without NINTs, including after dose adjustment (trajectory, P<0.0001).
  • Ferritin and interleukin‑6 trajectories correlated with NINTs status but not dose group, while C‑reactive protein trajectories differed across both NINTs status and dose groups.
• sBCMA as a marker of antimyeloma burden:
  • Following CARVYKTI infusion, sBCMA levels decreased rapidly regardless of dose and declined below the median value observed in healthy controls by day 21.
    • By day 56, values were below the control median in 18 patients (n=20), increasing to 19 patients by day 100.
  • Baseline sBCMA levels were not associated with an increased incidence of NINTs.
• Longitudinal flow cytometry profiling through day 100:
  • Patients receiving >0.5×10⁶ CAR-T cells/kg achieved higher peak absolute CAR+ T cell counts than those receiving the reduced dose (median 9564, IQR 3691-17,665 vs 2054, IQR 844-4102 cells/µL).
  • CAR-T cell expansion kinetics differed between patients with and without NINTs.
  • CAR+ cells were detectable in 10 patients at day 56 and in 9 patients at day 100 (n=20).
  • CD4:CD8 T cell ratio:
    • The ratio did not differ across dose groups by AUC over days 5-21 but was higher in patients who developed NINTs compared with those who did not.
    • At peak expansion, phenotypic composition was similar across dose groups, with effector memory T cells (T_EM) predominating among total CAR+ cells and within the CAR+ CD4 and CD8 subsets.
    • Through day 100, the proportion of T_EM cells declined to approximately 56-60% in the low‑dose and NINT‑negative groups, with corresponding increases in terminally differentiated effector memory (T_EMRA) and central memory T cells (T_CM), whereas in NINT‑positive patients, T_EM levels remained high (≥81.5%) with lower contributions from T_EMRA and T_CM.

CAR-PRISM – Preliminary Analysis

Results

Nadeem et al (2024)² presented the safety and efficacy results for the first 6 patients enrolled in the safety run-in cohort of CAR-PRISM at a median follow-up of 10.5 months.

Patient Characteristics

• Baseline patient characteristics are presented in Table: CAR-PRISM: Patient Characteristics.

Safety: Primary Endpoint

• No DLTs were observed in the safety run-in cohort.²
• One patient experienced grade 1 Bell’s palsy (self-limiting and resolved within 2 weeks).²
• One patient experienced grade 4 immune-related thrombocytopenia (resolved within 2 weeks).²
• Hematologic toxicities included transient grade 3 neutropenia without any febrile neutropenia.²
• One patient experienced transient grade 3 aspartate aminotransferase (AST)/alanine transaminase (ALT) elevation, which was resolved.²
• There were no grade 3 infections reported to date.²
• There were no secondary malignancies reported to date.²

Cytokine Release Syndrome

• All 6 patients experienced CRS, with 4 patients having grade 1 CRS and 2 patients having grade 2 CRS. No patients experienced grade 3 or higher CRS.²
• Four patients received tocilizumab, and 2 patients received dexamethasone.²

Efficacy: Secondary Endpoint

• The median follow-up for the safety run-in cohort was 10.5 months.²
• Stem cell collection was successful in all eligible patients, with an average stem cell yield of 8.94×10⁶ cluster of differentiation (CD) 34+ cells/kg.²
• The ORR was 100%, and all 6 patients achieved CR as their best response.²
• All 6 patients achieved MRD negativity at the 10^-6 threshold. The first 3 patients had sustained MRD negativity after 1 year of follow-up. The remaining patients were
  MRD negative at the time of the last follow-up.²
• To date, no patients experienced biochemical or SLIM-CRAB progression.²

Pharmacokinetics

• CAR+ T cells expanded after CARVYKTI infusion in patients with high-risk SMM at both doses.²
• Variable peak expansion and persistence were observed among patients.²
  • The median time to peak expansion (t_max) was approximately 14 days (range, 14-14), with a mean (standard deviation [SD]; range) peak concentration (C_max) of 4212 cells/μL (4773; 580-13555).
  • At peak expansion, most T cells were CAR+ T cells (mean [SD; range], 83% [14; 57-97]).
• CAR+ CD4+ and CAR+ CD8+ T cells expanded after CARVYKTI infusion, with a preferential expansion of CAR+ CD4+ T cells at t_max in patients with high-risk SMM.²

LitErature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) was conducted on 12 May 2026.